Editing Citric acid cycle (section)

== Major metabolic pathways converging on the citric acid cycle ==
Several [[catabolic]] pathways converge on the citric acid cycle. Most of these reactions add intermediates to the citric acid cycle, and are therefore known as [[anaplerotic reactions]], from the Greek meaning to "fill up". These increase the amount of acetyl CoA that the cycle is able to carry, increasing the [[Mitochondrion|mitochondrion's]] capability to carry out respiration if this is otherwise a limiting factor. Processes that remove intermediates from the cycle are termed "cataplerotic" reactions.<ref>{{Cite journal|last1=Owen|first1=Oliver E.|last2=Kalhan|first2=Satish C.|last3=Hanson|first3=Richard W.|date=2002|title=The Key Role of Anaplerosis and Cataplerosis for Citric Acid Cycle Function|url=|journal=Journal of Biological Chemistry|volume=277|issue=34|pages=30409–30412|doi=10.1074/jbc.r200006200|pmid=12087111|doi-access=free}}</ref>

In this section and in the next, the citric acid cycle intermediates are indicated in ''italics'' to distinguish them from other substrates and end-products.

[[Pyruvate]] molecules produced by [[glycolysis]] are [[active transport|actively transported]] across the inner [[Mitochondrion|mitochondrial]] membrane, and into the matrix. Here they can be [[Redox|oxidized]] and combined with [[coenzyme A]] to form CO<sub>2</sub>, ''[[acetyl-CoA]]'', and [[NADH]], as in the normal cycle.<ref name=Voet>{{cite book|vauthors=Voet D, Voet JG, Pratt CW|title=Fundamentals of Biochemistr|edition=2nd|publisher=John Wiley and Sons, Inc.|year=2006|pages=[https://archive.org/details/fundamentalsofbi00voet_0/page/547 547, 556]|isbn=978-0-471-21495-3|url=https://archive.org/details/fundamentalsofbi00voet_0/page/547}}</ref>

However, it is also possible for pyruvate to be [[carboxylated]] by [[pyruvate carboxylase]] to form ''oxaloacetate''. This latter reaction "fills up" the amount of ''oxaloacetate'' in the citric acid cycle, and is therefore an anaplerotic reaction, increasing the cycle's capacity to metabolize ''acetyl-CoA'' when the tissue's energy needs (e.g. in [[striated muscle tissue|muscle]]) are suddenly increased by activity.<ref name=stryer>{{cite book|vauthors=Stryer L|title= Biochemistry|chapter= Citric acid cycle|edition= Fourth|location= New York|publisher= W. H. Freeman and Company|date= 1995|pages= 509–527, 569–579, 614–616, 638–641, 732–735, 739–748, 770–773|isbn=978-0-7167-2009-6}}</ref>

In the citric acid cycle all the intermediates (e.g. ''[[Citric acid|citrate]]'', ''iso-citrate'', ''[[Alpha-Ketoglutaric acid|alpha-ketoglutarate]]'', ''[[Succinic acid|succinate]]'', ''[[Fumaric acid|fumarate]]'', ''[[Malic acid|malate]]'', and ''[[Oxaloacetic acid|oxaloacetate]]'') are regenerated during each turn of the cycle. Adding more of any of these intermediates to the mitochondrion therefore means that that additional amount is retained within the cycle, increasing all the other intermediates as one is converted into the other. Hence the addition of any one of them to the cycle has an anaplerotic effect, and its removal has a cataplerotic effect. These anaplerotic and cataplerotic reactions will, during the course of the cycle, increase or decrease the amount of ''oxaloacetate'' available to combine with ''acetyl-CoA'' to form ''citric acid''. This in turn increases or decreases the rate of [[Adenosine triphosphate|ATP]] production by the mitochondrion, and thus the availability of ATP to the cell.<ref name=stryer />

''[[Acetyl-CoA]]'', on the other hand, derived from pyruvate oxidation, or from the [[beta-oxidation]] of [[fatty acids]], is the only fuel to enter the citric acid cycle. With each turn of the cycle one molecule of ''acetyl-CoA'' is consumed for every molecule of ''oxaloacetate'' present in the mitochondrial matrix, and is never regenerated. It is the oxidation of the acetate portion of ''acetyl-CoA'' that produces CO<sub>2</sub> and water, with the energy thus released captured in the form of ATP.<ref name=stryer /> The three steps of beta-oxidation resemble the steps that occur in the production of oxaloacetate from succinate in the TCA cycle. Acyl-CoA is oxidized to trans-Enoyl-CoA while FAD is reduced to FADH<sub>2</sub>, which is similar to the oxidation of succinate to fumarate. Following, [[Trans-2-enoyl-CoA reductase (NADPH)|trans-enoyl-CoA]] is hydrated across the double bond to beta-hydroxyacyl-CoA, just like fumarate is hydrated to malate. Lastly, beta-hydroxyacyl-CoA is oxidized to beta-ketoacyl-CoA while NAD+ is reduced to NADH, which follows the same process as the oxidation of malate to [[Oxaloacetic acid|oxaloacetate]].<ref>{{Cite book|title=Biochemistry|vauthors=Garrett RH, Grisham CM|date=2013|publisher=Brooks/Cole, Cengage Learning|isbn=978-1-133-10629-6|edition=5th|location=Belmont, CA|pages=623–625, 771–773|oclc=777722371}}</ref>

In the liver, the carboxylation of [[cytosol]]ic pyruvate into intra-mitochondrial ''oxaloacetate'' is an early step in the [[gluconeogenesis|gluconeogenic]] pathway which converts [[lactic acid|lactate]] and de-aminated [[alanine]] into glucose,<ref name=Voet /><ref name=stryer /> under the influence of high levels of [[glucagon]] and/or [[epinephrine]] in the blood.<ref name=stryer /> Here the addition of ''oxaloacetate'' to the mitochondrion does not have a net anaplerotic effect, as another citric acid cycle intermediate (''malate'') is immediately removed from the mitochondrion to be converted into cytosolic oxaloacetate, which is ultimately converted into glucose, in a process that is almost the reverse of [[glycolysis]].<ref name=stryer />

In [[protein catabolism]], [[protein]]s are broken down by [[protease]]s into their constituent amino acids. Their carbon skeletons (i.e. the de-aminated amino acids) may either enter the citric acid cycle as intermediates (e.g. ''alpha-ketoglutarate'' derived from glutamate or glutamine), having an anaplerotic effect on the cycle, or, in the case of [[leucine]], [[isoleucine]], [[lysine]], [[phenylalanine]], [[tryptophan]], and [[tyrosine]], they are converted into ''acetyl-CoA'' which can be burned to CO<sub>2</sub> and water, or used to form [[ketone bodies]], which too can only be burned in tissues other than the liver where they are formed, or excreted via the urine or breath.<ref name=stryer /> These latter amino acids are therefore termed "ketogenic" amino acids, whereas those that enter the citric acid cycle as intermediates can only be cataplerotically removed by entering the gluconeogenic pathway via ''malate'' which is transported out of the mitochondrion to be converted into cytosolic oxaloacetate and ultimately into [[glucose]]. These are the so-called "glucogenic" amino acids. De-aminated alanine, cysteine, glycine, serine, and threonine are converted to pyruvate and can consequently either enter the citric acid cycle as ''oxaloacetate'' (an anaplerotic reaction) or as ''acetyl-CoA'' to be disposed of as CO<sub>2</sub> and water.<ref name=stryer />

In [[fat catabolism]], [[triglyceride]]s are [[hydrolysis|hydrolyzed]] to break them into [[fatty acid]]s and [[glycerol]]. In the liver the glycerol can be converted into glucose via [[dihydroxyacetone phosphate]] and [[glyceraldehyde-3-phosphate]] by way of [[gluconeogenesis]]. In skeletal muscle, glycerol is used in [[glycolysis]] by converting glycerol into [[Glycerol 3-phosphate|glycerol-3-phosphate]], then into [[dihydroxyacetone phosphate]] (DHAP), then into glyceraldehyde-3-phosphate.<ref>{{cite journal|vauthors=van Hall G, Sacchetti M, Rådegran G, Saltin B|title=Human skeletal muscle fatty acid and glycerol metabolism during rest, exercise and recovery|journal=The Journal of Physiology|volume=543|issue=Pt 3|pages=1047–1058|date=September 2002|pmid=12231658|pmc=2290548|doi=10.1113/jphysiol.2002.023796}}</ref>

In many tissues, especially heart and skeletal [[muscle tissue]], [[fatty acid]]s are broken down through a process known as [[beta oxidation]], which results in the production of mitochondrial ''acetyl-CoA'', which can be used in the citric acid cycle. [[Beta oxidation]] of [[fatty acid]]s with an odd number of [[methylene bridge]]s produces [[propionyl-CoA]], which is then converted into ''[[succinyl-CoA]]'' and fed into the citric acid cycle as an anaplerotic intermediate.<ref name="pmid2647392">{{cite journal|vauthors=Halarnkar PP, Blomquist GJ|title=Comparative aspects of propionate metabolism|journal=Comparative Biochemistry and Physiology. B, Comparative Biochemistry|volume=92|issue=2|pages=227–31|year=1989|pmid=2647392|doi=10.1016/0305-0491(89)90270-8}}</ref>

The total energy gained from the complete breakdown of one (six-carbon) molecule of glucose by [[glycolysis]], the formation of 2 ''acetyl-CoA'' molecules, their catabolism in the citric acid cycle, and oxidative phosphorylation equals about 30 [[Adenosine triphosphate|ATP molecules]], in [[eukaryote]]s. The number of ATP molecules derived from the beta oxidation of a 6 carbon segment of a fatty acid chain, and the subsequent [[Redox|oxidation]] of the resulting 3 molecules of [[Acetyl-CoA carboxylase|''acetyl-CoA'' is]] 40.{{Citation needed|date=June 2020}}