Reactome | PDH complex synthesizes acetyl-CoA from PYR

PDH complex synthesizes acetyl-CoA from PYR

Stable Identifier

R-HSA-9861559

Type

Pathway

Species

Homo sapiens

Compartment

mitochondrial inner membrane, mitochondrial matrix

ReviewStatus

5/5

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PDH complex synthesizes acetyl-CoA from PYR

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The mitochondrial pyruvate dehydrogenase complex catalyzes the reaction of pyruvate, CoASH, and NAD+ to form acetylCoA, CO2, and NADH. The enzyme complex contains multiple copies of E1 alpha, E1 beta, E2, and E3, each with distinct catalytic activities (Reed and Hackert 1990; Zhou et al 2001), and the X-component (PDHX) which is required for anchoring E3 to E2 (Hiromasa et al., 2004; Vijayakrishnan et al., 2010). The reaction starts with the oxidative decarboxylation of pyruvate catalyzed by E1 alpha and beta (pyruvate dehydrogenase). Lipoamide cofactor associated with E2 is reduced at the same time. Next, the acetyl group derived from pyruvate is transferred to coenzyme A in two steps catalyzed by E2 (DLAT, dihydrolipolyl transacetylase). Finally, the oxidized form of lipoamide is regenerated and electrons are transferred to NAD+ in two steps catalyzed by E3 (DLD, dihydrolipoyl dehydrogenase). The biochemical details of this reaction have been worked out with pyruvate dehydrogenase complex and subunits purified from bovine tissue and other non-human sources. Direct evidence for the roles of the corresponding human proteins comes from studies of patients expressing mutant forms of E1 alpha (Lissens et al. 2000), E1 beta (Brown et al. 2004), E2 (Head et al. 2005), and E3 (Brautigam et al. 2005). The most common PDH complex deficiencies are caused by defects in PDHA and PDHX but can be caused by defects in any component of the complex (e.g. Pavlu-Pereira et al., 2020; reviewed in Prasad et al., 2011).

Literature References

PubMed ID	Title	Journal	Year
16049940	Clinical and genetic spectrum of pyruvate dehydrogenase deficiency: dihydrolipoamide acetyltransferase (E2) deficiency Zolkipli, Z, Shahdadpuri, R, Head, RA, Brown, GK, Clayton, PT, King, MD, Brown, RM	Ann Neurol	2005
2188967	Structure-function relationships in dihydrolipoamide acyltransferases. Reed, LJ, Hackert, ML	J Biol Chem	1990
15138885	Mutations in the gene for the E1beta subunit: a novel cause of pyruvate dehydrogenase deficiency Boubriak, II, Leonard, JV, Thomas, NH, Head, RA, Brown, GK, Brown, RM	Hum Genet	2004
14638692	Organization of the cores of the mammalian pyruvate dehydrogenase complex formed by E2 and E2 plus the E3-binding protein and their capacities to bind the E1 and E3 components Fujisawa, T, Aso, Y, Roche, TE, Hiromasa, Y	J Biol Chem	2004
33092611	Pyruvate dehydrogenase complex deficiency: updating the clinical, metabolic and mutational landscapes in a cohort of Portuguese patients Rivera, I, Ferreira, AC, Tavares de Almeida, I, Bandeira, A, Gomes, R, Sequeira, S, Duarte, S, Janeiro, P, Silva, MJ, Gomes, D, Oliveira, A, Florindo, C, Soares, S, Martins, E, Vicente, JB, Rodrigues, AL, Pavlu-Pereira, H	Orphanet J Rare Dis	2020
20361979	Solution structure and characterisation of the human pyruvate dehydrogenase complex core assembly Lindsay, JG, Gilbert, RJ, Forsyth, T, Callow, P, Bhella, D, Kelly, SM, Byron, O, Vijayakrishnan, S	J Mol Biol	2010
15946682	Crystal structure of human dihydrolipoamide dehydrogenase: NAD+/NADH binding and the structural basis of disease-causing mutations Tomchick, DR, Machius, M, Chuang, DT, Chuang, JL, Brautigam, CA	J Mol Biol	2005
11752427	The remarkable structural and functional organization of the eukaryotic pyruvate dehydrogenase complexes. Reed, LJ, Stoops, JK, McCarthy, DB, O'Connor, CM, Zhou, ZH	Proc Natl Acad Sci U S A	2001
21908116	Pyruvate dehydrogenase deficiency and epilepsy Rupar, T, Prasad, AN, Prasad, C	Brain Dev	2011
10679936	Mutations in the X-linked pyruvate dehydrogenase (E1) alpha subunit gene (PDHA1) in patients with a pyruvate dehydrogenase complex deficiency Patel, MS, Robinson, BH, Lissens, W, Seneca, S, Wexler, ID, Kuroda, Y, Ito, M, Brown, GK, Brown, RM, De Meirleir, L, Kerr, DS, Liebaers, I, Naito, E, Seyda, A	Hum Mutat	2000