Krebs’ Cycle

 

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Krebs’ Cycle

Definition

The citric acid cycle (CAC) also known as the Tricarboxylic acid cycle (TCA cycle) or the Krebs cycle is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins.   

Introduction

The TCA cycle is used by organisms that respire (as opposed to organisms that ferment) to generate energy, either by anaerobic respiration or aerobic respiration. In addition, the cycle provides precursors of certain amino acids, as well as the reducing agent NADH, that are used in numerous other reactions. Even though it is called as a 'cycle', at least three segments of the citric acid cycle have been observed.

The name of this metabolic pathway is derived from the citric acid (a Tricarboxylic acid, often called citrate, as the ionized form predominates at biological pH that is consumed and then regenerated by this sequence of reactions to complete the cycle. The cycle consumes acetate (in the form of acetyl-CoA) and water, reduces NAD⁺ to NADH, releasing carbon dioxide. The NADH generated by the citric acid cycle is fed into the oxidative Phosphorylation (electron transport) pathway. The net result of these two closely linked pathways is the oxidation of nutrients to produce usable chemical energy in the form of ATP.

In eukaryotic cells, the citric acid cycle occurs in the matrix of the mitochondrion. The overall yield of energy-containing compounds from the TCA cycle is three NADH, one FADH₂, and one GTP and a total 38ATP.

Over view- One of the primary sources of acetyl-CoA is from the breakdown of sugar by Glycolysis which yield pyruvate that in turn is decarboxylated by the pyruvate dehydrogenase complex generating acetyl-CoA according to the following reaction scheme:

CH₃C (=O)C(=O)O⁻pyruvate + HSCoA + NAD⁺ → CH₃C(=O)SCoAacetyl-CoA + NADH + CO₂

The product of this reaction, acetyl-CoA, is the starting point for the citric acid cycle. Acetyl-CoA may also be obtained from the oxidation of fatty acids. Above is a schematic outline of the cycle –

Regulation- Its regulating factors are given below-

1. Allosterical regulation by metabolites-The regulation of the citric acid cycle is largely determined by substrate availability and inhibitory influences exerted by its own intermediates and products.

2. Citrate- It inhibits phosphofructokinase. This prevents a constant high rate of flux when there is an accumulation of citrate and a decrease in substrate for the enzyme.

3. Regulation by calcium- Calcium regulates various enzymes used in the citric acid cycle.

4. Transcriptional regulation-There is an important link between intermediates of the citric acid cycle and the regulation of hypoxia-inducible factors (HIF). HIF plays a role in the regulation of oxygen homeostasis, and is a transcription factor that targets glucose utilization in the cell.

Energy Yield

The theoretical maximum yield of ATP through oxidation of one molecule of glucose in Glycolysis, citric acid cycle, and oxidative Phosphorylation is 38 (assuming 3 molar equivalents of ATP per equivalent NADH and 2 ATP per FADH₂). Two equivalents of NADH and four equivalents of ATP are generated in Glycolysis, which takes place in the cytoplasm. Transport of two of these equivalents of NADH into the mitochondria consumes two equivalents of ATP, thus reducing the net production of ATP to 36. Furthermore, inefficiencies in oxidative Phosphorylation due to leakage of protons across the mitochondrial membrane and slippage of the ATP synthase/proton pump commonly reduces the ATP yield from NADH and FADH₂ to less than the theoretical maximum yield. The observed yields are, therefore, closer to ~2.5 ATP per NADH and ~1.5 ATP per FADH₂, further reducing the total net production of ATP to approximately 30. An assessment of the total ATP yield with newly revised proton-to-ATP ratios provides an estimate of 29.85 ATP per glucose molecule.