All the intermediates of the cycle are potentially glucogenic, since they can give rise to oxaloacetate, and hence production of glucose (in the liver and kidney, which carry out gluconeogenesis). The key enzyme that catalyzes transfer out of the cycle into gluconeogenesis is phosphoenol pyruvate carboxykinase, which catalyzes the decarboxylation of oxaloacetate to phosphoenolpyruvate, with GTP acting as the phosphate donor . The GTP required for this reaction is provided by the GDP-dependent isoenzyme of succinate thiokinase. This ensures that oxaloacetate will not be withdrawn from the cycle for gluconeogenesis unless GTP was supplied. Otherwise this would lead to depletion of citric acid cycle intermediates, and hence reduced generation of ATP.

Net transfer into the cycle (ie, anaplerosis) occurs as a result of several reactions. Among the most important of such anaplerotic reactions is the formation of oxaloacetate by the carboxylation of pyruvate, catalyzed by pyruvate carboxylase (see Figure 16–4). This reaction is important in maintaining an adequate concentration of oxaloacetate for the condensation reaction with acetyl-CoA. If acetyl-CoA accumulates, it acts as both an allosteric activator of pyruvate carboxylase and an inhibitor of pyruvate dehydrogenase, thereby ensuring a supply of oxaloacetate. Lactate, an important substrate for gluconeogenesis, enters the cycle via oxidation to pyruvate and then carboxylation to oxaloacetate. Glutamate and glutamine are important anaplerotic substrates. They yield α-ketoglutarate as a result of the reactions catalyzed by glutaminase and glutamate dehydrogenase. Transamination of aspartate leads directly to the formation of oxaloacetate, and a variety of compounds that are metabolized can yield propionyl CoA, which can be carboxylated and isomerized to succinyl CoA, are also important anaplerotic substrates.

Aminotransferase(transaminase) reactions form pyruvate from alanine, oxaloacetate from aspartate, and α-ketoglutarate from glutamate. Because these reactions are reversible, the cycle also serves as a source of carbon skeletons (ie, cataplerosis) for the synthesis of these amino acids. Other amino acids contribute to gluconeogenesis because their carbon skeletons give rise to citric acid cycle intermediates. Alanine, cysteine, glycine, hydroxyproline, serine, threonine, and tryptophan yield pyruvate; arginine, histidine, glutamine, and proline yield α-ketoglutarate; isoleucine, methionine, and valine yield succinyl-CoA; tyrosine and phenylalanine yield fumarate ( Figure 1).

Fig1. Involvement of the citric acid cycle in transamination and gluconeogenesis. The bold arrows indicate the main pathway of gluconeogenesis.

The citric acid cycle itself does not provide a pathway for the complete oxidation of the carbon skeletons of amino acids that give rise to intermediates such as α-ketoglutarate, succinyl CoA, fumarate, and oxaloacetate, because this results in an increase in the amount of oxaloacetate. For complete oxidation to occur a cataplerotic route has to be used. Oxaloacetate must leave the cycle to undergo phosphorylation and carboxylation to phosphoenolpyruvate (at the expense of GTP), then be dephosphorylated to form pyruvate (catalyzed by pyruvate kinase). Pyruvate can then undergo oxidative decarboxylation to acetyl-CoA (catalyzed by pyruvate dehydrogenase).

In ruminants, main metabolic fuel is short-chain fatty acids formed by bacterial fermentation and the formation of propionate. Propionate is the major glucogenic product of rumen fermentation. It enters the cycle at succinyl-CoA via the methylmalonyl-CoA pathway  to form glucose via gluconeogenesis.

مواضيع ذات صلة

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

The Flux Through Metabolic Pathways Must be Regulated In A Concerted Manner

Metabolic Pathways at The Organ & Cellular Level

Pathways To Process The Major Products Of our Diet