TCA cycle steps and regulation, Exercises of Biochemistry

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TCA CYCLE

STEPS

REGULATION AND

SIGNIFICANCE

Introduction

The citric acid cycle is the central metabolic hub of the cell.  It is the final common pathway for the oxidation of fuel molecule such as amino acids, fatty acids, and carbohydrates. In eukaryotes, the reactions of the citric acid cycle take place inside mitochondria, in contrast with those of glycolysis, which take place in the cytosol.

Overview of the Citric Acid Cycle

• A four- carbon compound (oxaloacetate) condenses with a two-carbon acetyl unit to yield a six-carbon tricarboxylic acid (citrate).
• An isomer of citrate is then oxidatively decarboxylated.
• The resulting five-carbon compound (α-ketoglutarate) also is oxidatively decarboxylated to yield a four carbon compound (succinate).
• Oxaloacetate is then regenerated from succinate.
• Two carbon atoms enter the cycle as an acetyl unit and two carbon atoms leave the cycle in the form of two molecules of carbon dioxide.

Overview of the Citric Acid Cycle o Three hydride ions (hence, six electrons) are transferred to three molecules of nicotinamide adenine dinucleotide (NAD+), whereas one pair of hydrogen atoms (hence, two electrons) are transferred to one molecule of flavin adenine dinucleotide (FAD). o The function of the citric acid cycle is the harvesting of high- energy electrons from carbon fuels.

Reactions of the Citric Acid Cycle

• Step-1 Formation of Citrate- The citric acid cycle begins with the condensation of a four- carbon unit, oxaloacetate, and a two-carbon unit, the acetyl group of acetyl CoA. Oxaloacetate reacts with acetyl CoA and H2O to yield citrate and CoA.
• This reaction, which is an aldol condensation followed by a hydrolysis, is catalyzed by citrate synthase.

Step- 1 - Formation of Citrate Oxaloacetate first condenses with acetyl CoA to form citryl CoA, which is then hydrolyzed to citrate and CoA.

Step- 2 - Formation of Isocitrate Aconitase is an iron-sulfur protein , or nonheme iron protein. It contains four iron atoms that are not incorporated as part of a heme group.

Step- 2 - Formation of Isocitrate (contd.)

• The poison Fluoroacetate is toxic, because fluoroacetyl-CoA condenses with oxaloacetate to form fluorocitrate, which inhibits Aconitase, causing citrate to accumulate.

Step- 3 - Formation of α- Keto Glutarate

Respiratory chain-linked oxidation of isocitrate proceeds almost completely through the NAD

• dependent enzyme.

Step- 4 - Formation of Succinyl Co A The conversion of isocitrate into α- ketoglutarate is followed by a second oxidative decarboxylation reaction, the formation of Succinyl CoA from α-ketoglutarate.

Step- 4 - Formation of Succinyl Co A

• As in the case of pyruvate oxidation, arsenite inhibits the reaction, causing the substrate, α - ketoglutarate, to accumulate.

Step- 5 - Formation of Succinate

• Succinyl CoA is an energy-rich thioester compound
• The cleavage of the thioester bond of succinyl CoA is coupled to the phosphorylation of a purine nucleoside diphosphate, usually GDP.
• This reaction is catalyzed by succinyl CoA synthetase (succinate thiokinase).

Step- 5 - Formation of Succinate

• The GTP formed is used for the decarboxylation of oxaloacetate to phosphoenolpyruvate in gluconeogenesis, and provides a regulatory link between citric acid cycle activity and the withdrawal of oxaloacetate for gluconeogenesis. Nongluconeogenic tissues have only the isoenzyme that uses ADP.

Step- 6 - Formation of Fumarate

• The first dehydrogenation reaction, forming fumarate, is catalyzed by succinate dehydrogenase, which is bound to the inner surface of the inner mitochondrial membrane.
• The enzyme contains FAD and iron-sulfur (Fe:S) protein, and directly reduces ubiquinone in the electron transport chain.