Editing Succinic acid (section)

=== Intracellular signaling ===
{{See also|Dioxygenase}}
[[File:Enzymatic inhibition by succinate accumulation.png|thumb|544x544px|Accumulated succinate inhibits dioxygenases, such as histone and DNA demethylases or prolyl hydroxylases, by competitive inhibition. Thus, succinate modifies the epigenic landscape and regulates gene expression.]]
Accumulation of either fumarate or succinate reduces the activity of [[2-oxoglutarate (2OG)-dependent dioxygenases|2-oxoglutarate-dependent dioxygenases]], including histone and DNA [[demethylase]]s, [[Procollagen-proline dioxygenase|prolyl hydroxylases]] and collagen prolyl-4-hydroxylases, through [[competitive inhibition]].<ref>{{Cite journal|last1=Xiao|first1=Mengtao|last2=Yang|first2=Hui|last3=Xu|first3=Wei|last4=Ma|first4=Shenghong|last5=Lin|first5=Huaipeng|last6=Zhu|first6=Honguang|last7=Liu|first7=Lixia|last8=Liu|first8=Ying|last9=Yang|first9=Chen|date=2012-06-15|title=Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors|journal=Genes & Development|volume=26|issue=12|pages=1326–1338|doi=10.1101/gad.191056.112|issn=0890-9369|pmc=3387660|pmid=22677546}}</ref> 2-oxoglutarate-dependent dioxygenases require an iron cofactor to catalyze hydroxylations, desaturations and ring closures.<ref name=Hewitson2005rev>{{Cite journal|last1=Hewitson|first1=K. S.|last2=Granatino|first2=N.|last3=Welford|first3=R. W. D.|last4=McDonough|first4=M. A.|last5=Schofield|first5=C. J.|date=2005-04-15|title=Oxidation by 2-oxoglutarate oxygenases: non-haem iron systems in catalysis and signalling|journal=Philosophical Transactions of the Royal Society of London A: Mathematical, Physical and Engineering Sciences|volume=363|issue=1829|pages=807–828|doi=10.1098/rsta.2004.1540|pmid=15901537|bibcode=2005RSPTA.363..807H|s2cid=8568103}}</ref> Simultaneous to substrate oxidation, they convert [[Alpha-Ketoglutaric acid|2-oxoglutarate]], also known as alpha-ketoglutarate, into succinate and CO<sub>2</sub>. 2-oxoglutarate-dependent dioxygenases bind substrates in a [[Ping pong mechanism|sequential, ordered manner]].<ref name=Hewitson2005rev/> First, 2-oxoglutarate coordinates with an Fe(II) ion bound to a conserved 2-histidinyl–1-aspartyl/glutamyl triad of residues present in the enzymatic center. Subsequently, the primary substrate enters the binding pocket and lastly dioxygen binds to the enzyme-substrate complex. [[Oxidative decarboxylation]] then generates a ferryl intermediate coordinated to succinate, which serves to oxidize the bound primary substrate.<ref name=Hewitson2005rev/> Succinate may interfere with the enzymatic process by attaching to the Fe(II) center first, prohibiting the binding of 2-oxoglutarate. Thus, via enzymatic inhibition, increased succinate load can lead to changes in transcription factor activity and genome-wide alterations in histone and DNA methylation.

==== Epigenetic effects ====
Succinate and fumarate inhibit the [[Tet methylcytosine dioxygenase 2|TET]] (ten-eleven translocation) family of [[5-methylcytosine]] DNA modifying enzymes and the [[(Histone-H3)-lysine-36 demethylase|JmjC domain-containing histone lysine demethylase]] (KDM).<ref name=Yang2013comment>{{Cite journal|last1=Yang|first1=Ming|last2=Pollard|first2=Patrick J.|title=Succinate: A New Epigenetic Hacker|journal=Cancer Cell|volume=23|issue=6|pages=709–711|doi=10.1016/j.ccr.2013.05.015|pmid=23763995|date=10 June 2013|doi-access=free}}</ref> Pathologically elevated levels of succinate lead to hypermethylation, epigenetic silencing and changes in neuroendocrine differentiation, potentially driving cancer formation.<ref name=Yang2013comment/><ref name=Yang2013rev/>

==== Gene regulation ====
Succinate inhibition of [[prolyl hydroxylase]]s (PHDs) stabilizes the transcription factor [[HIF1A|hypoxia inducible factor (HIF)1α]].<ref name=Tretter2016rev/><ref name=Haas2016rev/><ref name=Koivunen2007rev>{{cite journal|last1=Koivunen|first1=P|last2=Hirsilä|first2=M|last3=Remes|first3=AM|last4=Hassinen|first4=IE|last5=Kivirikko|first5=KI|last6=Myllyharju|first6=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|date=16 February 2007|volume=282|issue=7|pages=4524–32|doi=10.1074/jbc.M610415200|pmid=17182618|doi-access=free}}</ref> PHDs hydroxylate proline in parallel to oxidatively decarboxylating 2-oxyglutarate to succinate and CO<sub>2</sub>. In humans, three HIF prolyl 4-hydroxylases regulate the stability of HIFs.<ref name=Koivunen2007rev/> Hydroxylation of two prolyl residues in HIF1α facilitates ubiquitin ligation, thus marking it for proteolytic destruction by the [[Proteasome|ubiquitin/proteasome]] pathway. Since PHDs have an absolute requirement for molecular oxygen, this process is suppressed in hypoxia allowing HIF1α to escape destruction. High concentrations of succinate will mimic the hypoxia state by suppressing PHDs,<ref name=Yang2013rev/> therefore stabilizing HIF1α and inducing the transcription of HIF1-dependent genes even under normal oxygen conditions. HIF1 is known to induce transcription of more than 60 genes, including genes involved in [[vascularization]] and [[angiogenesis]], energy [[metabolism]], cell survival, and tumor invasion.<ref name=Tretter2016rev/><ref name=Koivunen2007rev/>