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 phosphorylation regulates citric acid cycle activity . Thus, cycle 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, ultimately on the utilization of ATP in chemical and physical work. Thus as ATP usage increases (eg, muscle contraction) this will generate ADP to help drive the cycle. If ATP demand is low the cycle will slow down to match the demand. In addition, individual enzymes of the cycle are regulated. In general these regulatory events help to couple rapid changes in energy demand with citric acid cycle flux. The main sites for regulation are the nonequilibrium reactions catalyzed by pyruvate dehydrogenase, citrate synthase, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase. The dehydrogenases are activated by Ca2+, which increases in concentration during contraction of muscle and during secretion by other tissues, when there is increased energy demand. In a tissue such as brain, which is largely dependent on glucose to supply acetyl-CoA, control of the citric acid cycle may occur at pyruvate dehydrogenase.

Several enzymes are also responsive to the energy status as reflected by the [ATP]/[ADP] and [NADH]/[NAD+] ratios. Thus, there is allosteric inhibition of citrate synthase 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 α-ketoglutarate dehydrogenase complex is regulated in the same way as is pyruvate dehydrogenase . Succinate dehydrogenase is inhibited by oxaloacetate, and the availability of oxaloacetate is controlled by malate dehydrogenase and depends on the [NADH]/[NAD+] ratio. Since the K_m of citrate synthase for oxaloacetate 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.

Hyperammonemia, as occurs in advanced liver disease and a number of (rare) genetic diseases of amino acid metabolism, leads to loss of consciousness, coma and convulsions, and may be fatal. This is largely because of the withdrawal (cataplerosis) of α-ketoglutarate to form glutamate (catalyzed by glutamate dehydrogenase) and then glutamine (catalyzed by glutamine synthetase) from the citric acid cycle, which is not matched by anaplerosis. It lowers concentrations of all citric acid cycle inter mediates, citric acid cycle flux, and the generation of ATP. The equilibrium of glutamate dehydrogenase is finely poised, and the direction of reaction depends on the ratio of NAD+:NADH and the concentration of ammonium ions, which is elevated in liver disease. In addition, ammonia inhibits α-ketoglutarate dehydrogenase, and possibly also pyruvate dehydrogenase further decreasing citric acid cycle flux.

مواضيع ذات صلة

Glycolysis Can Function Under Anaerobic Conditions

The Citric Acid Cycle Takes Part in Fatty Acid Synthesis

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

Reactions of The Citric Acid Cycle Generate Reducing Equivalents & CO2

The Citric Acid Cycle Provides Substrates for The Respiratory Chain

Carbohydrates Occur in Cell Membranes & in Lipoproteins

Dyslipidemia and Cardiovascular Risk

Lipoprotein and Lipid Metabolism

Biomedically, Glucose is the Most Important Monosaccharide

Saccharides are Aldehyde or Ketone Derivatives of Polyhydric Alcohols

A Supply of Oxidizable Fuel is Provided in Both The Fed & Fasting States

Many Metabolic Fuels are Interconvertible