Reactome | Succinate <=> Fumarate (with FAD redox reaction on enzyme)

Succinate <=> Fumarate (with FAD redox reaction on enzyme)

Stable Identifier

R-HSA-70994

Type

Reaction [transition]

Species

Homo sapiens

Compartment

mitochondrial matrix, mitochondrial inner membrane

ReviewStatus

5/5

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Succinate <=> Fumarate (with FAD redox reaction on enzyme)

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The succinate dehydrogenase complex (SDH), associated with the inner mitochondrial membrane, catalyzes the dehydrogenation of succinate to fumarate, reducing the FAD cofactor bound to the enzyme. This redox potential is then used in the electron transfer chain to drive a proton motive force to generate ATP.
The endogenous metabolite itaconate has been shown to bind and inhibit SDH, leading to an accumulation of succinate. Elevated succinate levels modulate immune, hypoxic and metabolic reprogramming pathways, including during oncogenesis (Booth et al, 1952; Dervertanian et al, 1964; Cordes et al, 2016; Lampropoulou et al, 2016). Studies examining the impact of elevated citric acid cycle intermediates such as succinate and fumarate led to the recognition of the role of metabolites in driving cancer progression ('oncometabolites') (Selak et al, 2005; Pollard et al, 2005; Koivunen et al, 2007; reviewed in Hayashi et al, 2018).

Literature References

PubMed ID	Title	Journal	Year
16143825	Succinate dehydrogenase deficiency in human Djouadi, F, Gimenez, AP, El Ghouzzi, V, Favier, J, Briere, JJ, Rustin, P, Benit, P	Cell Mol Life Sci	2005
30844107	Hypoxia/pseudohypoxia-mediated activation of hypoxia-inducible factor-1α in cancer Harada, H, Yokota, A, Hayashi, Y, Huang, G	Cancer Sci	2019
27189937	Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels Metallo, CM, Wallace, M, Cordes, T, Murphy, AN, Koseki, H, Divakaruni, AS, Michelucci, A, Sapcariu, SC, Cabrales, P, Hiller, K, Sousa, C	J Biol Chem	2016
14249115	STUDIES ON SUCCINATE DEHYDROGENASE. I. SPECTRAL PROPERTIES OF THE PURIFIED ENZYME AND FORMATION OF ENZYME-COMPETITIVE INHIBITOR COMPLEXES DERVARTANIAN, DV, VEEGER, C	Biochim Biophys Acta	1964
17182618	Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: possible links between cell metabolism and stabilization of HIF Myllyharju, J, Remes, AM, Hirsilä, M, Hassinen, IE, Kivirikko, KI, Koivunen, P	J Biol Chem	2007
15987702	Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations Wortham, NC, Griffiths, JR, Moat, SJ, Pollard, PJ, Barclay, E, Barwell, J, Mitchell, M, Tomlinson, IP, Alam, NA, Hargreaves, IP, Poulsom, R, Dalgleish, A, Heales, SJ, Hodgson, SV, Hunt, T, Gleeson, MJ, McGrath, JA, Brière, JJ, Rustin, P, Chung, YL, Olpin, S	Hum Mol Genet	2005
27374498	Itaconate Links Inhibition of Succinate Dehydrogenase with Macrophage Metabolic Remodeling and Regulation of Inflammation Jones, RG, Sergushichev, A, Khader, S, Lampropoulou, V, Pearce, EJ, Cervantes-Barragan, L, Diamond, MS, Ma, X, Loginicheva, E, Bambouskova, M, Griss, T, Artyomov, MN, Vincent, EE, Diwan, A, Randolph, GJ, Weinheimer, CJ, Nair, S, Huang, SC	Cell Metab	2016
15652751	Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase MacKenzie, ED, Boulahbel, H, Selak, MA, Pan, Y, Armour, SM, Watson, DG, Gottlieb, E, Mansfield, KD, Simon, MC, Thompson, CB	Cancer Cell	2005
14946179	The inhibitory effects of itaconic acid in vitro and in vivo DEEDS, F, BOOTH, AN, WILSON, RH, Taylor, J	J Biol Chem	1952