The Citric Acid Cycle Plays A Pivotal Role In Metabolism

The citric acid cycle is not only a pathway for oxidation of two-carbon units—it is also a major pathway for interconversion of metabolites arising from transamination and deamination of amino acids. It also provides the substrates for amino acid synthesis by transamination, as well as for gluconeogenesis and fatty acid synthesis. Because it functions in both oxidative and synthetic processes, it is amphibolic (Figure 16-4).

The Citric Acid Cycle Takes Part in Gluconeogenesis, Transamination, & Deamination

All the intermediates of the cycle are potentially gluco-genic, since they can give rise to oxaloacetate and thus net production of glucose (in the liver and kidney, the organs that carry out gluconeogenesis; see Chapter 19). The key enzyme that catalyzes net transfer out of the cycle into gluconeogenesis is phosphoenolpyruvate carboxykinase, which decarboxylates oxaloacetate to phosphoenolpyruvate, with GTP acting as the donor phosphate (Figure 16-4).

Net transfer into the cycle occurs as a result of several different reactions. Among the most important of such anaplerotic reactions is the formation of oxaloacetate by the carboxylation of pyruvate, catalyzed by pyruvate carboxylase. This reaction is important in maintaining an adequate concentration of oxaloacetate for the condensation reaction with acetyl-CoA. If acetyl-CoA accumulates, it acts both as an allosteric activator of pyruvate carboxylase and as an inhibitor of pyruvate dehydrogenase, thereby ensuring a supply of oxaloac-etate. Lactate, an important substrate for gluconeogene-sis, enters the cycle via oxidation to pyruvate and then carboxylation to oxaloacetate.

Aminotransferase (transaminase) reactions form pyruvate from alanine, oxaloacetate from aspartate, and a-ketoglutarate from glutamate. Because these reactions are reversible, the cycle also serves as a source of carbon skeletons for the synthesis of these amino acids. Other amino acids contribute to gluconeogenesis because their carbon skeletons give rise to citric acid cycle

Hydroxyproline

Serine

Cysteine

Threonine

Glycine

Tryptophan

Glucose

Tyrosine Phenylalanine

Acetyl-CoA

Isoleucine | Methionine Valine J

Propionate

Histidine Proline Glutamine Arginine

Acetyl-CoA

Hydroxyproline

Serine

Cysteine

Threonine

Glycine

Tryptophan

Glucose

Tyrosine Phenylalanine

Isoleucine | Methionine Valine J

Propionate

Glutamate

Figure 16-4. Involvement of the citric acid cycle in transamination and gluconeo-genesis. The bold arrows indicate the main pathway of gluconeogenesis.

Glutamate

Figure 16-4. Involvement of the citric acid cycle in transamination and gluconeo-genesis. The bold arrows indicate the main pathway of gluconeogenesis.

intermediates. Alanine, cysteine, glycine, hydroxyproline, serine, threonine, and tryptophan yield pyruvate; arginine, histidine, glutamine, and proline yield a-ke-toglutarate; isoleucine, methionine, and valine yield succinyl-CoA; and tyrosine and phenylalanine yield fu-marate (Figure 16-4).

In ruminants, whose main metabolic fuel is short-chain fatty acids formed by bacterial fermentation, the conversion of propionate, the major glucogenic product of rumen fermentation, to succinyl-CoA via the methylmalonyl-CoA pathway (Figure 19-2) is especially important.

The Citric Acid Cycle Takes Part in Fatty Acid Synthesis (Figure 16-5)

Acetyl-CoA, formed from pyruvate by the action of pyruvate dehydrogenase, is the major building block for long-chain fatty acid synthesis in nonruminants. (In ruminants, acetyl-CoA is derived directly from acetate.)

Pyruvate dehydrogenase is a mitochondrial enzyme, and fatty acid synthesis is a cytosolic pathway, but the mitochondrial membrane is impermeable to acetyl-CoA. Acetyl-CoA is made available in the cytosol from citrate synthesized in the mitochondrion, transported into the cytosol and cleaved in a reaction catalyzed by ATP-citrate lyase.

Regulation of the Citric Acid Cycle Depends Primarily on a Supply of Oxidized Cofactors

In most tissues, where the primary role of the citric acid cycle is in energy-yielding metabolism, respiratory control via the respiratory chain and oxidative phos-phorylation regulates citric acid cycle activity (Chapter 14). Thus, activity is immediately dependent on the supply of NAD+, which in turn, because of the tight coupling between oxidation and phosphorylation, is dependent on the availability of ADP and hence, ulti-

Pyruvate -

i Glucose

Fatty acids

Pyruvate -

i Glucose

Fatty acids

Figure 16-5. Participation of the citric acid cycle in fatty acid synthesis from glucose. See also Figure 21-5.

mately, on the rate of utilization of ATP in chemical and physical work. In addition, individual enzymes of the cycle are regulated. The most likely sites for regulation are the nonequilibrium reactions catalyzed by pyruvate dehydrogenase, citrate synthase, isocitrate de-hydrogenase, and a-ketoglutarate dehydrogenase. The dehydrogenases are activated by Ca2+, which increases in concentration during muscular contraction and secretion, when there is increased energy demand. In a tissue such as brain, which is largely dependent on carbohydrate to supply acetyl-CoA, control of the citric acid cycle may occur at pyruvate dehydrogenase. Several enzymes are responsive to the energy status, as shown by the [ATP]/[ADP] and [NADH]/[NAD+] ratios. Thus, there is allosteric inhibition of citrate syn-thase by ATP and long-chain fatty acyl-CoA. Allosteric activation of mitochondrial NAD-dependent isocitrate dehydrogenase by ADP is counteracted by ATP and NADH. The a-ketoglutarate dehydrogenase complex is regulated in the same way as is pyruvate dehydrogenase (Figure 17-6). Succinate dehydrogenase is inhibited by oxaloacetate, and the availability of oxaloacetate, as controlled by malate dehydrogenase, depends on the [NADH]/[NAD+] ratio. Since the Km for oxaloacetate of citrate synthase is of the same order of magnitude as the intramitochondrial concentration, it is likely that the concentration of oxaloacetate controls the rate of citrate formation. Which of these mechanisms are important in vivo has still to be resolved.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

Get My Free Ebook


Post a comment