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

Stable Identifier
R-HSA-70994
Type
Reaction
Species
Homo sapiens
Compartment
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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
Participants
Participates
Catalyst Activity

succinate dehydrogenase (ubiquinone) activity of SDH complex (ox.) [mitochondrial inner membrane]

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