TCA

• The tricarboxylic acid (TCA) cycle, also known as the Krebs cycle, is a common pathway for the final oxidation of all metabolic fuels.
• The TCA cycle has two major functions: energy production and biosynthesis.
• The TCA cycle is involved in catabolic processes and anabolic processes such as Gluconeogenesis, Lipogenesis, and Synthesis of amino acids.
• The TCA cycle is a part of the central pathways of energy metabolism.
• The tricarboxylic acid cycle functions as a common ground for interconversion of fuels and metabolites.
• Biosynthetic reactions proceeding from the TCA cycle require the input of carbons from intermediates other than acetyl-CoA.
• Dihydrolipoyl dehydrogenase transfers electrons from reduced lipoic acid to produce NADH and regenerate the oxidized form of lipoic acid.
• The PDH Reaction involves E1: pyruvate dehydrogenase, which removes CO2 and transfers the remaining acetyl group to the enzyme bound coenzyme thiamine pyrophosphate E-1A.
• The complex functions as a unit consisting of three principal enzymes: pyruvate dehydrogenase, dihydrolipoyl transacetylase, and dihydrolipoyl dehydrogenase.
• Deficiencies of thiamine or niacin can cause serious central nervous system problems because brain cells are unable to produce sufficient ATP for proper function if pyruvate dehydrogenase is inactive.
• The PDH Complex is a multi-enzyme complex that allows for efficient direct transfer of product from one enzyme to the next.
• Citrate rearranges to isocitrate in a reaction catalysed by acotinase.
• Dihydrolipoyl transacetylase transfers the acetyl CoA to its lipoic acids coenzyme with a reduction of the lipoic acid.
• The PDH Enzyme Complex functions by linking glycolysis and the TCA cycle, oxidizing pyruvate to CO2, and acetyl CoA (substrate for the TCA cycle).
• The PDH Reaction is highly regulated and is activated by pyruvate, ADP and Ca ions, and inhibited by increases in the ratio (NADH/NAD+) and by the product acetyl-CoA.
• PDH regulation involves product inhibition, availability of substrate, and covalent modification.
• Oxaloacetate is first condensed with an acetyl group from acetyl coenzyme A (CoA), and then Oxaloacetate is regenerated as the cycle is completed.
• Genetic defects in PDH can result in decrease or complete loss of activity, causing symptoms such as lactic acidosis, neurological disorders, and early death.
• The TCA Cycle involves the reactions of citrate, isocitrate, and α-ketoglutarate.
• Four pairs of electrons are transferred during one turn of the cycle: three pairs of electrons reducing three NAD+ to NADH one pair reducing FAD to FADH2.
• Isocitrate dehydrogenase is the major regulatory enzyme of the TCA cycle.
• This reaction involves simultaneous coupling of GDP and Pi to form GTP, a substrate-level phosphorylation with energy being conserved in the form of GTP.
• Malate to oxaloacetate is catalyzed by malate dehydrogenase.
• Conversion of alfa-ketoglutarate to succinyl CoA, CO2, and NADH is catalyzed by an analog to PDH complex, which is made up of three enzyme activities with similar array of activities and coenzymes requirements.
• The number of ATP molecules produced from the oxidation of one molecule of acetyl CoA (using both substrate-level and oxidative phosphorylation) is 2.
• This is a dual reaction that combines decarboxylation to release CO2 and oxidation, with capture of the electrons in NADH.
• Succinate dehydogenase (SDH), tightly associated with inner mitochondrial membrane reduction, catalyzes the conversion of succinate to fumarate with the transfer of electrons to FAD to form FADH2.
• Isocitrate dehydrogenase converts isocitrate to alfa-ketoglutarate.
• Succinyl CoA is hydrolyzed to succinate and CoA by Succinate thiokinase.
• OAA is then able to react with another acetyl CoA molecule to begin the cycle again.
• The net reaction of the TCA cycle is: Acetyl-CoA + 3NAD+ + FAD + GDP + Pi + 2H2O 2CO2 + 3NADH + FADH2 + GTP + 2H+ + + HSCoA.
• Another NADH is formed in the synthesis of OAA from malate.
• Fumarate to malate which is converted to OAA, completing the cycle, is catalyzed by fumarase.
• Two carbon atoms enter the cycle as acetyl CoA and leave as 2 CO2.
• Niacin, also known as Vitamin B3, exists in NAD and is a coenzyme of the alfa ketoglutarate dehyrogenase enzyme system, isocitrate dehydrogenase, and malate dehyrogenase.
• Inhibitors of the TCA cycle include fluoroacetate, aconitase, arsenite, and malonate.
• The TCA cycle is controlled by the regulation of several enzyme activities.
• The most important of these regulated enzymes are those that catalyze reactions with highly negative Δ G 0 : citrate synthase, isocitrate dehydrogenase (rate limiting step), α-ketoglutarate dehydrogenase complex.
• Riboflavin, also known as Vitamin B2, is the prosthetic group of succinate dehydrogenase.
• Pantothenic acid is a component of Coenzyme A (CoASH) and CoASH is the cofactor of active carboxylic acid residues, such as acetyl-CoA and succinyl-CoA.