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BIOCHEMISTRY
Thermal Properties of Water:
1) Specific Heat:
a) A measure of the energy required to effect a temperature change per gram (physical property)
b) LARGE! 4.18 J/gC. Therefore, it takes a lot of energy to effect a temperature change!
c) Don’t confuse with heat capacity (measured in different units)
2) Heat of Vaporization:
a) The energy required to effect a change of state from liquid to vapor (physical property)
b) VERY LARGE because must overcome H bonding energy (2280 J/g or 41 kJ/mol) Endothermic
c) Important because chemical processes are inefficient and often manifest heat that needs to be dissipated by evaporation. Impeded by humidity (saturation)
i) Heat Transfer Mechanisms: Do not help humans if the environmental temperature exceeds body temperature.
1) Radiation: Humans do not do this
2) Convection: A warmer body surrounded by air warms the air around it. The air becomes less dense and moves away – the cool air moves in and the process is repeated.
3) Conduction: A warm body close to a cold body - heat flows from hot to cold.
Solvent Properties of Water:
• “Like dissolves like!” Is actually a comparison of intermolecular forces.
• Solvent: Liquid
• Solute: Gets dissolved
• Solution: Mixture of solute + solvent. The formation of a solution is exothermic!
• Breaking Bonds: Endothermic (+ ∆H) Non-spontaneous
• Forming bonds: Exothermic (-∆H) Spontaneous
Electrical Properties of Water:
• Auto Protolysis of Water: H2O + H2O ( ( H3O+ + OH- (A proton transfer reaction)
• Ion Product of Water: [H2O]2 K = Kw = [H3O+] [OH-] = 1 x 10-14
• As [H3O+] ↑, the [OH-] ↓
• [H3O+] < 1 x 10-7, the pH is > 7, and it is basic
• [H3O+] > 1 x 10-7, the pH is < 7, and it is acidic
• pH = - log10[H3O+]
• [H3O+] = 10-pH
• pH of 5 is 10x the [H3O+] of pH 6
• pH of 5 is 100x the [H3O+] of pH 7
• pH of 5 is 1,000x the [H3O+] of pH 8
• pH of 5 is 10,000x the [H3O+] of pH 9
Intermolecular Forces:
• In a gas, the kinetic energy of the molecules exceeds the intermolecular forces.
• In a liquid, the intermolecular forces exceed the kinetic energy of the molecules.
• Water demonstrates dipole-dipole interactions, Ion-dipole interactions, and H bonding. Therefore, water can dissolve polar, ionic, and H bonded solutes.
• Electronegativity:
o A measure of the ability of an atom in a molecule to attract electrons to itself.
o Increases as you move from left to right (periods) and top to bottom (groups) of the periodic chart.
1) Ion-Dipole: A purely ionic molecule interacts with other dipole molecules (i.e.: Na+ and water). The positive charge of the ion is attracted to the negative end of the dipole.
2) Dipole-Dipole: An interaction between two polar molecules (i.e.: water and water) where the positive end of one dipole is attracted to the negative end of the other dipole.
a) Hydrogen Bonding: An electrostatic attraction between molecules of H bound to an O, F, or N and another O, F, or N. Causes anomalous behavior of water! 15 – 20 kJ/mol
3) Dipole – Induced Dipole (“Dispersion”): A polar molecule creates a dipole (charge separation) in an adjacent non-polar molecule. The strength increases as molar mass increases.
4) Induced Dipole – Induced Dipole: Momentary attraction and repulsion between electrons and nuclei creates induced dipoles and leads to a net stabilization due to attractive forces.
a) London Forces: A weak dispersion force due to the circulation of electrons between 2 non-polar covalent molecules.
Micelles:
• Amphipathic agents: Have both a hydrophobic and a hydrophilic end. Tend to form clusters based on interactions.
o The hydrophobic end uses London Forces
o The hydrophilic end uses Ion-Dipole interactions.
• Micelle: A collection of amphipathic agents, typically in a polar solvent. Scatters light and produces the Tindell Effect.
o Not a true solution – is a dispersion or an emulsion
o Is the lower energy conformation, and is formed spontaneously (exothermic).
o Can be broken by changes in pH. (Needs a base to keep it ionized and not protonated)
• Mixed Micelle: The hydrophobic agent gets locked up in the hydrophobic portion of the micelle.
o This allows the polar solvent to accommodate hydrophobic solutes!
o Used in the digestion process when bile is produced after a fatty meal.
Electrolyte:
• A solute which, when dissolved in water, produces a solution that conducts electricity. (Are classically ionic species.)
• Pure water is an insulator!
• Strong electrolyte: Will dissociate 100% in solution – a good conductor – strong acids.
• Weak electrolyte: Will dissociate < 100% in solution. Classic examples are weak acids.
o Ka = [H+][A-] / [HA] (equilibrium table)
o Ka = x2/[HA] ( [H+] = x = the square root of [HA][Ka]
o Assume [HA] – x = [HA] (approximation)
• Non-electrolytes: Dissociate 0% in solution – typically are molecular substances like glucose or alcohol. Good insulators.
• The extent of dissociation does not equal solubility!
o Solubility: The amount of a substance dissolved in moles/L (Ksp). You must know the [products] at equilibrium.
▪ As pH increases, the solubility decreases
o Extent of Dissociation: The extent of ionization of a solute.(H+ and OH-)
o Glucose is soluble, but does not dissociate.
o Silver Chloride is insoluble, but does dissociate.
Buffer Solutions:
• A chemical system that is designed to resist a change in pH.
• Prevents acidosis and alkalosis.
• Always contains a weak acid and its conjugate base in similar concentrations.
• Buffer Capacity: The amount of added acid or base that a buffer system can control.
• Recall LeChatlier!!!
• Henderson-Hassellbach:
o pH = pKa + log [CB] / [acid]
o When [acid] = [CB], pH = pKa
• To determine pH after adding acid or base:
o Write equation (weak acid plus water …)
o Dissociate the added substance (i.e.: NaOH ( Na+ + OH-)
o Determine what will increase / decrease and write in arrows
o Calculate initial moles
o Calculate new moles (add / subtract in appropriate places)
o Calculate pH with moles using the H&H equation
• Features of a buffer system:
o pH – determined by:
▪ pKa of the proton donor (WA)
▪ Ratio of acid and base
o Buffer Capacity – determined by [] of the WA and CB
• Physiological Buffers:
o Inorganic Phospate – Intracellular
▪ H2PO4-
▪ HPO42-
o Sodium Bicarbonate – Extracellular
▪ CO2 (Acid - donates a proton from water)
▪ HCO3-
• Metallic oxides, when dissolved in water, produce basic solutions
• Nonmetallic oxides, when dissolved in water, produce acidic solutions (i.e.: CO2)
Gas Solubility:
• As temperature increases, solubility decreases (inversely proportional)
• As pressure increases, solubility increases (directly proportional) ( Henry’s Law
Primary Alkali Deficit:
• Deficiency of a proton acceptor (base) – Therefore, the ratio is less, the log is less, and the pH is lower than it should be. = Acidotic
• Compensations:
o Respiratory: Hyperventilation (to decrease pressure and restore plasma pH)
o Renal: Excretion of NH4+ (to restore buffer capacity)
• If uncompensated ( Metabolic Acidosis
o Generally related to a pathology such as diabetes mellitis; starvation, chronic diarrhea
Primary Alkali Excess:
• Excess of a proton acceptor (base) – Therefore, the ratio is more, the log is more, and the pH is higher than it should be. = Alkalotic
• Compensations:
o Respiratory: Hypoventilation (to increase pressure and restore plasma pH)
o Renal: Excretion of HCO3- (to restore buffer capacity)
• If uncompensated ( Metabolic Alkalosis
o Can be caused by excessive vomiting, or by ingesting large amounts of HCO3-
Primary CO2 Excess:
• Excess of a proton donor (acid) – Therefore, the ratio is less, the log is less, and the pH is lower than it should be. = Acidotic
• Compensations:
o Respiratory: None (caused by respiratory problem)
o Renal: Excretion of NH4+ (to restore buffer capacity)
• If uncompensated ( Respiratory Acidosis
o Generally related to restricted breathing / respiratory disorders
Primary CO2 Deficit:
• Deficiency of a proton donor (acid) – Therefore, the ratio is more, the log is more, and the pH is higher than it should be. = Alkalotic
• Compensations:
o Respiratory: None (caused by respiratory problems)
o Renal: Excretion of HCO3- (to restore buffer capacity)
• If uncompensated ( Metabolic Acidosis
o Generally caused by hyperventilation or increased altitude
Renal Mechanism for Adjusting Blood Plasma pH:
• CO2 in the blood plasma diffuses across its [gradient] to the renal tubule cells and undergoes hydrolysis:
o CO2(plasma) + H2O ( ( H+ + HCO3(renal)-
• This converts the plasma CO2 to plasma HCO3- and throws out NH4+ in the meantime. (This causes the pH to increase as H+ is lost)
o H+ + HCO3(renal ( plasma)- ( NH4(urine)+
o Normal urine pH = 6.1
o The NH4+ is excreted into the tubular fluid (urine), causing its pH to decrease as the H+ is added. (Becomes more acidic)
o The HCO3- is secreted back into the blood plasma, causing its pH to increase and become more basic.
Amino Acids:
• Contain a carboxylate group, an amine group, and an R-Group
• Are categorized based on their R-Groups
o Hydrophobic (non-polar)
o Polar (Uncharged)
o Polar (Charged)
o Aromatic ( contain benzene
• If the pH is < or > 7 (physiological pH), the polar charged R-Groups may not be charged. As the pH decreases, they may be protonated.
o The charge of an amino acid is a function of the environment!
• Zwitterion: A molecule with two charges but no NET charge
• A hydrophobic R-Group shows 2 breaks in graph form.
• A charged R-Group can show 3 or more breaks in graph form.
• Buffer areas are represented by flat areas on the graph
• Isoelectric Form:
o Occurs at the isoelectric pH
o For hydrophobic R-Groups = the zwitterions form
o Use to isolate proteins (they selectively precipitate out due to pH)
o [pic]
o Typical for amphiprotic agents that can be a proton donor or acceptor
o As the amino acid becomes more complex (i.e. Charged R-Groups), there are more isoelectric forms.
o There may be multiple isoelectric forms, but there is only one isoelectric pH!
• Peptide Linkages:
o A classic interaction between carboxylate and amine functions that results in a substituted amide.
o A type of covalent bond.
o A dipeptide has one peptide linkage
o A pentapeptide has 5 amino acids and 4 peptide linkages
o A peptide always has a COOH on one end and an amine on the other end.
o 2 amino acids = 4 dipeptides (2 combinations, and 2 as they react with themselves), 3 = 27, 4 = 256, etc.
o Most polypeptides have 100s of amino acids, so there is an almost infinite number of variations.
Substructures of Proteins:
1) Primary Structure: The amino acid sequence of a polypeptide
a) The defining feature is the peptide linkage (covalent bond)
b) Increased energy content in bonds.
2) Secondary Structure: Alpha Helix
a) There are many of these superimposed on the primary structure.
b) The defining feature is the Hydrogen bonding between amide planes.
i) Amide Planes are created due to the double bond characteristics of the C-N bond
1) The interfacing carbon always has an H and an R-Group.
2) Rotation (C-alpha C and the N-alpha C bonds) is limited by steric hindrance.
3) Every amide plane is H bonded to 2 other amide planes (i.e.: #5 is bonded to #2 and #8)
ii) The alpha helix is locked in place by the H bonds between amide planes
iii) To break an alpha helix is endothermic. Therefore, the alpha helix is the lower energy conformation and it is spontaneous.
iv) The R-Groups are arranged radially with respect to the helix and its axis.
a) The hydrophilic nature of the helix is due to the hydrophilic nature of the R-Groups. (Therefore, the solubility of the helix can increase or decrease depending upon the R-Groups)
3) Tertiary Structure: The 3-D arrangement of a polypeptide chain that has assumed its secondary structure. (Configuration / Folding of helix to create catalytic sites)
a) The defining features are interactions between the R-Groups:
i) Disulfide Linkages – must be oxidized
1) A covalent bond between sulfhydryl components
2) Only seen with cysteine – methionine is not a good reducing agent
ii) Electrostatic Interactions
1) Ion-Ion interactions between charged R-Groups
iii) Hydrogen Bonding
1) Ion-Dipole interactions between polar uncharged R-Groups
iv) Hydrophobic Interactions
1) Similar to a micelle
b) These are superimposed upon the primary and secondary structures.
c) The tertiary structure is lower in energy than the secondary structure
4) Quaternary Structure: The arrangement of the subunits of a protein that has more than one polypeptide chain.
a) The defining features are an aggregate of interactions (H bonding, Hydrophobic, etc.)
b) A series of discrete globules locked together as a result of the increasing molecular weight of the polypeptide.
c) The least stable formation (highest energy) – therefore it is easily disrupted.
Denaturation:
• The unfolding into random coils of proteins.
• The nature of a protein is its lowest energy level.
• Denaturation occurs due to modifications of the environment (i.e.: termperature, pH, etc.)
• Heating destroys the tertiary and quaternary structures!
Protein Classifications:
• Fibrous
o Water insoluble
o Structural (i.e.: Tendons, skin, etc.)
o Formation of Collagen:
▪ A protein containing lots of proline is formed within the cell via translation, and is then hydroxylated. (**Requires Vitamin C!**)
▪ The helix forms – tight due to the fact that every 3rd amino acid is glycine.
▪ Glycosylation: Carbohydrate units are added to increase the solubility of the fiber ( creates Procollagen which is secreted into the interstitial fluid via exocytosis.
▪ The cross-linking of occasional aldehydes = Collagen
▪ Scurvy: A CT disorder where the proline is not hydroxylated properly for cross-linking – due to vitamin C deficiency.
• Globular:
o Water soluble
o Functional
▪ Transport (i.e.: Hemoglobin – transports oxygen from the lungs to a cellular site. It is capable of being titrated as a monoprotic weak acid.)
• The Bohr Effect: The ability of hemoglobin to bind to oxygen is a function of pH
o As pH decreases, oxygen binding decreases
▪ Enzymes
▪ Hormones
▪ Acid-Base Buffers
▪ Immunoglobulins, etc.
Respiration:
• Buffer Systems:
1. CO2(diss) + H2O ( ( H+ + HCO3- pKa = 6.1 (strongest)
2. Oxygenated (Arterial): HHbO2 (( H+ + HbO2- pKa = 6.6 (prevalent form)
3. Deoxygenated (Venous): HHb ( ( H+ + Hb- pKa = 8.2 (weakest)
Arterial (Heart to Organs):
• RBC contains oxygenated hemoglobin (#2).
• CO2 (from metabolic processes) diffuses from the peripheral cells, through the plasma, and into the RBC. It reacts with water in the following manner:
o CO2(diss) + H2O ( ( H+ + HCO3-
• The proton reacts with the hemoglobin (HbO2 is a stronger base than HCO3-) and causes it to change to its least stable form:
o HbO2 + H+ (( HHbO2-
• The product dissociates:
o HHbO2 (( HHb + O2
o The oxygen diffuses into peripheral cells.
o The HHb is the venous hemoglobin.
• The HCO3- diffuses into the plasma due to its concentration gradient. At the same time, Cl- diffuses from the plasma into the RBC due to the charge gradient. (This keeps the charges in balance.) = “Chloride Shift”
Venous (Organs to Heart): (Converts plasma HCO3- to CO2 that can be exhaled – the pH impact would be greater if it remained as CO2 because it would be a higher percentage.)
• RBC contains deoxygenated hemoglobin (#3).
• The oxygen in the pulmonary capillaries diffuses across the plasma and reacts with the hemoglobin in the RBC
o O2 + HHb (( HHbO2
• The acid then dissociates:
o HHbO2 (( H+ + HbO2-
o The pressure increases, driving the reaction to the right
o The dissociation also pushes the reaction to the right
• The HCO3- in the plasma diffuses into the RBC to react with the H+
o HCO3- + H+ ( ( CO2 + H2O
• The CO2 diffuses to the pulmonary capillaries and out of the system via the lungs. (This pushes the reaction to the left and increases protonation.)
• To balance the charges, there is a Chloride Shift from the RBC into the plasma.
Energetics:
• Bond Dissociation Energy:
o The energy required to break a chemical bond.
o Also evolves the same amount of energy when the bond is formed.
• Energy Distribution – Boltzmann Curve:
o All particles in a system do not have the same energy.
o If the system needs a large energy for the reaction to occur, however, some of the particles may have that energy.
o Rxn Rate = Total # Collisions X Energy Factor X Orientation Factor
▪ Energy Factor: The energy content of the collisions. This helps to mitigate the total number of collisions.
▪ Orientation Factor: A set statistical number based on the structure of the molecule. This helps to mitigate the total number of collisions.
• Energy of Activation: The minimum energy required by reacting molecules – the energy that has to be put into a system to get it to go.
o ∆H > Ea = Spontaneous (exothermic)
o ∆H < Ea = Non-spontaneous (endothermic)
o The larger the Ea, the fewer # of particles with sufficient energy, the lesser the energy factor, and the slower the reaction.
o The smaller the Ea, the faster the reaction!
o Small changes in Ea produce huge changes in the reaction rate!
o Does not effect the ∆H (thermodynamics)!
• Catalysts:
o Lowers the Ea, therefore there are more particles with sufficient energy.
o Speeds up a reaction – can be used to regulate kinetics.
• Vmax = the maximum concentration of a substrate where it will have an effect of the velocity.
o Most enzyme-catalyzed reactions have a very low [substrate]
o Therefore, a small change in the substrate will produce a large change in velocity.
• E + S ((k1) (k2)( ES
• ES ( (k1) (k2) ( E + P
• Assumptions:
o There is very little tendency of the product to react with the enzyme. Therefore, the rate constant (k2) is zero.
o Steady State Approximation: The ES Complex tends to decay as fast as it forms. The result is that the [ES] at any time is fixed
▪ [pic]
• Michaelis-Menten Constant: Utilized as a measure of the affinity of an enzyme for its substrate. Predicts how velocity is related to [S] if [enzyme] is held constant. (Smaller Km = more effective enzyme = faster reaction)
o [pic]
• Velocity is a function of [S], Vmax, and Km
o [pic]
o [pic]
o Km = [S]
o Whatever [S] will produce Vmax/2, that [S] will be Km
o Can find Vmax and Km by plotting data points on a graph. Produces a hyperbola.
• Lineweaver-Burk Equation:
o A linear presentation of the kinetic response for an enzyme catalyzed process
o Only need two data points to define, but can get same information!
o [pic]
Enzyme Inhibition:
1. Competitive Inhibition: A molecule (inhibitor) chemically resembles the substrate, so the enzyme gets “confused.” This slows down the rate of reaction because less enzyme is reacting with the substrate.
a. The inhibitor is occupying the catalytic sites.
b. Therefore, there is competition for the sites and two reactions are occurring:
i. E + S ( ( ES Complex ( E + Product
ii. E + I ( ( EI Complex
c. Reversal Mechanism:
i. Increase [S]
1. i shifts to the right (ES complex)
2. This decreases the [enzyme] and ii shifts to the left
3. This allows us to approach Vmax
ii. Example: Ethyl Alcohol and Ethylene Glycol (radiator fluid) are both catalyzed by alcohol dehydrogenase. The first forms acid aldehyde, and the second forms oxalate – very toxic! So, if ingest #2, provide with #1 so that oxalate is not produced.
1. Km (etOH) < Km (glycol)
d. Features of C-I Process:
i. Constant Vmax
ii. Process can be reversed by adding additional substrate
2. Non-Competitive Inhibition: A molecule (inhibitor) reacts with an area remote from the catalytic site. This permanently reduces Vmax.
a. Usually involves heavy metals that have a tendency to react with enzymes that have sulfhydryl groups in their amino acid components. (i.e.: Cysteine)
b. The inhibitor is occupying non-catalytic sites.
c. Three reactions are occurring:
i. E + S ( ( ES Complex ( E + Product
ii. E + I ( ( EI Complex
iii. ES + I ( ( ESI
d. Reversal Mechanism:
i. Increasing [S] does not work
ii. Add something else that the inhibitor would rather react with than the enzyme.
1. Chelating Agents have multiple electron pairs that can interact with the inhibitor.
a. Add to #2 and it reacts with the inhibitor (removal of a reactant) to form an organo-metallic compound. The reaction shifts to the left, increasing the amount of the enzyme.
b. Add to #3 and the reaction shifts to the left (removal of a reactant) and the ES complex can generate the product.
e. Features of NC-I Process:
i. Permanently modified Vmax
ii. Process can be reversed by creating a reaction with the inhibitor (instead of with the enzyme)
3. Irreversible Inhibition:
a. A rapid process that is deleterious to the gross organism.
b. i.e.: Sarin Gas
i. Interferes with acetyl choline esterase
1. Acetyle choline is not hydrolyzed
2. Post synaptic membrane does not repolarize
3. Muscles cannot relax
4. Suffocation
c. Reversal Mechanism: None
d. Features of I-I Process:
i. Process cannot be reversed
Carbohydrates
Simple Sugars / Monosaccharides: Cn(H2O)n
• CH2O ( Formaldehyde
• C2H4O2 ( Acetic Acid
• C3H6O3 ( Glyceraldehyde
o Used by cells / made by life forms
o 2 possible enantiomers (same formula & MWT; undergo all same reactions except those with other chiral agents)– only the first one is biologically significant
▪ dextrorotary-glyceraldehyde – used as fuel - -OH on chiral carbon goes to the right (or up)
▪ levorotary-glyceraldehyde
o Chiral
• C5H10O5 ( Ribose
o 8 Stereoisomers
▪ 2n = maximum number of stereoisomers. (n = # of chiral carbons)
o Found in RNA, ATP, etc.
o An aldopentose
• C6H12O6 ( Glucose
o 16 stereoisomers (24)
o “Blood Sugar”
o An aldohexose
o Glucose & galactose are stereoisomers, diastereomers (stereoisomers that are not mirror images and have different physical properties), and epimers – they have the same structure, except at C4.
o The aldehyde and alcohol portions can react via self-condensation to form a hemiacetal with an anomeric carbon.
▪ Anomeric Carbon: Has 2 oxygen bound to it
• Has the lowest number assigned
• Is the hemiacetal / hemiketal carbon
• In a ring, it is always –OH. In a chain, it is always a carbonyl.
• If there is also an R group coming off this carbon = ketose
• If there is only an H coming off this carbon = aldose
Reducing Sugars:
• A substance which will react as a reducing agent, and which will allow itself to be oxidized by an oxidizing agent.
• Must have one or more –OH groups alpha to the carbonyl carbon, or be in equilibrium to a molecule that does.
o An oxidizing agent will react with the whole system due to equilibrium shifts.
Disaccharides: Cn(H2O)n-1
• Contain simple sugar components
• Contain Glycosidic Linkages
o The first anomeric carbon (“bound”) determines if the linkage is alpha or beta.
o The last anomeric carbon (“unbound”) determines if the molecule is alpha or beta.
• Maltose:
o Hydrolysis yields 2 glucose
o Alpha 1,4 linkage
• Lactose:
o Hydrolysis yields glucose and galactose
o Beta 1,4 linkage
• Sucrose:
o Hydrolysis yields glucose and fructose
o Alpha 1, Beta 2 linkage
o Has no unbound anomeric carbons! (Therefore, cannot determine if the molecule is alpha or beta)
• Trihalose (sp?):
o Hydrolysis yields 2 glucose
o Alpha 1, alpha 1 linkage
Oligosaccharides:
• Carbohydrates with 3 to 15 simple sugars
• Dietary Fiber because they are mostly undigestible by humans
Polysaccharides:
• Carbohydrates that contain 12 – 15+ simple sugars
• Starch:
o Associated with plants – energy storage
o A homopolymer (same repeating units) of glucose
o Occasional 1,6 branches every 18 to 20 units
o May fragment:
▪ Amylose
• Only 1,4 linkages
• The smaller fragment -- Typically has 18 – 20 subunits
• Soluble in hot water
▪ Amylopectin
• 1,4 and 1,6 linkages
• The larger fragment
• Not as water soluble
• Glycogen:
o Associated with animals – energy storage
o A homopolymer of glucose
o Occasional 1,6 branches every 8 – 10 units
o Stored in liver and skeletal muscle cells
• Cellulose:
o Wood ( about 50% of the organic carbon in the Earth’s crust
o Beta 1,4 linkages are undigestible
o No branches
• Hydrolysis begins from the non-reducing ends (the end without an anomeric carbon – the branches always terminate with a non-reducing agent) – this increases the number of substrates to meet the fuel demands of the cell.
Fatty Acids:
• The 3rd type of building block molecule
• Characteristics:
o A long HC tail (hydrophobic)
o Punctuated by a carboxylate group (hydrophilic)
o Positioning of one or more double bonds
▪ Does not effect water solubility
▪ Destroys the symmetry (due to bond angles)
▪ Are always cis
▪ Lowers the MP of the fatty acid and any lipid with which it is involved (# double bonds increases, MP decreases)
▪ Always numbered with a Δ – counted from the carbonyl end (The omega notation starts from the HC end)
▪ Saturated: Has no double bonds
▪ Unsaturated: Has one or more double bonds – missing at least 2 hydrogen!
• Mono = 1 double bond
• Di = 2 double bonds
• Poly = more than one double bond
• Glycerol is a trialcohol that accommodates 3 fatty acids via esterification
• Triacylglycerol (TAG) is a storage mode for lipids
o This is always the format of consumed fats!
o Stored as adipocytes – “Depo Fat”
o Also stored in the cytoplasm of all cells (except RBCs and CNS cells) as “fat droplets”
o Not water soluble regardless if its fatty acids are saturated or unsaturated
o Therefore, does not need to be separated from the rest of the cell with a membrane
o 2 Types of TAG:
▪ Oils:
• Liquid at room temperature due to increased number of double bonds (unsaturated)
• Plant source
▪ Fats:
• Solid at room temperature (saturated)
• Animal source
Polar Lipids:
• Have a hydrophobic (two HC chains) and hydrophilic end (amphipathic)
• Found in membranes, micelles, etc.
• i.e.: Fetal Development – A specialized polar lipid is needed to lower the surface tension of the liquid in the lungs so that gasses (oxygen) can pass through the membranes.
• Two Categories:
o Diacylglycerols – contain 2 acyl groups
o Sphingolipids
▪ From sphingosines (a molecule with a HC tail)
▪ Has only one fatty acid in its structure
▪ Is an amide – there are no ester linkages
▪ Has 2 HC tails
• Sterol Nucleus:
o Four fused rings
o Found in all steroids, bile salts, vitamin D, etc.
o Very hydrophobic
o Cholesterol
▪ A structural component of many lipid bi-layers
▪ We do not metabolize – there is no energy content
▪ Classified as a lipid due to its hydrophobic nature
Metabolism:
• Is about energy transfer and conversion
o Fuel is converted to energy
• Adenisine Tri Phosphate (ATP)
o A nucleotide (contains a N-base, a pentose, and one or more phosphate groups)
o ATP + Water ( ADP + Pi
o Work Potential (measured by ΔG) is NOT from the breaking of the phosphate bond, it is from the forming of the bond between water and phosphate!
o ΔG (Hydrolysis of ATP) = - 31 kJ / mol
o Therefore, it requires +31 kJ / mol of energy to phosphorylate ADP
o Required for:
▪ Contraction of skeletal muscle
▪ Biosynthesis
▪ Active Transport (maintain fluid and pressure balance)
• Gibbs Free Energy (ΔG):
o A measure of the maximum magnitude of the net useful work that can be obtained from a reaction.
o If negative = spontaneous (product-favored)
o If positive = non-spontaneous (reactant-favored)
Carbohydrate Digestion:
• All carbohydrates must be converted into simple sugar components to be absorbed into the bloodstream – otherwise they stay in the intestinal lumen and are excreted.
• Starch: (Hydrolytic – no energy transfer or ATP)
o Mouth: Salivary Amylase (pH = 7) – catalyzes the breaking of every other 1,4 linkage (produces maltose)
o Stomach: Salivary amylase is denatured by the acid and digested by the pepsin.
o Duodenum of SI: Acidic nature destroyed by bicarbonate
o Small Intestine: Pancreatic Amylase – destroys every other 1,4 linkage and creates a mixture of fragments. Cannot break down1,6 linkages
▪ Dextrins: Small polysaccharides with 1,4 and 1,6 glycosidic linkages
o Intestinal Mucosa: Specialized enzymes (glucosidases and dextrinases) produce glucose which is then absorbed.
Lactose Intolerance:
o Lactose is a disaccharide that requires digestion via lactase. If lactase is not produced, the lactose stays in the SI.
o Micro-organisms in the ilium digest the lactose ( produces gas, distention, and diarrhea.
o Is NOT an allergy!
Oxidation Series:
• Alkane
• Alcohol
• Aldehyde / Ketone
• Carboxylic Acid
Ring Stability:
• 6C = most stable
• > 6C = Torsional Strain
• < 6C = Bond Angle Strain
Glycolysis: Glucose ( 2 Lactate + 2 ATP
• The oxidation of glucose (derived from blood plasma)
• Occurs in cellular cytoplasm
• Anaerobic – Skeletal Muscle
• Aerobic – Brain
• No net redox
• Functions as a result of the demand for ATP
• As [ADP] increases, ADP + ADP ( ATP + AMP
• Negative (Allosteric) Modulator: ATP (inhibits enzyme)
• Positive Modulator: AMP (encourages enzyme)
• Resting muscle has a high [ATP]
• As contract muscle, [ATP] decreases, and [ADP] increases ( inverse relationship
• ATP reacts at two sites with different levels of affinity (Km)
o Allosteric Site: Larger Km
o Catalytic Site: Smaller Km – Greater affinity for ATP (because it is responsive to lower levels of ATP)
▪ Therefore, the system runs best at low [ATP]
o Small Km = Increased rate!
• Phosphofructokinase is an allosteric enzyme. Therefore, there is a sigmoidal kinetic curve.
o Curve shifts to the right as [ATP] increases or [AMP] decreases
o Curve shifts to the left as [ATP] decreases or [AMP] increases ( hyperbola
Hexose Monophosphate Shunt:
• Converts hexoses to pentoses
• Generate reducing agents (NADPH)
• Driven by demand
• Anabolic
• Transketolase: An enzyme that moves a 2 carbon fragment
• Transaldolase: An enzyme that moves a 3 carbon fragment
• 2% in skeletal muscle cells; 30% in liver cells
Tricarboxylic Acid / TCA / Citric Acid / Kreb Cycle:
CH3COOH + H2O ( 2 CO2 + 8 H
• Another cycle needed due to oxidation levels:
o Mentally break all of the bonds and assign (-) to the more EN atom and (+) to the less EN atom. Add the signs.
o Used to determine if a redox reaction has occurred.
• Major source of CO2
• Reduce H ( H+ (H+ = oxidation agent)
• Oxidize C ( CO2 (CO2 = reduction agent)
• Occurs in mitochondria
• 2 acetyl CoA / glucose (2 are lost to CO2)
• 2 CO2 / cycle ( 4 CO2
• Aerobic
• Pyruvate/lactate vs. TCA depends on available oxygen:
o If oxygen is available, glycolysis proceeds to pyruvate in the cytoplasm, then enters the mitochondria for TCA to create ATP.
o If no oxygen, glycolysis proceeds to lactate which leaves the cell.
• Is a stand-alone pathway – it does not require carbs as fuel
• All glucose carbons are converted to CO2 ( 2/3 by the TCA cycle
• O2 is an oxidizing agent that creates ATP in 4 places ( this replenishes redox agents
• Occurs in the mitochondria and is aerobic
o If O2 is available in a cell, the glycolysis proceeds to pyruvate which then enters the mitochondria, goes through the TCA cycle, and creates ATP
• ATP from TCA: 12
• ATP from TCA and precursor: 15
• CO2 count from TCA: 2
• Per glucose = 24 ATP from TCA cycle
• Per glucose = 36 ATP from TCA and precursor and NADH
• CO2 count from precursor and TCA: 3
• 2 types of Phosphorylation:
o Substrate Level: i.e.: Formation of GTP
o Oxidative: Redox provides energetics
• NADH in cytoplasm = 2 ATP
• NADH in mitochondria = 3 ATP
• Substrate Level Phosphorylation:
o When want to make ATP, first prepare an item which is higher in energy than ATP and use it to phosphorylate ADP.
o Generate work potential at the expense of fuel (glyceraldehyde 3-P ( oxidized to 3 phosphoglycerate).
Reduction / Oxidation:
• Oxidation:
o Gain O
o Lose H
o If oxidized = reducing agent
• Reduction:
o Lose O
o Gain H
o If reduced = oxidizing agent
Pyruvate Dehydrogenase Enzyme System:
• 3 Enzymes:
o Pyruvate Decarboxylase
o Dihydrolpoyl Transacetylase
o Dihydrolpoyl Dehydrogenase
• 3 Items Recycled:
o Thiamine Pyrophosphate
o Lipoic Acid
o FAD
• 5 Co-Enzymes:
o Thiamin (in TPP)
o Pantothenic Acid (in CoASH)
o Niacin (in NAD)
o Riboflavin (in FAD)
o Lipoic Acid
• C is oxidized
• NAD+ is reduced
Acetyl Choline Synthesis:
• Pre-synaptic
• Requires Thiamin – if deficient, the pre-synaptic neurons cannot make Acetyl CoA to make acetyl choline
• Beri-Beri:
o Skeletal muscles atrophy
o Edema
o Cardiac muscle problems ( congestive heart failure
o Typically only found in alcoholics
| |RBCs |Brain |Muscle / Cardiac |Adipocytes |Hepatocytes |
|Glycolysis |√ |NO |√ |√ |√ |
|Shunt |√ |√ |√ |√ |√ |
|TCA |NO |√ |√ |NO |√ |
|Pyruvate Dehydrogenase Enzyme |NO |√ |√ |√ |√ |
|System | | | | | |
|Fatty Acid Synthesis |NO |NO |NO |√ |√ |
|Gluconeogenesis |NO |NO |NO |NO |√ |
|Glycerol Phosphate Shuttle |NO |NO |√ |NO |NO |
|Cori Cycle |NO |NO |√ |NO |NO |
|Malate Shuttle |NO |NO |√ (heart) |NO |√ |
|KB Production |NO |NO |NO |NO |√ |
|Electron Transport |NO | | | | |
|Beta Oxidation |NO | | | | |
| | | | | | |
Glycogen:
• A homopolymer of glucose that is stored in the liver (about 10% by weight) and skeletal muscle cells (about 1 – 2 % by weight)
• 1,4 linkages with some 1,6 linkages
• Glucose is stored as a polymer so that water does not flow into the cell in order to equalize the osmotic pressure (due to a concentration gradient). This way, the cell is not destroyed, and it does not have to expend ATP to pump water out. Requires 1 ATP per glucose unit installed on the glycogen (glycogen synthesis), but it avoids having to spend more energy with a pump.
• Glycogen synthesis occurs in the cellular cytoplasm:
o Glucose is phosphorylated (costs 1 ATP)
o G-6-P isomerizes to G-1-P
o G-1-P interacts with UTP (a high energy phosphate molecule that is an analog of ATP) to become UDP-Glucose ( the format for glucose donation
o UDP-glucose interact with glycogen to yield glycogen +1 ( glycogen synthase
o The glycogen can be phosphorylated to yield G-1-P ( Glycogen Phosphorylase – this occurs if the demand for ATP is high because the G-1-P will isomerize to G-6-P which will proceed to glycolysis and TCA cycle to provide 36 ATP
• Glycogen synthesis and hydrolysis are separate pathways – one is not the reverse of the other!
Skeletal Muscle Fibers:
• Red:
o More mitochondria
o Continuous performance (high endurance)
o Aerobic ( 36 ATP
o Store less glycogen
o “Slow Twitch”
• White:
o Less Mitochondria
o Flight muscle – fast – no endurance
o Anaerobic ( 2 ATP
o Stores more glycogen
o “Fast Twitch”
Fructose:
• Very sweet
• Gained from honey (1:1 glucose & fructose) and sucrose
• Low glycemic index ( little effect on blood sugar
• Some cells use fructose selectively as fuel ( they are able to make fructose at the expense of glucose (i.e. Seminal Vesicles)
• Catabolism occurs in the liver ( there is not much freely roaming in the body
o Fructose is phosphorylated (costs 1 ATP) ( Fructokinase
o F-1-P is broken into 2 three carbon fragments (DHAP which isomerizes to GA3P and enters the glycolytic pathway and glyceraldehyde) ( Aldolase
o Glyceraldehyde is reduced to yield glycerol
o Glycerol phosphorylated (chiral, but no racemic mixture because the enzyme is stereospecific to L) ( Glycerol Kinase
o L-Glycerol-Phosphate is oxidized to yield glyceraldehyde-3-P which enters the glycolytic pathway
o The 6 carbons of fructose yield 2 lactate
o Net ATP = 2
• Fructokinase Deficiency / Central Fructose Urea:
o Cannot phosphorylate fructose – no substrate for the aldolase
o Lots of fructose circulates in the blood and urine
o Benign – no intervention is needed
• Aldolase Deficiency:
o Fructose is phosphorylated but cannot be broken into 2 three carbon molecules
o F-1-P piles up in the cell – this consumes the cell’s phosphate supply and leads to liver damage or failure because the cells are deprived of ATP
o The only solution is to avoid fructose
Galactose:
• Dietary source: the hydrolysis of lactose (found in milk products)
• Functions:
o A polar component of polar lipids
o Used by the liver to install a carbohydrate to solubilize a substance (glycosylation)
o Lactation
• Catabolism occurs in the liver
o Galactose is phosphorylated (costs 1 ATP) ( Galactokinase
o Gal-1-P interacts with UDP-glucose to yield G-1-P ( Gal-1-P Uridyl Transferase
o G-1-P can isomerize to G-6-P and proceed to glycolysis or the shunt
o UDP-glucose is recovered by epimerase
• Galactokinase Deficiency:
o Galactose is not phosphorylated so it stays in the plasma
o This increased concentration can lead to cataracts
Carbohydrate Metabolism Regulation:
• Hexokinases (to phosphorylate glucose) are different in different cells ( different Km
• All are inhibited by G-6-P
• If cell has G-6-P, the G-6-P carb uptake is limited and the glucose stays in the blood plasma
• The transport mechanism of skeletal muscle cells and adipocytes is dependent upon insulin
• Liver:
o Receives carb intake from normal cellular mechanisms and via the hepatic portal vein
o Do not require insulin to uptake carbs – they can assimilate by diffusion
o Glucose is phosphorylated by glucokinase (not an allosteric enzyme)
▪ Glucokinase (Liver cells) Km = 10mM ( not responsive to normal glucose levels
▪ Hexokinase (most cells) Km = 0.1 mM ( only needs a small amount to run fast
▪ Plasma glucose = 5 mM
o Can use G-6-Phosphatase to return G-6-P back to glucose to be released into the blood
o G-6-P is not made like crazy due to:
▪ Insulin: This hormone, supplied when blood sugar is high, limits uptake
▪ Impact of incumbent G-6-P on hexokinase
o The liver regulates carb uptake via Glucose-6-Phosphatase (Km = 3mM) ( this reverses G-6-P back to glucose so it can go back into the bloodstream
Enzyme Inhibition: Substrate Cycle:
• Pyruvate Dehydrogenase is deactivated by Pyruvate Dehydrogenase Kinase
• Pyruvate Dehydrogenase is activated by Pyruvate Dehydrogenase Phosphatase
• Can control this cycle by controlling the kinase to impact the balance of the system
• Starting materials (Pyruvate, CoASH, NAD+) short out the kinase and thereby activate the Pyruvate Dehydrogenase
• Products (Acetyl CoA, CO2, NADH) activate the kinase and thereby deactivate the Pyruvate Dehydrogenase
• Excess ATP activates kinase
Control Points of the TCA Cycle:
1. Citrate Synthase
2. Isocitrate Dehydrogenase ( inhibited by energetics
• Energy demand controls carbohydrate synthesis!
• PFK – Allosteric
• Pyruvate Dehydrogenase – Taken into or out of account based on active/inactive form (not allosteric!)
• Same effect ( different mechanisms
• Increased energy available = obviates the effect of the enzyme = decreases the rate of reaction
• Reactions are pulled by energy demands, not pushed by supply
Carbohydrates:
• Sweetness is measured with a relative scale, with sucrose (a compound of glucose and fructose) being the item all else is compared to ( rated at 100 units
• Fructose = 170, Glucose = 70, Galactose = 32
• Polysaccharides are not rated because they have no sweetness
• Honey (mixture of glucose and fructose) is sweeter than sucrose
• When we eat, the blood sugar concentration increases regardless if one ate glucose, sucrose, etc.
• Sweetness in mouth has no effect on blood sugar levels!
• Glycemic Index:
o The area under the glucose response/tolerance curve
o Measures the impact of a specific carbohydrate on blood glucose levels
o Compared to ingesting the same amount of glucose
Energy Transfer:
• Work potential needs to be harnessed and converted by a machine
o Machines should convert energy as efficiently as possible – humans are about 40% efficient.
• 1st Law of Thermodynamics:
o The energy change of a process is equated to the heat evolved and the work done by that process.
o ∆E = Q + W = δq - δw
o A path independent function – the heat and work may be different, but the energy change is the same regardless.
▪ Heat is path dependent
• 2nd Law of Thermodynamics:
o To order a random system, work must be done
▪ The more ordered (less probable) you want it to be (quantify by probability), the more work must be done.
▪ The work done to order a random system is never recovered.
o Entropy is the measure of randomness or disorder in a system. The natural tendency is towards increasing entropy (decreasing order, increasing randomness)
o There is a relationship between the entropy and the probability of a system – the more random = the more probable (and the more spontaneous)
• Free Energy Change of a Process: ∆G
o ∆G = ∆H - T∆S
▪ The free energy change of a process is equal to the enthalpy change minus the product of the absolute temperature and the entropy change.
▪ A new criterion for spontaneity
o ∆G = ∆G0 + RTlnQ
▪ R = Gas Constant
▪ T = Absolute Temp (Kelvin)
▪ ln = Natural Log
▪ Q = Reaction Quotient
|∆G Value |Reaction Spontaneity |Work |
|0 |Non-Spontaneous (+) |Surroundings work on system |
|= 0 |Equilibrium | |
|∆H |∆S |∆G |Reaction Spontaneity |
|- |+ |- |Spontaneous |
|+ |- |+ |Non-Spontaneous |
|- |- |Depends | |
|+ |+ |Depends |High Temp = Spontaneous |
| | | |Low Temp = Non-Spontaneous |
• Reaction Quotient (Q):
o The product of the [products] divided by the product of the [reactants]
o Similar to K, but measured in different conditions (non-equilibrium)
▪ K > Q = Spontaneous
▪ K < Q = Non-Spontaneous
▪ K = Q = Equilibrium
o Recall LeChatlier’s Principle!
o To relate the standard free energy to the equilibrium constant, superimpose equilibrium on ∆G:
▪ ∆G = ∆G0 + RTlnQ
▪ 0 = ∆G0 + RTlnQ
▪ ∆G0 = - RTlnK
|- |∆G0 < 0 |K > 1 |Product Favored (at equilibrium) |
|+ |∆G0 > 0 |K < 1 |Reactant Favored (at equilibrium) |
• For a given system at a fixed temperature:
o ∆G0 , R and T are all constant
o lnQ is variable and has impact!
▪ If Q is small, the more negative the log term, the more likely to have a negative ∆G0
o The product in one step is the reactant in the next step ( this sucks the product out for the next reaction ( LeChatlier’s!
• This can be applied to the reaction steps of glycolysis, TCA, etc. The [products] and [reactants] can be manipulated to make the reaction more or less spontaneous.
o Increase reactants and / or decrease products = more spontaneous
o This manipulation to glycolysis can be graphed with ∆G on the Y axis and the progress of glycolysis on the X axis
▪ Pathways are contrived to drop off or be flat
▪ Flat areas are very close to equilibrium (= most of glycolysis)
▪ In comparison to ∆G , ∆G0 has more peaks and valleys and requires more work ( the only difference is the [component]
Cellular Energy Conversions:
• i.e.: the conversion of reducing power to phosphate power
• The mitochondria is the “machine” to harness the work potential
o The site of energy transformations
o A dual membrane system
▪ Outer membrane is mostly permeable
▪ Inner membrane is difficult to permeate
• It defines the matrix
• Uses pumps and gates
▪ Contains embedded proteins
• To transfer nutrient energy from the food supply to ATP:
1. Pyridine-Linked Dehydrogenase (Organic):
• An enzyme (therefore, a protein)
• NADH or NADPH (dinucleotide active forms of Niacin)
2. Flavin-Linked Dehydrogenase (Organic):
• An enzyme (protein)
• FAD or FMN – cofactors
• Manifestations of Riboflavin
3. Cytochromes:
• Organo-metallic containing polypeptides
• Chelating agents
• Simple proteins ( contain only amino acids
• Conjugated proteins ( Contain non-peptide entities
• Typically contain Iron
o Fe (II) or Fe (III)
• Typically display a heme structure – a ring with coordinate covalent bonding (one atom supplies both shared electrons)
o Has an outer organic (“Porphyrin”) section that decomposes to produce bilirubin
o Iron (in center of ring) can accommodate 6 coordination sites – the electron pairs are supplied by the R-groups of polypeptide chains
▪ The tertiary structure of the polypeptide wraps around the heme and locks onto 2 coordination sites.
4. Non-Heme Iron Proteins:
• A polypeptide with iron, but no organic substructure (heme)
• The iron is locked in by coordinate covalent bonds
5. Co-Enzyme Q:
• Not a polypeptide
• Can be a redox
• Found in all aerobic organisms
Electron Transport:
• NADH + H+ + ½ O2 ( NAD+ + H2O (Summary) ∆G0 = -220 kJ
• Compare to sequence of reactions:
o No work potential is conserved in the one step process because no ATP is produced. Therefore, it remains potential. In the electron transport system, 3 ATPs are produced
o The more steps in a process, the more efficiently it is done
▪ % Efficiency = total work potential conserved X 100
total work potential available
▪ Complex organisms can modify metabolic efficiency ( i.e. Dieting causes the body to be more efficient which obviates its intended effect ( to lose weight, the body should be less efficient! (This is a thermodynamic effect – not a rate effect! There is no “speeding up” of the metabolism)
o Has the same initial and final conditions
o Same ∆G0 therefore is path independent (total work potential is the same)
o The efficiency can be different (increases as increase the number of steps)
o The reducing agents are passed off
o The ultimate electron acceptor is oxygen!
o All components start out oxidized and end up oxidized ( the only items altered are oxygen and NADH
• Complex:
o Represents an aggregate of proteins that move reducing equivalents along
o Are embedded in cell membranes
• Phosphorylation:
1. High Energy Phosphate
• Use this to phosphorylate ADP (i.e.: PEP)
• Does not account for an intact mitochondrial membrane / system (The formation of this model used fragments of cell organelles)
2. Proton Gradient Creation (Oxidative Phosphorylation)
• The work potential from redox reactions in the membrane is used to achieve a proton gradient / pump
• Protons are moved across a membrane and this creates a [ ] or charge gradient.
o NADH reduces FMN to FMNH2. (The resulting NAD can be oxidized via the TCA cycle)
o The electron portion of hydrogen is used to reduce the iron, the proton portion is expelled into the cytoplasm (pH decreases)
o 2 protons are later taken from the matrix (pH increases)
o The polypeptide system functions as a gate and undergoes a conformation change to allow the protons to move back into the matrix ( Exergonic (collapse of proton gradient) ( Powers the formation of ATP
o ATP enters the cytoplasm and is used as fuel. The ADP then returns to the matrix.
• Chemiosmotic Hypothesis:
o For oxidative phosphorylation to occur, the mitochondrial membrane must be continuous and it must have a matrix or it cannot create a gradient!
o Redox and phosphorylation are “Coupled Reactions” – need one in order for the other to occur. Therefore, oxygen is required.
▪ Lack of oxygen, NADH, etc. would cause a lack of redox
▪ Lack of ADP, Pi, etc. would cause a lack of phosphorylation
▪ Uncouplers make the mitochondrial membrane porous to protons ( continue to burn fuel, but produce no ATP (increased inefficiency)
o Can plot on a graph with O2 pressure on the Y axis and time on the X axis
▪ In the mitochondrial system (with electron transport), the pressure of the oxygen is decreasing because it is consumed as the process proceeds.
▪ If run out of ADP, O2 consumption stops (can’t make ATP, proton gradient won’t collapse, can’t push protons across, redox stops) and the O2 pressure flattens out.
▪ If ADP is added back in, the O2 pressure drops as it is consumed
▪ Add rotenone and the system flattens out for the same reason as above
▪ Add succinate and the O2 pressure drops as it is consumed
▪ Add oligomycin (an antibacterial that inhibits the transport of ADP into the matrix) and the system flattens
▪ Add 2,4 DNP (an uncoupler that makes the inner membrane permeable to protons – obviates the proton gradient – O2 used up in redox – no ATP) and the system drops
▪ Add cyanide ions (they form a stable complex with copper in cytochrome A3 / complex IV) and the system flattens
Glycerol Phosphate Shuttle:
• Depends on the availability of oxygen
• Transfers reducing agents across the membrane – no metabolite crosses membrane!
• Accounts for extra ATPs in carbohydrate metabolism
• Is aerobic!
• NADH (generated in glycolysis) goes from the cellular cytoplasm to the mitochondria – must be reduced!
• DHAP gets reduced to an alcohol (must be recovered so that ATP can be continually generated)
• Glycerol Phosphate gets oxidized to DHAP
• Pasteur Effect:
o If there is a cellular system functioning anaerobically using glucose as a fuel to make ATP (cell is also making lactate), the introduction of oxygen causes:
▪ [Lactate] stop increasing
• The pyruvate goes to the TCA cycle with the O2 – costs 1/18 of the glucose to yield same amount of ATP
• NADH is deflected to interact with DHAP so it is not available to reduce the pyruvate
• Lactate is made back into pyruvate and generates another NADH ( therefore, lactate is a viable aerobic fuel to produce ATP
▪ Drop in the rate of glucose utilization
• Anaerobic: 2 ATP / glucose
• Aerobic: 36 ATP / glucose
• Therefore, uses 1/18 of the glucose to yield the same amount of ATP (Or, can say that it creates 18 times more ATP)
• Reduced FADH2 is located in the matrix and is used to reduce CoQ
Cori Cycle:
• In skeletal muscle, glucose goes through glycolysis to yield lactate. The lactate is immediately removed from the cell, through the blood plasma, and into the liver.
• In the liver, some of the lactate is oxidized to form pyruvate which then proceeds through TCA cycle and generates ATP
• The liver uses the generated ATP to convert some of the lactate into glucose ( “Gluconeogenesis”
• Only the lactate that is oxidized will consume O2 (1/6 oxidized) – the lactate that is converted to glucose (5/6) does not use O2!
• This cycle identifies an oxygen debt
Malate Shuttle:
• Is tissue / cell specific ( Associated with the liver and cardiac muscle (the glycerol phosphate shuttle is associated with skeletal muscle)
• Is bi-directional ( It can be reversed! (The glycerol phosphate shuttle is uni-directional)
o If the reducing agent is in the cytoplasm, it fuels biosynthesis
o If the reducing agent is in the mitochondria, it fuels ATP production
• Contains two transamination reactions where ketone and amine functions of two molecules are traded.
• Produces cytoplasmic NAD+ under aerobic conditions
• Skeletal muscle cells can store relatively little ATP
• Creatin is a specialized metabolite made by skeletal muscles
o Contains N ( cellular synthesis requires amino acids
o Contains S ( cellular synthesis requires methionine
o Can undergo reversible phosphorylation at the expense of ATP to form Creatin-Phosphate
• This is a one-step mechanism to produce ATP!
• Cells can store much more Cr-P than ATP
• As the cell contracts, it uses the incumbent ATP ( It also calls on Cr-P because it can sustain the cell for 8 – 10 seconds while glycolysis kicks in.
• Cr-P can undergo a spontaneous decay to produce Creatinine (not reversible) – this can generate energy to fuel the production of additional Cr-P
o Therefore, the system starts to make Cr-P and then takes an occasional one and shreds it to harness the work potential in order to make more Cr-P.
o Creatinine is cleared by the kidneys and excreted in the urine. This results in the loss of methyl groups! (Men typically excrete 20-26 mg/kg while women typically excrete 14-22 mg/kg)
• This process allows cells to store phosphate energy
• 3 metabolites are involved
Lipids:
• The main energy storage mode = Triacylglycerols (TAGs)
• TAGs vary in the nature of the fatty acid, the length of the HC chain, the # and position of double bonds, etc.
• Digestion:
o Complicated due to hydrophobic nature of the TAG and the hydrophilic nature of the enzymes
o Does not occur in solution, so is called a “Heterogeneous Phase Reaction”
▪ The reaction occurs at the surface of the heterogeneous phase
▪ To increase the reaction, you must increase the surface area. This is performed by bile
o Bile is a water solution with bile salts and unreacted cholesterol that is made in the liver and stored in the gall bladder. It is delivered to the small intestine where it functions to increase the surface area of the lipid which increases the reaction sites available which increases the rate of reaction (digestion)
o The amphipathic agents of bile salts form micelles and sequester fats in the hydrophobic core (breaks the fats into smaller pieces)
o No lipid digestion occurs in the mouth
o In the stomach, gastric lipase performs an insignificant amount of hydrolysis
o In the small intestine, the bile converts the lipid into smaller particles via physical means (no chemical reactions at this stage)
o The small pieces are subject to hydrolytic reactions and small ionized fatty acids (R-COO-) are chopped off (catalyzed by the pancreatic enzyme, steapsin) The R-COO- are amphipathic and can form micelles. This adds to the impact of bile and accelerates the process.
▪ This is an incomplete process that produces an array of products that are then absorbed into the intestinal mucosal cells:
• 40% glycerol
• 2 – 10% unchanged
• 50% 2-monoacylglycerol and ________________
▪ Once absorbed, they are transformed back into TAGs, but they are now intracellular.
▪ The TAGs are then complexed into an enormous macromolecule called a “Chylomicron”
• A lipoprotein
• A micelle whose inner hydrophobic core contains many TAGs
• Leave the cell via the lymphatic system. From there, they are drained into the Left Subclavian Vein and enter general circulation.
• Lipid Activation:
o R-COO- + CoASH + ATP ( R-COOSCoA + AMP + PPi
o The acyl group of a cytoplasmic fatty acid is activated to yield an activated fatty acid.
o Must hydrolyze PPi at the cost of one ATP
• Mitochondrial Entry (Preparation for Beta Oxidation):
o Requires the transport molecule “Carnitine”
o Induces transesterification
o A 2nd transesterification releases the carnitine and leaves the R-COOSCoA in the matrix
• Beta Oxidation of Fatty Acids: Mitochondrial
o REDOX: Creates a trans C=C between the # 2 & 3 carbons
o HYDROLYSIS: Hydration of an alkene produces an alcohol – the alcohol is located on the #2 carbon to create the L-isomer ( chiral = Beta Hydroxy
o REDOX: Secondary alcohol is oxidized to produce a ketone
o THIOLYTIC CLEAVAGE: Add CoA to cleave between the #2 and 3 carbons. This produces a fatty acid with 2 less carbons and Acetyl CoA
o Continue the cycle until only 4 carbons left – this creates 2 copies of Acetyl CoA
o This cycle yields:
▪ FADH2 (reducing agent) ( yields 2 ATP
▪ NADH + H+ (reducing agent) ( yields 3 ATP
▪ Acetyl CoA ( yields 12 ATP (TCA cycle)
▪ ***Lose 1 ATP due to activation! ***
o The number of Acetyl CoA and reducing agents depends upon the starting length of the chain
▪ Cn saturated fatty acid
• (n/2) - 1 = # of times through cycle
• n/2 = # Acetyl CoA
• (n/2) – 1 = # of FADH2
• (n/2) – 1 = # of NADH + H+
o Every time the fatty acid gets longer by 2 carbons, it provides another 17 ATP!
o The ultimate fate of the carbons in fatty acids is CO2
o This process is AEROBIC – there is no anaerobic alternative (therefore, mature RBCs cannot use fat because they have no mitochondria)
• C18 fatty acid yields 147 ATP while 3 glucose (C18) only yield 108 ATP
o The fatty acid is more reduced and requires a bigger energy jump to oxidize to CO2 – this provides more ATP / carbon (~8.2)
o The carbohydrate is more oxidized and needs less energy to jump to oxidative state of CO2 – therefore, it provides less ATP / carbon (~ 5.5)
o We store energy as the most reduced form so there is less weight to carry around for the amount of ATP
• Unsaturated Fatty Acids:
o Starts as usual – each time Beta Oxidation is performed, the ∆ # changes (always odd) until it eventually is a ∆3. (The 2nd bond will always be even and will eventually be a ∆2)
o Isomerase is an enzyme that moves a double bond to the #2 carbon and makes it trans ( the process can continue as usual
o No FAD in this cycle because it is already oxidized (the chain already has a double bond) ( therefore, only 15 ATP are generated (vs 17)
o An unsaturated fatty acid has a higher oxidative state, therefore the energy content is less, therefore it always produces less ATP than its saturated analog
• Fatty Acids with an Odd # of Carbons:
o Beta Oxidation eventually yields a 3 carbon residue (Propanyl CoA)
o Undergoes carboxylation ( Co-factor: Biotin ( produces Methyl Malonyl CoA
o MMCoA isomerizes (Enzyme: Methyl malonyl mutase; Co-Factor: Cobalamin) to form Succinyl CoA which proceeds to the TCA cycle (5 ATP)
▪ The transfer of a 1 carbon fragment always involves the cofactor cobalamin
▪ If have a Biotin deficiency, unable to metabolize branched chain fatty acids. (Biotin is involved in carboxylation reactions)
Proteins:
• Remove Nitrogen to use AA carbons
o Oxidative Amination
o Transamination
▪ Pyruvate + X = Alanine + Y (3 Cs)
▪ Oxaloacetate + X = Aspartate + Y (4 Cs)
▪ Alpha-Keto-Glutarate + X = Glutamate + Y (5 Cs)
• AA Classifications:
o Glycogenic (carbohydrate precursor) – Pyruvate (malate, fumarate, etc.)
▪ Not – Acetyl CoA, FAs, Cholesterol
o Ketogenic (ketone body precursor)
o Both
• Gluconeogenesis:
• A reversal of PEP ( Pyruvate
• Pyruvate + CO2 + ATP ( ADP + Pi + Oxaloacetate
o Uses Pyruvate Carboxylase with Biotin and Acetyl CoA as co-factors
• OAA is reduced to malate
• The malate moves from the mitochondria to the cytosol and is oxidized back to OAA
• The OAA is decarboxylated to form PEP using PEP Carboxykinase – costs 1 GTP
• The reaction converts mitochondrial pyruvate to cytoplasmic PEP at the expense of 2 ATP
• ATP excess forces the subsequent equilibrium reactions to the right until reaches G6P (PEP ( 2 PG ( 3PG ( ( ( F16P ( F6P ( G6P)
• G6P ( Glucose occurs in the liver
• Takes two pyruvates and ATP to make glucose
o Pyruvate ( glucose costs 6 ATP
• Pyruvate is considered to be a carbohydrate precursor (as are any compounds that make pyruvate – i.e.: Malate, Fumarate, Succinate, Succinyl CoA)
• In a catabolic context, the fate of pyruvate is Acetyl CoA ( not a carbohydrate precursor
• FA ( ( ( Acetyl CoA (Therefore, FAs are not carbohydrate precursors!)
• Amino Acids can be carbohydrate precursors if they contain a glycogenic component
Starvation:
• OAA of the liver that is normally used to produce citrate is being used to make glucose. (It is no longer available to react with Acetyl CoA to make citrate) The Acetyl CoA converts to Ketone Bodies – this can lead to ketoacidosis. The body responds by trying to make glucose from AAs via the TCA cycle
• The liver gets amino acids from skeletal muscle protein
• Long Term: The gluconeogenesis flattens out and more Ketone Bodies are produced. They are used as fuel so less glucose needs to be made and less muscle protein is destroyed.
• Proteins can support an average male for 12 – 14 days with no carbohydrate intake ( after that time, fat reserves are used.
Cori Cycle:
• A ratio of lactate burned to lactate converted to glucose (1:5)
o 1/6 lactate burned
o 5/6 lactate converted to glucose
• Skeletal muscle portion is anaerobic; Liver portion is aerobic
• Lactate ( 3 CO2 (+ 15 ATP)
• 2 Lactate ( Glucose (- 6 ATP)
• (# ATP made)(# burned) = [(# lactate - # lactate burned) / 2] (6 ATP)
3 Sources of Glucose:
1) Exogenous Sources (from diet) – used for first 4 hours
2) Glycogen (from Liver) – from 3+ to ~ 16 hours
3) Gluconeogenesis (from muscle protein) – from 16 hours on
Phases:
• Absorptive (0 – 4 hours) – Exogenous
• Post Absorptive (4 – 16 hours) – Liver Glycogen
• Early Starvation (16 – 28 hours) – Gluconeogenesis
• Intermediate Starvation (2 – 24 days) **Ketone Bodies used**
• Prolonged Starvation (24 – 40 days)
Substrate Cycle:
• Controls pathways
• Forward and reverse reactions typically have different enzymes
• It is not a smooth flow – some still get through to go through the rest of the pathway = “Flux”
• Small changes in concentration generate large changes in the flux
• If you want to increase the product, increase A ( B, or decrease B ( A
• i.e.: F1P ( F16BP
• Kinetic control is under the influence of the enzymes
• Also seen with the Pyruvate Dehydrogenase System
Hormones:
• Chemical agents present in plasma and cellular environments
• Small amounts create a dramatic effect
• Present extracellular, but effect is intracellular
• Produced at one site and transmitted via plasma to the target
• Typically not metabolized
• Have a half-life
1) Polypeptide (Extracellular)
• Large aggregates of amino acids hooked together with peptide linkages (not large enough to be a protein)
o Insulin: A polypeptide derived from the pancreas that lowers blood sugar by enabling carbohydrates (glucose) to move from the plasma to the interior of cells. It does not catabolize carbohydrates!
▪ Is in response to increased blood sugar
▪ Most cells regulate insulin to uptake carbs from the plasma (except liver cells)
▪ The liver limits the uptake of glucose by the large Km of glucokinase
▪ Diabetes Mellitis: A failure of the insulin mechanism
• Pancreas may not produce insulin
• Muscle cell / adipocytes receptor sites do not properly accommodate insulin
• Produces chronic hyperglycemia
• Type I: Juvenile onset – typically pancreatic failure triggered by a disease process
• Type II: Mature onset – A receptor site problem with a genetic component (due to a problem with protein synthesis). Generally seen in 40s & 50s. Risk factors include heredity, age, obesity, etc.
• Gestational: Transitional diabetes developed during pregnancy
• Symptoms:
o Hyperglycemia: Elevated blood sugar
o Urinary Glucose
o Ketone Body Production: Leads to ketoacidosis as the body switches to fat metabolism for fuel
o Dehydration: Produced by the hyperglycemia and ketone body production in order to clear the ammonia, ketone bodies, and carbs.
o BP Drops: Due to the dehydration (blood volume decreases)
o Rapid Pulse: Caused by hyperventilation associated with ketone body production and decrease in BP
o Shock / Coma / Death possible
Glucagon: A polypeptide supplied by the pancreas that increases blood sugar. It encourages gluconeogenesis and discourages glycolysis in hepatic cells.
▪ Liver glycogen is synthesized at the expense of G-1-P. Activated by glycogen phosphorylase A (active form) – consumes ATP
2) Catecholamine (Extracellular)
• Catechole (organic) structure
o Epinephrine: Supplied by the adrenal medulla – raises blood sugar. (Benzene rings are supplied by phenyl alanine or tyrosine.)
▪ Increases blood sugar in response to external stimulus by impacting mainly skeletal muscle glycogen.
▪ Hydrolysis provides fuel for muscle activity – anaerobic)
▪ Stimulates the pancreatic release of glycogen (indirect effect)
o Norepinephrine:
3) Steroid (Intracellular)
• i.e. Corticosteroids, sex hormones
Adenyl Cyclase:
• A plasma membrane bound polypeptide which has active sites on the interior and exterior.
• Glucagon travels via plasma to receptor site (hepatocytes)
• Induces the formation of cAMP ( impacts the cAMP stimulated protein kinase ( etc.
Glycogen Synthesis:
• Uses Glycogen Synthase (2 forms)
o Glycogen Synthase Independent: Does not need G6P
o Glycogen Synthase Dependent: Requires G6P as a cofactor
• Falling blood sugar releases glucagon (hormone)
• Therefore, [G6P] is low so there is no cofactor for glycogen synthase. No glycogen synthesis occurs – hydrolysis is encouraged
• When fed, there is more insulin and less glucagon
o Increased blood sugar, therefore glucagon is not supplied. [G6P] increases and encourages the hydrolysis of glycogen phosphorous phosphatase – also encourages glycogen synthase phosphatase
o cAMP undergoes a decay process to produce AMP
o 2 maneuvers shut the system down:
▪ Increased levels of G6P
▪ Ongoing effect of phosphodiesterase (when no longer inhibited by producing cAMP)
• When starving, there is less insuline and more glucagon
Fatty Acid Biosynthesis:
• Required for:
o Repair / production of cell and organelle membranes
o Efficient storage of fuel with the least amount of weight
• Mitigated by glucagon (response to low blood sugar, so body does not want to use glucose for FA synthesis) and epinephrine (carbs may be available, but the body wants to use them as fuel – not store them!)
• Not many intermediates – mostly concerted reactions
• Occurs in the cellular cytoplasm
• Looks like a reversal of Beta Oxidation
• Start with Acetyl CoA and carboxylate to create Malonyl CoA (an acyl carrier protein that contains a sulfhydryl group)
• Combine the two products - lose CO2 and ACPSH – the carbon chain is elongated by two carbons
• The ketone is reduced to an alcohol with NADPH (reducing agent – gets oxidized and then goes through the shunt)
• Dehydration to produce an alkene
• The alkene is reduced to an alkane with NADPH
• Another copy of Malonyl ACP – lose CO2 and ACPSH – results in a 6 carbon fragment
• Beta ketone will go through again until get a 6 carbon reduced product
• Another copy of Malonyl ACP
• Reduction, etc. repeated – each time the FA is elongated by 2 carbons – until C16 (palmitate)
• Spends 2 reducing agents and one Malonyl CoA
• Starting material is Acetyl CoA – can be made from:
o Pyruvate (produced at the expense of carbohydrates which can be made from glycogenic AAs)
o Ketogenic AAs
o Ketone Bodies – more likely to be used for fuel instead of biosynthesis
Pyruvate-Citrate Cycle:
• The first time Acetyl CoA is seen in the cytoplasm
o It cannot permeate the membrane, so it gets out as citrate which then breaks
o Converted into Palmitate (C16 FA)
o Loses CO2 as malate is converted to pyruvate
• Start with 6 carbons, and each time cycles:
o The FA gets bigger by 2 carbons
o 1 C exits as CO2
o 2 are stored as FA
o 3 continue as pyruvate to proceed with cycle
• To make palmitate:
o Requires 4.5 glucose – 8 times through cycle with 1 pyruvate left
o Takes 27 carbons to make a 16 carbon FA
▪ Requires a lot of reduction
▪ Therefore, carbon is oxidized to CO2 and 1/3 are lost as CO2
Lipids:
1) Triacylglycerides:
• Depot fat ( storage / fuel reserves
• Adipocytes
2) Polar Lipids:
• Involved in membrane structures
• Phosphatides, sphingolipids (a polar lipid with a HC tail – produced from palmitate and serine)
Lipid Production:
• Starting Material: DHAP
• Reduced to an alcohol
• Transesterification ( produces a phosphatide that can be used for membrane structures on demand
• Another copy of fatty CoA
• Produces a depot fat (TAG) – a major component of adipocytes
Desaturation:
• Institution of a double bond decreases the melting point range of a lipid
• i.e.: C16 Saturated FA oxidized to create a double bond. In humans, it appears at the Delta 9 position
o Any other double bonds appear towards carboxylate ions
Elongation:
• Adds to the carbonyl end
• The combination of the above can produce a variety of FAs with different melting point ranges
Cholesterol:
• It is a required substance – humans are able to synthesize (mostly in the liver)
• Animal sources only
• There is only one minor excretory process (liver is the chief disposal organ)
• A white waxy solid that is marginally soluble in water
• Soluble in bile and other HCs
• Amphipathic ( forms micelles
• Used for:
o Membrane Component
o Precursor
▪ Bile Salts
▪ Steroid Hormones
• It is not metabolized, so there are no energetic consequences
• Most is made in the liver and converted into water soluble bile salts – Anterohepatic Cycle:
o Produced by hepatocytes and distributed via ducts and sphincters from the gall bladder to the small intestine when lipids are ingested
o Sent to the gall bladder where the mucosal cells absorb water in order to concentrate the bile
o Functions as an emulsifying agent to break up lipids
o Once TAGs are digested, the bile components are reabsorbed in the small intestine
▪ Bile Salts are absorbed via the Hepatic Portal Vein
▪ Unreacted Cholesterol is absorbed as a chylomicron (lymphatics)
▪ About 1 gram is excreted per day
Cholesterol Synthesis:
• Starts with Acetyl CoA (can synthesize starting with glucose, ketone body, etc.)
• 3 copies of Acetyl CoA to produce HMG CoA – enzyme to mevalonate = Allosteric Control Point
• Proceeds until generates 3,3’-dimethyl allyl pyrophosphate – 6 of these condense with themselves to yield Squalene
• The system cyclizes to ultimately form Lanosterol (4 fused rings) ( Cholesterol
High Fat Diets:
• Increased bile production
• Lots of bile accumulates in the gall bladder – it can form crystals and block the sphincter ( Gall Stones
• 90% of gall stones are cholesterol
• Risk Factors: High Fat Diet, Obestity, Fair Skin, Female
Cholesterol Reducing Drugs:
• Interfere with Anterohepatic Cycle to prevent reabsorption of bile salts. Causes more to be excreted.
• Limit the synthesis of HMG CoA reductase and impedes the synthesis of cholesterol
Lipid Transport:
• Lipids are very hydrophobic and require stylized mechanisms due to the aqueous environment of the human body
• Specialized mixed micelles with a hydrophilic shell (DAGs)
o Occasional embedded cholesterol (“Free Cholesterol”)
o Large proteins embedded in shell ( recognition sites
o Hydrophobic interior (nonpolar) ( TAGs and Cholesterol Esters
o A chylomicron is one type of lipoprotein
• Lipoprotein Types (All are micelles): (Increase density = decreased fat %
o Chylomicrons:
▪ Formed in intestinal mucosal cells ( lymphatics ( blood plasma
▪ Exogenous TAGs are hydrolyzed by lipoprotein lipase of an adipocyte
• FAs, MAGs, and Glycerol move from the cytoplasm into the adipocyte where they reform the TAG for storage
• The Chylomicron Remnant (devoid of TAGs) carries the following to the liver
o Cholesterol Esters
o Cholesterol
o Water insoluble agents
o Vitamins (It is, therefore, possible to overdose on fat soluble vitamins like Vitamin A and do liver damage)
▪ Provides an environment for the assimilation of hydrophobic things
▪ Carries exogenous TAGs
o Very Low Density Lipoproteins (VLDLs):
▪ Formed in the liver – similar to the chylomicron
▪ Carries endogenous TAGs
• From the liver to the cytoplasm
• Hydrolyzed by the Lipoprotein Lipase of an adipocyte
o MAGs and Free FAs move from the cytoplasm into the adipocyte where they reform into TAGs
o IDL goes back into the liver or assimilates cholesterol esters to create an LDL
▪ Imbued with Apolipoprotein C2 (a recognition feature) from HDL
▪ Intermediate density lipoprotein
o Low Density Lipoproteins (LDLs):
▪ Cholesterol transport
▪ Major repositories of cholesterol esters (located in the hydrophobic inner core)
▪ Taken up by a peripheral site with a B100 Receptor via endocytosis ( Is a cholesterol donor
• In skeletal muscle cells, the LDL won’t be a hormone or bile precursor because those are not made by muscle!
▪ The “Bad” Cholesterol
o High Density Lipoproteins (HDLs):
▪ Cholesterol transport
▪ Donor of Apolipoprotein C2 to chylomicrons and VLDLs
▪ A Cholesterol Acceptor and a CE donor
▪ Lecithin + Cholesterol ( Cholesterol Ester + 2-acyl lecithin
• Lecithin is a polar lipid that is a source of FAs to form cholesterol esters. It is found in vegetable lipids
▪ Possess Lecithin Cholesterol Acyl Transferase (LCAT) to catalyze the conversion of cholesterol into a cholesterol ester
• Once formed, the cholesterol esters are donated to an IDL to make an LDL
• Cholesterol is recycled!
▪ The “Good” Cholesterol because it scarfs up plasma cholesterol
• 3 polypeptides in the cholesterol loop:
o Apolipoprotein C2: Associated with lipoprotein lipase
o Apolipoprotein B100: Associated with B100 receptor sites
o LCAT: Source of FAs to convert cholesterol into cholesterol esters
• Cholesterol Inhibition Process:
o Cholesterol inhibits HMG CoA Reductase ( therefore, mRNA formation is inhibited!
o Insulin: A high blood sugar response that lowers blood sugar
▪ Encourages / excites Phosphatase
▪ Encourages the active form of HMG CoA Reductase
▪ Therefore, high blood sugar can increase the synthesis of cholesterol
▪ Major inhibitor of adenyl cyclase (ATP ( cAMP)
o Glucagon: A low blood sugar response that raises blood sugar
▪ Inhibits Phosphatase
▪ Keeps the inactive form of HMG CoA Reductase
▪ Initiates fat mobilization, etc.
• The liver can assimilate cholesterol via LDL receptors and chylomicron remnants
Free FAs
o A complexed FA in the blood plasma
o Looks for sites that need energy (i.e.: Skeletal muscle, liver, etc.)
• FAs are used for fuel by skeletal muscle, small intestine, etc.
o Not by neurons of the CNS (use ketone bodies) or RBCs
| |Total Cholesterol |TAG |LDL |HDL |Cardiac Risk Factor |
|Inactive |212 |154 |136 |43.3 |4.9 |
|Jogger |204 |106 |125 |58 |3.5 |
|Marathon Runner |187 |73 |107 |65 |2.9 |
Cardiac Risk Factor: (TC / HDL)
• > 4.5 is cause for concern
• Even moderate exercise is beneficial because it raises the HDLs
• Moderate ( extreme exercise does not change as much
• Also depends upon age
CNS Fuels:
| |O2 |Glucose |Lactate |Aceto-Acetate |B-OH Butyrate |FFA |
|Fed |-3.37 |-0.51 |0 |0 |0 |0 |
|5-6 Weeks Starvation|-2.96 |-0.26 |+0.20 |-0.06 |-0.34 |-0.02 |
| |~ 10% drop |~ 50% drop |CNS is producing |Ketone bodies are taking up the slack| |
| | | |some due to |to provide fuel in lieu of | |
| | | |anaerobic activity|carbohydrates | |
| | | |– not an | | |
| | | |alternative fuel | | |
Glucose – FA Cycle:
• Starts with eating
• As [glucose] decreases
o Hydrolyze glycogen
o Synthesize glucose
o Fat mobilization – therefore FAs are available as a fuel source
• Cannot make ketone bodies from glucose because pyruvate can be made into Acetyl CoA and OAA (which reacts with Acetyl CoA and proceeds via TCA)
• FFAs are formed because FAs form micelles in the plasma and are not assimilated well. It requires energy to break the micelle apart. [FA] would have to be tiny in order to avoid making micelles!
AA Biosynthesis (Starvation Context) – Alanine-Glucose Cycle:
• Falling blood sugar causes glucagon to be released and liver glycogen to be hydrolyzed.
• Gluconeogenesis is initiated. – carbon source is skeletal muscle protein
• Skeletal muscle protein is hydrolyzed into AAs – transamination with pyruvate from glycolysis to produce alanine
• Alanine goes into the plasma and then to the liver where it is transaminated back into pyruvate
• Pyruvate is made into glucose and then sent back into plasma for assimilation
• The carbon atoms from the protein end up as alanine and glucose
• The Nitrogen atoms from the protein end up in Glutamine in the liver – then excreted
• Starvation uses Skeletal Muscle Protein for:
o Alanine as a carbohydrate precursor for the liver
o Glutamine as N source for acid/base balancing of the kidneys
One Carbon Transfers:
• Used with many B vitamins – must be ongoing because we lose methyl groups through creatin cycle
• One carbon metabolites:
o Carbon Dioxide – most innocuous –reduction forms the following
o Formic Acid (HCO2H)
o Formaldehyde (H2CHO)
o Methyl Alcohol (CH3OH)
o Methane (CH4)
• Methionine is a one carbon methyl group source
o An essential AA
o Contains sulfur
o Often seen as S-Adenisine Methionine (SAM)
• Folic Acid:
o A B complex vitamin (growth factor for organisms)
o Complex life forms require, but cannot manufacture
o Contains Para Amino Benzoic Acid (PABA) and Glutamate
o Tends to be a one-carbon carrier (with the extra carbon, it is 5,10-methylene tetrahydra folate) ( this is the active (and reduced) form
o In nature, it tends to appear in its oxygenated form
o 5,10 methylene H4 folate is irreversibly reduced to 5 methyl H4 folate and the methyl group is passed to SAM, creating H4 folate
o Methionine is regenerated at the expense of folic acid
▪ A folic acid deficiency also produces a deficiency in methionine
▪ Folic acid allows us to minimize consumption of methionine
o H4 folate reacts with glycine (lose CO2 and NH4) to regenerate folic acid
o Homocysteine H4 folate methyl transferase requires Cobalamin (B12) as a cofactor. If deficient in cobalamin:
▪ Methionine requirements increase
▪ A folic acid shortfall is created
o Epinephrine is metabolized by the liver, glycosolated, and excreted through urine
Cobalamin (B12):
o Functions:
▪ 1 Carbon transfer in odd # FAs
▪ 1 Carbon transfer in [the above sequence]
o When ingest, the gastric mucosa secrete a glycoprotein that combines with B12 to produce a conjugated cobalamin
o This ends up in the small intestine and is absorbed by the hepatic portal vein
▪ It must be conjugated in order to be absorbed, and this requires glycoprotein
o Cobalamin = Extrinsic Factor
o Glycoprotein = Intrinsic Factor (A shortage requires shots)
o Deficiency ( Pernicious Anemia
▪ A gradual decrease in RBC count due to an impeded production
▪ We require about 10 E-9 moles / day
▪ The liver stores about 2mMoles (10 E-6) = enough for 3+ years!
▪ Food Source: Red Meat
Nitrogen Bases:
• Are routinely synthesized by organisms
• 2 Classes:
o Pyrimidines:
▪ Cytosine, Thymine, and Uracil
▪ N is derived from AAs
▪ The nucleus is created from Carbamyl Phosphate and Aspartate
▪ Common Intermediate: UMP
▪ Phosphorylate to UTP (used in RNA) to CTP (for RNA or DNA) to TMP (for DNA)
o Purines:
▪ Adenine and Guanine
▪ A fused ring nucleus created from Formate, Glutamine, Glycine, CO2, and Aspartate
▪ Common Intermediate: Inosinic Acid
▪ Forms Adenine or Guanine which are then phosphorylated to ATP and GTP
• Adenine and Guanine can both degrade to form Xanthine which goes on to form Uric Acid – cleared by the kidneys
o Base Pairing:
▪ Used in transcription and double helix formation
▪ DNA: AT and CG
▪ RNA: AU and CG
• Peptides grow from the carboxylate end – the initial AA amine group is “blocked” by a folic acid so that the peptide only grows in one direction
• Ways to lose N:
o Urea from gluconeogenesis
o Creatin ( Creatinine
o Uric Acid
• Uric Acid:
o Formed by the degradation of Purines
o Not very soluble in water, so if the levels increase, it saturates the plasma and precipitates out
o Ends up as:
▪ Urate kidney stones
▪ In cartilage = Gout (Genetic Disorder)
• Nose, ear, etc. – painless
• Joints – excruciating
• Intervention: Inhibit the enzyme that catalyzes the reaction that forms xanthine (Competitive Inhibition with Alopurinal) This prevents the formation of uric acid
Neurotransmitters:
• Neurons: Cell body, axon, dendrite, synaptic knob, vesicle, nodes of ranvier, myelin sheath, etc.
• Pre-synaptic cell, post-synaptic cell, synaptic cleft, etc.
• Pre-Synaptic Neuron:
o Cellular choline interacts with Acetyl CoA to form Acetylcholine (stored in vesicles)
o Once released from vesicles due to neural directions, acetyl choline reacts with the receptor site of the post-synaptic membrane in equilibrium (recall LeChatlier’s!) This can cause depolarization of the cell membrane
o The acetylcholine is hydrolyzed by acetylcholine esterase into acetate and choline
▪ The acetate becomes part of the interstitial fluid and is not recovered
▪ The choline goes back into a cellular context (recycled)
▪ The [acetylcholine] decreases, pulls away from the receptor site, and the cell membrane repolarizes
o There is competition between the receptor site and the AC esterase
o The NT must be removed or the cell membrane will remain polarized
o Formation of acetylcholine is cytoplasmic ( the carbon atoms must come from glucose! (The glucose is trashed to produce the NT)
o If cannot make acetyl CoA (due to thiamine deficiency – Beri Beri), then acetylcholine cannot be produced – can lead to congestive heart failure due to the impact on the cardiac muscle
o Acetylcholine is removed via hydrolysis
• To be effective, the NT:
o Must be synthesized in the pre-synaptic neuron
o Must be put into the synaptic cleft
o Must have a removal mechanism that terminates its effect
• Ways to Remove the NT:
o Destruction
o Transporter Proteins:
▪ Return the NT (i.e.: Dopamine) to the pre-synaptic neuron
▪ Cocaine interferes with this:
• Occupies the transporter proteins so that the receptor sites are getting hit
• The receptor sites decay with use – will regenerate if stop using them
• There is an initial increase in the firing rate, then a decrease (associated with euphoria ( dull)
• The more addicted, the fewer receptor sites
Special Topics:
Diabetic Bloodwork:
• Symptoms include: Dehydration, LBP, rapid pulse, ketone bodies in urine, acetone on breath, glucose in urine, & lack of tissue elasticity
|Plasma Components |Patient (mM) |Normal (mM) |
|[HCO3-] |12 |24 – 35 |
| |Should be low due to the presence of ketone| |
| |bodies that are reacting with / using up | |
| |the bicarbonate | |
|pH |7.1 |7.3 – 7.5 |
| |Should be lower (more acidic) due to | |
| |decreased levels of bicarbonate and | |
| |increased levels of ketone bodies – | |
| |metabolic acidosis (hyperventilation) | |
|Urea |8 |2.5 – 7.5 |
| |Should be larger due to the gluconeogenesis| |
| |at the expense of amino acids – excess | |
| |Nitrogen must be discarded | |
|[Na+] |136 |138 – 150 |
| |Close to normal | |
|[K+] |5.8 |3.8 – 5.6 |
| |Should be higher due to dehydration | |
| |(intracellular concentration is decreased) | |
|Ketone Bodies |350 |0 – 3 |
| |Should be much higher | |
|Osmolality |385 mosmol/l |285 - 295 |
|(A measure of osmotic pressure) |Should be higher – the fluid transfer | |
| |between inter and intra cellular is greater| |
Alcohol Metabolism:
• Ethyl alcohol = CH3CH2OH – has a low molecular weight and is soluble in water
• When ingested, it appears in all water-based fluids (i.e.: Plasma, CSF, etc.)
• The majority (95% +) is absorbed and then cleared via hepatic oxidative maneuvers – a very small amount is lost via urine or sweat
|Response |[EtOH] mg/dl |
|Normal |5 – 15 |
|Social (1 – 2 drinks) |< 50 (0.05%) |
|Exhilarated but sober | |
|Pre-Intoxication – 4 – 6 drinks |50 – 150 (0.05 to 0.15%) |
|Decreased coordination and judgment |* 0.08 = Legally intoxicated * |
|Intoxicated |150 – 300 (0.15% +) |
|Impaired speech, motor skills, etc. | |
|Stuporous |300 – 400 |
|Asleep, but responsive to strong stimulus | |
|Comatose |400 – 600 |
|Non-responsive to stimulus | |
|Death |600+ |
• Oxidation is a zero-order process – therefore, it has a fixed rate regardless of the [substrate]
o Hepatic oxidation clears about 100 mg/kg/hour
o Food only serves to slow down the absorption rate – it still takes the same amount of time to clear
• EtOH ( acetaldehyde is catalyzed by alcohol dehydrogenase (pyridine-linked) – cytoplasmic
• Acetaldehyde is oxidized to acetate using acetaldehyde dehydrogenase
o Deficiency of this enzyme is common in Asian populations – leads to a build up of acetaldehyde. Therefore, even one drink can make them very sick
• If drinking heavily and not eating and then go to sleep, there is a long time with no fuel. Liver glycogen is used up.
• Impact:
o Gluconeogenesis is almost obviated: The oxidizing agents must be recovered, so the liver must produce lactate to handle the alcohol. It is unable to convert lactate ( pyruvate ( glucose due to the lack of oxidizing agents.
▪ Lactate is exported – can lead to lactic acidosis (a type of metabolic acidosis)
▪ All of the oxaloacetate is being made into malate
▪ Dehydration (increased urea)
▪ Hypoglycemia
o Fatty Liver / Cirrhosis:
▪ Hydrolysis of TAGs is encouraged – become Free FAs and move to the liver to be made into ketone bodies
▪ Need to be oxidized, but the liver does not have oxidizing agents available, so they become TAGs and produce a fatty liver ( this is a short-term, reversible response!
▪ Progresses to cirrhosis (scarring) which is long-term and irreversible
o Effectively enhances the dosage of other chemicals
▪ Alcohol is cleared preferentially, allowing the other chemicals more time to work
• Downer = depress the system
• Upper = may lead to heart arrhythmia
• Alcohol = 7 cal/g that are simply stored
o 12 oz beer = 130-150 cal
o mixed drink = 150 cal
o cream based mixed drink = 250 cal
• A “hangover” is a collection of symptoms – all of which must be addressed to gain relief:
o Dehydration
o Hypoglycemia
o Acidosis
Minerals:
• Non-organic – most are water soluble (i.e.: Na+, K+, etc.)
• Iron:
o A cytochrome component
o Prevalent in hemoglobin (carry oxygen)
▪ 3 components of hemoglobin:
• Collection of AAs (peptide)
• Chelating Agent (porphyrin ring structure) – becomes bilirubin and is excreted
• Iron (gets recycled)
o Can be toxic and do liver damage unless sequestered
o Humans have only one minor (small intestinal) excretory mechanism – the only way to lose iron is to lose blood
▪ SI loss = 1 mg/day (about 1.6 mg/day average for pre-menopausal women)
• This is considered to be the “Physiological Iron Requirement”
• However, many dietary formats are hostile to absorption (insoluble)
▪ The “Nutritional Requirement” is about 10 – 12 times the physiological requirement
• Best sources are red meat and enriched white flour
o Absorption:
▪ Tends to form hydroxides in basic environments
▪ The reduced form FeOH II is more reduced and more soluble than III
▪ Absorption rate can be increased if taken in conjunction with Vitamin C
▪ Mucosal cells of the SI contain Apoferritin – a polypeptide that reacts with the Fe II from the lumen to form ferritin – regenerated as the Fe II goes into the plasma
▪ In the plasma, it reacts with apotransferrin produce transferrin (an iron containing polypeptide)
▪ This travels to other tissue sites
• Marrow – used to make RBCs
• Liver – used to make ferrin and be stored – the liver can store up to 1000 mg
▪ Absorption is limited by the availability of apoferritin
• Limited because iron loss is limited!
▪ The iron does not get loose – it is passed via peptides
Anemia is generally due to deficient dietary iron – prevalent in vegetarians due to the restricted bioavailability of iron in vegetable sources
▪ Jaundice:
• Breast milk is a poor source of iron, so prior to birth, the fetus assimilates an extra collection of RBCs. They are trashed, and the iron is stored in the liver.
• The heme portion of the destroyed RBCs deteriorates into bilirubin (water insoluble). This is generally glycosylated and cleared by the kidneys. If the liver cannot handle, it stays in the system and leads to jaundice.
• Intervention: Irradiation with blue light to energize the cis-double bond and reform it as a more soluble trans-double bond
▪ Iron Poisoning: If there is an overload of iron in the lumen, the mucosal block is overpowered and iron gets into the liver. It forms hemosiderin which is very toxic and damaging.
B Vitamins:
|B Vitamin |Active Form |Function |
|Niacin (“Nicotinamide”) |NAD |A redox coenzyme always used in ATP |
| |(NADH = reduced form) |formation |
| | |Glycolysis |
| | |TCA Cycle |
| | |Shunt |
| | |Pyruvate Dehydrogenase Enzyme System |
|Pantothenic Acid |Coenzyme A |Has a sulfhydryl group to activate acyl |
| | |groups |
| | |Reacts with acetic acid to produce acetyl |
| | |CoA |
|Riboflavin |FAD |A redox dinucleotide |
| |(FADH = reduced form) |TCA Cycle |
| | |Pyruvate Dehydrogenase Enzyme System |
|Thiamin |Thiamin Pyrophosphate (TPP) |Pyruvate Dehydrogenase Enzyme System |
| | |Shunt |
| | |TCA Cycle |
| | |Required to produce Acetyl CoA |
| | |Lack = Beri Beri |
|Biotin | |Carboxylation reactions |
|Pyridoxin (B6) |Pyridoxal Phosphate |Transamination |
|Folic Acid |5,10 methylene H4 Folate |Methyl carrier |
|Cobalamin (B12) |Conjugated Cobalamin |Methyl Transfers |
| | |Odd # FA |
-----------------------
[pic]
[pic]
Dependant Variable
Independent Variable
Oxidized:
• Lose H
• Gain O
Reduced:
• Lose O
• Gain H
................
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