Cellular Biochemistry Notes



Cellular Biochemistry Notes

Chapter 19 "Lipid Metabolism"

Lipid Digestion, Absorption, and Transport

-Triacylglycerides constitute both ~90% of the dietary lipid and the major form of metabolic energy storage in humans; the

oxidative metabolism of fats yields over twice the energy of an equal weight of dry carbohydrate or protein

-Since triacylglycerols are water insoluble, whereas digestive enzymes are water soluble, triacylglycerol digestion takes place

at lipid-water interfaces; rate of digestion therefore depends on the surface area of the interface and is greatly increased by the emulsifying action of bile acids

-Enzymatic activity of pancreatic lipase greatly increases when it contacts the lipid-water interface, a phenomenon known as

interfacial activation; however, the enzyme does not bind unless it is in complex with pancreatic colipase

-Phospholipids are degraded by pancreatic phospholipase A2, which hydrolytically excises the fatty acid residue at C2 to

yield the corresponding lysophospholipids (powerful detergents); disrupt membranes and can lyse cells

-Bile acids and fatty acid-binding protein facilitate the intestinal absorption of lipids; bile acids not only aid lipid digestion but are essential for the absorption of lipid digestion products; inside intestinal cells, fatty acids form complexes with intestinal fatty acid-binding protein (I-FABP), a cytoplasmic protein which increases the solubility of these water-insoluble substances and protects the cell from their detergent-like effects

Lipids are transported in lipoprotein complexes Fig. 19-5

Dietary Lipids

-The lipid digestion products absorbed by the intestinal mucosa cells are converted to triacylglycerols and cholesterols and then packaged into chylomicrons.

-Triacylglycerols and cholesterols synthesized by the liver are packaged into very low density lipoproteins (VLDL)

-Triacylglycerol components of chylomicrons and VLDL are hydrolyzed to free fatty acids and glycerol in the capillaries of

adipose tissue and skeletal muscle by lipoprotein lipase; in the liver and kidneys, it is further converted to DHAP; VLDLs that have lost fatty acids are LDLs

Adipose Lipids

-Mobilization of triacylglycerols stored in adipose tissue involves hydrolysis to glycerol and free fatty acids by triacylglycerol lipase

-Free fatty acids are released into the bloodstream where they bind to albumin, a soluble protein that comprises about half of

the blood serum protein; rare individuals who suffer from analbuminemia, severely depressed levels of albumin, suffer no

apparent adverse symptoms, their fatty acids are transported in complex with other serum proteins

Fatty Acid Oxidation

-Before fatty acids can be oxidized, they must be "primed" for reaction in an ATP-dependent acylation to form fatty acyl-CoA this process is catalyzed by a family of at least 3 acyl-CoA synthetases; these enzymes catalyze the following reaction:

Fatty acid + CoA + ATP ( ( acyl-CoA + AMP + PPi

-These enzymes are associated with the ER or the outer mitochondrial membrane

Transport across the Mitochondrial Membrane

-A long-chain fatty acyl-CoA cannot directly cross the inner mitochondrial membrane--its acyl portion is first transferred to

carnitine

-Translocation process itself is mediated by a specific carrier protein that transports acyl-carnitine into the mitochondrion

while transporting free carnitine in the opposite direction

Oxidation

-Fatty acids are dismembered through the oxidation of fatty acyl-CoA, a process that occurs in 4 reactions Fig. 19-9

1) Formation of a trans-, double bond through dehydrogenation by the flavoenzyme acyl-CoA dehydrogenase; reoxidized via the electron-transport chain

2) Hydration of the double bond by enoyl-CoA hydratase to form a 3-L-hydroxyacyl-CoA

3)NAD+-dependent dehydrogenation of this -hydroxyacyl-CoA by 3-L-hydroxyacyl-CoA dehydrogenase to form the corresponding -ketoacyl-CoA

4) C--C cleavage in a thiolysis reaction with CoA as catalyzed by -ketoacyl-CoA thiolase (also called thiolase) to form acetyl-CoA and a new acyl-CoA containing 2 less C atoms than the original

-Acyl-CoA dehydrogenase deficiency has fatal consequences such as:

sudden infant death sydrome some 10% are deficient in acyl-CoA

dehydrogenase and the infants can't take the switch from glucose to fatty acid metabolism. Symptoms are hypoglycemia, vomiting, lethargy, encephalopathy, respiratory arrest, seizures, apnea, cardiac arrest, coma, and sudden and unexpected death. Long-term outcomes include developmental and behavioral disability, chronic muscle weakness, failure to thrive, cerebral palsy, and attention deficit disorder

Jamaican vomiting sickness unripe ackee fruit contain hypoglycin A an unusual amino acid that is metabolized to methylenecyclopropyllacetyl-CoA. This compound is a mechanism-based inhibitor of acyl-CoA dehydrogenase

-Fatty acid oxidation is highly exergonic; oxidation of acetyl-CoA via th CAC generates additional FADH2 and NADH which

are reoxidized through oxidative phosphorylation to form ATP

Oxidation of Unsaturated Fatty Acids

-Double bonds in fatty acids of biological origin are cis bonds and occur at three-carbon intervals

-Double bonds at these positions pose problems for the -oxidation pathway and are solved through the action Enoyl-CoA isomerase which converts the cis double bond to the more stable trans form

-Natural substrate for enoyl-CoA hydratase

Oxidation of Odd-Chain Fatty Acids

-Final round of oxidation of these fatty acids forms propionyl-CoA which is converted to succinyl-CoA for entry into the CAC

Peroxisomal Oxidation

-Oxidation of fatty acids occurs in the peroxisome as well as in the mitochondrion; peroxisomal oxidation in animals functions

to shorten very long chain fatty acids so as to facilitate their degradation by the mitochondrial -oxidation system

Ketone Bodies

-Ketogenesis which occurs primarily in liver mitochondria converts acetyl-CoA to acetoacetate or D--hydroxybutyrate;

these compounds together with acetone are referred to as ketone bodies and serve as important metabolic fuels for many

peripheral tissues, particularly heart and skeletal muscles; ketone bodies are water-soluble equivalents of fatty acids

-Brain uses ketone bodies during periods of starvation (Chp 21)

Fatty Acid Biosynthesis

Pathway Overview

-Fatty acid biosynthesis occurs through condensation of C2 units, the reverse of the B-oxidation process; it occurs in the cytosol with the growing fatty acids esterified to acyl-carrier protein (ACP)

-Involves two steps:

1) The ATP-dependent carboxylation of acetyl-CoA by acetyl-CoA carboxylase to form malonyl-CoA (3C)

2) The exergonic decarboxylation of the malonyl group in the condensation reaction catalyzed by fatty acid synthase

Fatty Acid Synthase

-The synthesis of fatty acids from acetyl-CoA and malonyl-CoA involves 7 enzymatic reactions: Fig 19-19, 19-22

-1 & 2 are priming reactions in which the synthase is "loaded" with

the condensation reaction precursors

-3 the condensation reaction--malonyl-ACP is decarboxylated with

the resulting carbanion attacking the acetyl-thioester to form a

ketoacyl-ACP

-4-6 are the reduction and dehydration that convert this ketone to

an alkyl group

Transport of Mitochondrial Acetyl-CoA into the cytosol

-Acetyl-CoA enters the cytosol in the form of citrate via the tricarboxylate transport system; cytosolic ATP-citrate lyase

then catalyzes the reaction. Fig 19-20

Citrate + CoA + ATP acetyl-coA + oxaloacetate + ADP + Pi

-When the need for ATP synthesis is low, this mitochondrial acetyl-CoA may be stored for future use as fat

Elongases and Desaturases

Palmitate (16:0), the normal product of the fatty acid synthase pathway, is the precursor of longer chain saturated and unsaturated

fatty acids through the actions of elongases and desaturases

-Elongases are present in both the mitochondrion and the ER but the mechanisms differ to add or remove carbons

-Unsaturated fatty acids are produced by terminal desaturases

-Linoleic acid must be obtained in the diet and is therefore and essential fatty acid because it is a required precursor of

prostaglandins

Synthesis of Triacylglycerols

-Triacylglycerols are synthesized from fatty acyl-coA esters and glycerol-3-phosphate or dihydroxyacetone phosphate

-The initial step in this process is catalyzed either by glycerol-3-phosphate acyltransferase (in mitochondria or ER) or

dihydroxyacetone phosphate acyltransferase (in ER or peroxisomes)

Regulation of Fatty Acid Metabolism Fig 19-27

-Synthesis and breakdown of glycogen and triacylglycerols concern the whole organism, with its organs and tissues forming an interdependent network connected by the blood stream

-Hormones also regulate the rates of the opposing pathways of lipid metabolism and therefore control whether fatty acids will be oxidized or synthesized; their targets are the regulatory enzymes of fatty acid synthesis and breakdown in specific tissues

-Short term regulation controls occur in a matter of minutes or less; examples include substrate availability, allosteric interactions, and covalent modification

-Long term regulation such as alteration of the amount of enzyme present by changes in the rates of protein synthesis and/or breakdown requires hours or days; starvation and/or regular exercise, by decreasing the glucose concentration in the

blood, change the body's hormone balance--this situation results in long-term increases in the levels of fatty acid oxidation enzymes accompanied by long-term decreases in those of lipid biosynthesis

-Fatty acid oxidation is regulated largely by the concentration of fatty acids in the blood, which is, in turn, controlled by the

hydrolysis rate of triacylglycerols in adipose tissue by hormone-sensitive triacylglycerol lipase; glucagon-insulin ratio is of

prime importance in determining the rate and direction of fatty acid metabolism

Cholesterol Metabolism

-Cholesterol is a vital constituent of cell membranes and the precursor of steroid hormones and bile acids--it is clearly

essential to life, yet its deposition in arteries has been associated with CV disease and stroke; intricate balance between the biosynthesis, utilization, and transport of cholesterol keeps its harmful deposition to a minimum

Cholesterol Biosynthesis

-All of the carbon atoms of cholesterol are derived from acetate that form isoprene units--C5

-HMG (hydroxymethylglutaryl)-CoA is a key cholesterol precursor; HMG-CoA reductase mediates the rate-determining step of cholesterol biosynthesis and is the most elaborately regulated enzyme of this pathway

-Cholesterol is synthsized from HMG-CoA in a 26-step process embedded in the ER membrane

-Cholesterol is transported in the blood and taken up by cells in lipoprotein complexes

-Liver and peripheral tissues have two ways of obtaining cholesterol: either synthesize it from HMG-CoA by the de novo

pathway, or obtain it from the bloodstream by receptor-mediated endocytosis; a small amount of cholesterol also enters the

cells by a non-receptor-mediated pathway

-While LDL transports cholesterol from the liver, cholesterol is transported back to the liver by high density lipoproteins (HDL); surplus cholesterol is disposed of by the liver as bile acids thereby protecting body from an overaccumulation of this water-insoluble substance

Control of cholesterol biosynthesis and transport

3 ways of maintaining cellular cholesterol supply

1) By regulating the activity of HMG-CoA reductase, the enzyme catalyzing the rate-limiting step in the de novo pathway

2) By regulating the rate of LDL receptor synthesis; high intracellular concentrations of cholesterol suppress LDL receptor

synthesis, whereas low cholesterol concentrations stimulate it

3) By regulating the rate of esterification and hence the removal of free cholesterol

Uptake of plasma LDL Fig 19-38

Normal

-Fatty acids are removed from VLDLs leaving LDL, LDL absorbed by receptor mediated endocytosis in liver

Familial Hypercholesterolemia

-genetically defective LDL receptors results in high conc. of LDLs in bloodstream

High Cholesterol Diet

-excess cholesterol eneters the liver cell (in chylomicrons fragments) and suppresses the synthesis of LDL receptors

Control

1) ingestion of resins that bind bile acids and prevent reabsorption. Liver must compensate and convert cholsterol to bile acids

2) inhibitors of HMG- reductase which include compactin, lovastin, pravistin and simvastrin

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