Editing Citric acid cycle (section)

== Regulation ==
'''Allosteric regulation by metabolites'''. The regulation of the citric acid cycle is largely determined by product inhibition and substrate availability. If the cycle were permitted to run unchecked, large amounts of [[Metabolism|metabolic]] energy could be wasted in overproduction of reduced coenzyme such as NADH and ATP. The major eventual substrate of the cycle is ADP which gets converted to ATP. A reduced amount of ADP causes accumulation of precursor NADH which in turn can inhibit a number of enzymes. NADH, a product of all dehydrogenases in the citric acid cycle with the exception of [[succinate dehydrogenase]], inhibits [[pyruvate dehydrogenase]], [[isocitrate dehydrogenase]], [[Alpha-ketoglutarate dehydrogenase|α-ketoglutarate dehydrogenase]], and also [[citrate synthase]]. [[Acetyl-coA]] inhibits [[pyruvate dehydrogenase]], while [[succinyl-CoA]] inhibits alpha-ketoglutarate dehydrogenase and [[citrate synthase]]. When tested in vitro with TCA enzymes, '''ATP''' inhibits [[citrate synthase]] and [[Alpha-ketoglutarate dehydrogenase|α-ketoglutarate dehydrogenase]]; however, ATP levels do not change more than 10% in vivo between rest and vigorous exercise. There is no known [[allosteric]] mechanism that can account for large changes in reaction rate from an allosteric effector whose concentration changes less than 10%.<ref name="Voet_2004">{{Cite book|vauthors=Voet D, Voet JG|year=2004|title=Biochemistry|edition=3rd|publisher=John Wiley & Sons, Inc.|location=New York|page=615}}</ref>

'''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.<ref>{{Cite book|last1=Nelson|first1=David L.|title=Lehninger principles of biochemistry|last2=Cox|first2=Michael M.|last3=Hoskins|first3=Aaron A.|last4=Lehninger|first4=Albert L.|date=2021|publisher=Macmillan International, Higher Education|isbn=978-1-319-22800-2|edition=Eighth|location=New York, NY}}</ref>

'''Regulation by calcium'''. 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.<ref>{{cite journal|vauthors=Ivannikov MV, Macleod GT|title=Mitochondrial free Ca²⁺ levels and their effects on energy metabolism in Drosophila motor nerve terminals|journal=Biophysical Journal|volume=104|issue=11|pages=2353–61|date=June 2013|pmid=23746507|pmc=3672877|doi=10.1016/j.bpj.2013.03.064|bibcode=2013BpJ...104.2353I}}</ref> It activates [[pyruvate dehydrogenase phosphatase]] which in turn activates the [[pyruvate dehydrogenase complex]]. Calcium also activates [[isocitrate dehydrogenase]] and [[Alpha-ketoglutarate dehydrogenase|α-ketoglutarate dehydrogenase]].<ref name="pmid171557">{{cite journal|vauthors=Denton RM, Randle PJ, Bridges BJ, Cooper RH, Kerbey AL, Pask HT, Severson DL, Stansbie D, Whitehouse S|title=Regulation of mammalian pyruvate dehydrogenase|url=https://docksci.com/regulation-of-mammalian-pyruvate-dehydrogenase_5d7f3a44097c47da4c8b456f.html|journal=Molecular and Cellular Biochemistry|volume=9|issue=1|pages=27–53|date=October 1975|pmid=171557|doi=10.1007/BF01731731|s2cid=27367543}}</ref> This increases the reaction rate of many of the steps in the cycle, and therefore increases flux throughout the pathway.{{cn|date=May 2023}}

'''Transcriptional regulation'''. There is a link between intermediates of the citric acid cycle and the regulation of [[hypoxia-inducible factors]] ([[HIF1A|HIF]]). HIF plays a role in the regulation of oxygen [[homeostasis]], and is a transcription factor that targets [[angiogenesis]], [[Vascular remodelling in the embryo|vascular remodeling]], [[glucose]] utilization, iron transport and [[apoptosis]]. HIF is synthesized constitutively, 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 hydroxylase|prolyl 4-hydroxylases]]. Fumarate and succinate have been identified as potent inhibitors of prolyl hydroxylases, thus leading to the stabilisation of HIF.<ref name="pmid17182618">{{cite journal|vauthors=Koivunen P, Hirsilä M, Remes AM, Hassinen IE, Kivirikko KI, Myllyharju J|title=Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: possible links between cell metabolism and stabilization of HIF|journal=The Journal of Biological Chemistry|volume=282|issue=7|pages=4524–32|date=February 2007|pmid=17182618|doi=10.1074/jbc.M610415200|doi-access=free}}</ref>