TCA Cycle (Krebs Cycle):
The TCA cycle, also known as the citric acid cycle or the Krebs cycle, is a series of chemical reactions used by all aerobic organisms to generate energy through the oxidation of acetate derived from carbohydrates, fats and proteins into carbon dioxide and chemical energy in the form of adenosine triphosphate (ATP). In addition, the cycle provides precursors of certain amino acids as well as the reducing agent NADH that is used in numerous other biochemical reactions. Its central importance to many biochemical pathways suggests that it was one of the earliest established components of cellular metabolism and may have originated abiogenically.
The name of this metabolic pathway is derived from citric acid (a type of tricarboxylic acid) that is consumed and then regenerated by this sequence of reactions to complete the cycle. In addition, the cycle consumes acetate (in the form of acetyl-CoA) and water, reduces NAD+ to NADH, and produces carbon dioxide as a waste byproduct. The NADH generated by the TCA 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.
Overview of TCA Cycle:
The TCA cycle is a key metabolic pathway that unifies carbohydrate, fat and protein metabolism. The reactions of the cycle are carried out by 8 enzymes that completely oxidize acetyl-CoA into two molecules of carbon dioxide. Through catabolism of sugars, fats, and proteins, a two-carbon organic product acetate in the form of acetyl-CoA is produced which enters the TCA cycle. The reactions of the cycle also converts three equivalents of nicotinamide adenine dinucleotide (NAD+) into three equivalents of reduced NAD+ (NADH), one equivalent of flavin adenine dinucleotide (FAD)into one equivalent of FADH2, and one equivalent each of guanosine diphosphate (GDP) and inorganic phosphate (Pi) into one equivalent of guanosine triphosphate (GTP). The NADH and FADH2 generated by the TCA cycle are in turn used by the oxidative phosphorylation pathway to generate energy-rich adenosine triphosphate (ATP).
One of the primary sources of acetyl-CoA is from the breakdown of sugars by glycolysis which yield pyruvate that in turn is decarboxylated by the enzyme pyruvate dehydrogenase generating acetyl-CoA according to the following reaction scheme:
- CH3C(=O)C(=O)O– (pyruvate) + HSCoA + NAD+ → CH3C(=O)SCoA (acetyl-CoA) + NADH + CO2
The product of this reaction, acetyl-CoA, is the starting point for the TCA cycle. Acetyl-CoA may also be obtained from the oxidation of fatty acids. Below is a schematic outline of the cycle:
- The TCA cycle begins with the transfer of a two-carbon acetyl group from acetyl-CoA to the four-carbon acceptor compound (oxaloacetate) to form a six-carbon compound (citrate).
- The citrate then goes through a series of chemical transformations, losing two carboxyl groups as CO2. The carbons lost as CO2 originate from what was oxaloacetate, not directly from acetyl-CoA. The carbons donated by acetyl-CoA become part of the oxaloacetate carbon backbone after the first turn of the TCA cycle. Loss of the acetyl-CoA-donated carbons as CO2 requires several turns of the TCA cycle. However, because of the role of the TCA cycle in anabolism, they might not be lost, since many TCA cycle intermediates are also used as precursors for the biosynthesis of other molecules.
- Most of the energy made available by the oxidative steps of the cycle is transferred as energy-rich electrons to NAD+, forming NADH. For each acetyl group that enters the TCA cycle, three molecules of NADH are produced.
- Electrons are also transferred to the electron acceptor Q, forming QH2.
- At the end of each cycle, the four-carbon oxaloacetate has been regenerated, and the cycle continues.
References for TCA Cycle (Krebs Cycle):