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The citric acid cycle, also known as the tricarboxylic acid (TCA) cycle or Krebs cycle, is a series of chemical reactions used by aerobic organisms to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins. This cycle occurs in the matrix of the mitochondrion in eukaryotic cells and in the cytosol of prokaryotic cells. The citric acid cycle is a key metabolic pathway that connects carbohydrate, fat, and protein metabolism and is responsible for the production of ATP through the oxidative phosphorylation pathway.
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It is believed that components of the citric acid cycle were derived from anaerobic bacteria, and that the TCA cycle itself may have evolved more than once. Theoretically, several alternatives to the TCA cycle exist; however, the TCA cycle appears to be the most efficient. If several TCA alternatives had evolved independently, they all appear to have converged to the TCA cycle. The citric acid cycle is a key metabolic pathway that connects carbohydrate, fat, and protein metabolism. The reactions of the cycle are carried out by eight enzymes that completely oxidize acetate, in the form of acetyl-CoA, into two molecules each of carbon dioxide and water. Through catabolism of sugars, fats, and proteins, the two-carbon organic product acetyl- CoA (a form of acetate) is produced which enters the citric acid cycle. Overview
The reactions of the cycle also convert 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 FADH 2 , and one equivalent each of guanosine diphosphate(GDP) and inorganic phosphate (Pi) into one equivalent of guanosine triphosphate (GTP). The NADH and FADH 2 generated by the citric acid cycle are, in turn, used by the oxidative phosphorylation pathway to generate energy- rich 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 CH^3 C(=O)C(=O)O − pyruvate
→ CH^3 C(=O)SCoA acetyl-CoA
NADH + CO^2
The citric acid 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 CO 2. The carbons lost as CO 2 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 citric acid cycle. Loss of the acetyl-CoA-donated carbons as CO 2 requires several turns of the citric acid cycle. However, because of the role of the citric acid cycle in anabolism, they might not be lost, since many citric acid 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 citric acid cycle, three molecules of NADH are produced.
In addition, electrons from the succinate oxidation step are transferred first to the FAD cofactor of succinate dehydrogenase, reducing it to FADH 2 , and eventually to ubiquinone(Q) in the mitochondrial membrane, reducing it to ubiquinol (QH 2 ) which is a substrate of the electron transfer chain at the level of Complex III. For every NADH and FADH 2 that are produced in the citric acid cycle, 2. and 1.5 ATP molecules are generated in oxidative phosphorylation , respectively. At the end of each cycle, the four-carbon oxaloacetate has been regenerated, and the cycle continues
Efficiency 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 equivalentsof ATP per equivalent NADH and 2 ATP per FADH 2 ). In eukaryotes, two equivalents of NADH are generated in glycolysis, which takes place in the cytoplasm. Transport of these two equivalents 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 FADH 2 to less than the theoretical maximum yield. The observed yields are, therefore, closer to ~2.5 ATP per NADH and ~1. ATP per FADH 2 , 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.
Calcium is also used as a regulator in the citric acid cycle. Calcium levels in the mitochondrial matrix can reach up to the tens of micromolar levels during cellular activation. It activates pyruvate dehydrogenase phosphatase which in turn activates the pyruvate dehydrogenase complex. Calcium also activates isocitrate dehydrogenase and α-ketoglutarate dehydrogenase. [32] This increases the reaction rate of many of the steps in the cycle, and therefore increases flux throughout the pathway. Citrate is used for feedback inhibition, as it inhibits phosphofructokinase, an enzyme involved in glycolysis that catalyses formation of fructose 1,6- bisphosphate, a precursor of pyruvate. This prevents a constant high rate of flux when there is an accumulation of citrate and a decrease in substrate for the enzyme. Recent work has demonstrated 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 angiogenesis, vascular remodeling, glucose utilization, iron transport and apoptosis. HIF is synthesized consititutively, and hydroxylation of at least one of two critical proline residues mediates their interaction with the von Hippel Lindau E3 ubiquitin ligase complex, which targets them for rapid degradation. This reaction is catalysed by prolyl 4-hydroxylases. Fumarate and succinate have been identified as potent inhibitors of prolyl hydroxylases, thus leading to the stabilisation of HIF.
Citric acid cycle intermediates serve as substrates for biosynthetic processes In this subheading, as in the previous one, the TCA intermediates are identified by italics. Several of the citric acid cycle intermediates are used for the synthesis of important compounds, which will have significant cataplerotic effects on the cycle. Acetyl-CoA cannot be transported out of the mitochondrion. To obtain cytosolic acetyl-CoA, citrate is removed from the citric acid cycle and carried across the inner mitochondrial membrane into the cytosol. There it is cleaved by ATP citrate lyase into acetyl-CoA and oxaloacetate. The oxaloacetate is returned to mitochondrion as malate (and then converted back into oxaloacetate to transfer more acetyl-CoA out of the mitochondrion). The cytosolic acetyl-CoA is used for fatty acid synthesis and the production of cholesterol. Cholesterol can, in turn, be used to synthesize the steroid hormones, bile salts, and vitamin D.
To turn them into amino acids the alpha keto-acids formed from the citric acid cycle intermediates have to acquire their amino groups from glutamate in a transamination reaction, in which pyridoxal phosphate is a cofactor. In this reaction the glutamate is converted into alpha-ketoglutarate, which is a citric acid cycle intermediate. The intermediates that can provide the carbon skeletons for amino acid synthesis are oxaloacetate which forms aspartate and asparagine; and alpha-ketoglutarate which forms glutamine, proline, and arginine. Of these amino acids, aspartate and glutamine are used, together with carbon and nitrogen atoms from other sources, to form the purines that are used as the bases in DNA and RNA, as well as in ATP, AMP, GTP, NAD, FAD and CoA. The pyrimidines are partly assembled from aspartate (derived from oxaloacetate). The pyrimidines, thymine, cytosine and uracil, form the complementary bases to the purine bases in DNA and RNA, and are also components of CTP, UMP, UDP and UTP. The majority of the carbon atoms in the porphyrins come from the citric acid cycle intermediate, succinyl-CoA. These molecules are an important component of the hemoproteins, such as hemoglobin, myoglobin and various cytochromes.
