Learning Objective: Energy Metabolism



Learning Objective: Energy Metabolism

3. Describe the pathways involved in energy metabolism: glycolysis, gluconeogenesis, beta-oxidation, amino acid breakdown, TCA cycle and electron transport chain. For each, include the cellular location, the major organs in which each pathway is active and the effect of starvation or flux of substrates through the pathway.

4. Outline how chemical energy released from the oxidation of food molecules is used to drive ATP synthesis and describe the role of the electron transport chain as an intermediate in this process.

a) Glycolysis – the oxidation of glucose

Glycolysis converts one molecule of glucose into 2 molecules of pyruvate (along with ‘reducing’ equivalents and ATP). In aerobic conditions, the pyruvate will go on to be further metabolised in the TCA cycle, whilst in anaerobic conditions, the pyruvate will be converted into lactate to later take part in gluconeogenesis.

Glycolysis itself is anaerobic.

Depending on which book you look at, Glycolysis consists of 2 or 3 phases. The first phase is the ‘chemical priming’ phase which requires energy in the form of ATP. The second phase yields ATP in 2 of its steps.

Regulation of Glycolysis;

In general, the points of regulation are at IRREVERSIBLE STEPS.

• The three regulatory enzymes in the process are Hexokinase, Phosphofructokinase and pyruvate kinase. This is because their reactions are accompanied by a free energy decrease and therefore the reverse reaction is not spontaneous.

• When blood sugar levels fall (i.e. in starvation), glycolysis is halted in order for gluconeogenesis to take place.

Further regulation;

1. Hormonally mediated

o Insulin and glucagon regulate enzymes of irreversible steps

o Fed state = Glucose = Insulin = Glycolysis

2. Circulating glucose

3. ATP demand

o PFK is inhibited by ATP and activated by ADP/AMP

▪ PFK also regulates by citrate (Signals CAC has sufficient substrate)

• 1,3-bisphosphoglycerate and phosphoenolpyruvate are high energy intermediateries, which also yield ATP.

• Hexokinase is the least important here as G6P can be derived from the breakdown of glycogen and therefore this step can be by-passed in glycolysis.

• Glycolysis takes place in the cytosol of the cell

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GULATION OF GLYCOLYSIS

b) Gluconeogenesis

• Gluconeogenesis is almost the opposite of Glycolysis in its function in the body. The ultimate outcome is to increase blood sugar levels.

• It is the biosynthesis of new glucose (i.e. not from glycogen) from carbon substrates such as lactate, glycerol and amino acids.

• This process takes place in the liver and to a much smaller extent, in the kidneys

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• Lactate is taken back to the liver where it is converted back into pyruvate in the cori cycle so that it can enter into gluconeogenesis

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• All 20 of the amino acids, excepting leucine and lysine, can be degraded to TCA cycle intermediates. This allows the carbon skeletons of the amino acids to be converted to those in oxaloacetate and subsequently into pyruvate, thereby, then being able to participate in gluconeogenesis (see amino acid breakdown)

• The glycerol backbone of lipids can be used for gluconeogenesis. This requires phosphorylation to glycerol-3-phosphate by glycerol kinase and dehydrogenation to dihydroxyacetone phosphate (DHAP) by glyceraldehyde-3-phosphate dehydrogenase (G3PDH).

• Regulation of gluconeogenesis is in direct contract to glycolysis

• Regulation of the activity of PFK-1 and F1,6BPase is the most significant site for controlling the flux toward glucose oxidation or glucose synthesis

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c) Beta-oxidation

• Beta-oxidation is the initial phase of fatty acid oxidation

• This occurs in the mitochondria

• There are quite a few reactions, but the result is that the fatty acid chains are broken into two-carbon acetic acid fragments, and coenzymes are reduced. Acetic acid molecules then fuse with coenzyme A, making acetyl CoA (which can then of course go into the TCA cycle to make energy)

• Entry of Acetyl CoA into the TCA cycle is limited and therefore, some of the acetyl CoA is directed into Ketogenesis

• Remember – fatty acids yield a huge amount of energy, therefore the oxidation of fatty acids often produces an over supply of acetyl CoA

(The term “beta oxidation” reflects the fact that the carbon in the beta (third) position is oxidized during the process and cleavage of the fatty acid in each case occurs between the alpha and beta carbons)

Reactions

1) Acyl-CoA dehydrogenase

2) Enoyl-CoA hydratase

3) 3-hydroxyacyl-CoA dehydrogenase

4) Thiolase

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• b-oxidation continues to cleave 2C units from acetyl group until final turn of the cycle produces 2 Acetyl CoAs

Fate of Acetyl CoA:

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d) amino-acid breakdown

• Amino acids are degraded to acetyl-CoA, either directly or via pyruvate

• Glucogenic amino acids (an amino acid that can be turned to glucose through gluconeogenesis) feed into the TCA cycle or glycolysis.

• Ketogenic amino acids (an AA that can be converted to ketones via ketogenesis) are degraded to acetyl-CoA.

• Obviously, this process is important for gluconeogenesis, which would be utilized in times of starvation.

(Only leucine and lysine are purely ketogenic, whereas some of the larger amino acids, including isoleucine and the three aromatic amino acids phenylalanine, tyrosine, and tryptophan, are both.)

• The Amino Group of the Amino Acids is released as Ammonia.

During amino acid catabolism, the nitrogen of the amino acids produces urea. Initially, however, it is released as ammonia. The most important ammonia-forming reaction, catalysed by glutamate dehydrogenase in liver and other tissues. This oxidative deamination/ reductive amination is freely reversible and can function both in the synthesis and degradation of glutamate. Either nicotinamide adenine dinucleotide (NAD) or nicotinamide adenine dinucleotide phosphate (NADP) can serve as a co-substrate, but NAD+ is mainly used as for glutamate degradation and NADPH is used for its synthesis. The glutamate dehydrogenase reaction implies that glutamate is both nonessential and glucogenic.

Most other amino acids do not form ammonia directly. They transfer their a-amino group to a-ketoglutarate to form glutamate. The enzymes that catalyse these reversible amino group transfers are called transaminases or aminotransferases. The a-amino group is turned into ammonia by successive transamination and oxidative deamination.

Ammonia is detoxified into Urea, which is synthesized in the Urea Cycle

Ammonia is a hazardous waste, which is neurotoxic in low concentrations. Urea is the quickest, most non-toxic way of disposing of this ammonia.

Most amino acid catabolism takes place in the liver, and the liver is also the only important site for ammonia detoxification in the urea cycle.

e) TCA cycle

• Occurs in the mitochondrion

• Final common pathway for oxidation of fuel molecules (Fatty acids, glucose, amino acids)

• May also provide intermediates for synthesis of larger biological molecules

• Defects involving enzymes of cycle are rare

• Essential to sustain life

• Strips e- from fuels via oxidation, thereby producing majority of reduced coenzymes used for generation of ATP in ETC

• 2 major functions

o Energy production

o Biosynthesis

Pneumonic to remember all the intermediaries;

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f) electron transport chain

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KEY ANABOLIC PATHWAYS

• Each step involves REDOX reaction where e- leave components with more –ve reduction potentials

• Each subsequent carrier has more +ve reduction potential or a greater tendency to accept electrons

• Free energy change drives transport of protons from matrix into intermembrane space

Notes:

Key Anabolic Pathways;

|Pathway |Main Substrate(s) |End Products |

|Gluconeogenesis |Lactate, alanine, glycerol |Glucose |

|Glycogen Synthesis |G-1-P |Glycogen |

|Protein Synthesis |Amino Acids |Protein |

|Lipogenesis |Acetyl CoA |Fatty Acids, triglycerides |

Key catabolic Pathways;

|Pathway |Main Substrate(s) |End Products |

|Glycolysis |Glucose |Pyruvate |

|TCA Cycle |Acetyl CoA |ATP, CO2, H2O |

|Glycogenesis |Glycogen |G-1-P, Glucose |

|Lipolysis (Beta-oxidation) |Triglycerides ( Fatty acids |Glycerol, Acetyl CoA |

|Proteolysis |Proteins |Amino Acids ( Glucose |

| | |Amino Acids ( Ketones |

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