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Deficiency of the pyruvate dehydrogenase complex
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
The second enzyme, E2 (EC 2.3.1.12), dihydrolipoyl transacetylase, is an acyl transferase; it catalyzes the transfer of the hydroxyethyl group and its oxidation to acetylCoA (Figure 50.1). Concomitantly, the disulfide bridge of the lipoic acid moiety attached to E2 is reduced to the SH form. This attached dihydrolipoic acid is reoxidized in the reaction catalyzed by the E3 enzyme, dihydrolipoyl dehydrogenase or lipoamide dehydrogenase (EC 1.6.4.3). The same E3 component is shared by 2-oxoglutarate dehydrogenase and the branched-chain ketoacid decarboxylase, providing a mechanism for patients who have defective activity in all three systems [2]. In PDHC, a lipoyl-containing catalytic protein has been referred to as protein X, which also functions in acyl transfer [3, 4]. Lipoic acid is attached to the E2 or X protein covalently to lysine moieties. Protein X may also serve in binding E3 to the rest of the complex [5].
Mitochondrial and peroxisomal disorders
Published in Steve Hannigan, Inherited Metabolic Diseases: A Guide to 100 Conditions, 2018
This is a disorder of carbohydrate metabolism (the breakdown of sugars, including glucose). In this condition there is an absence or a deiciency of the pyruvate dehydrogenase complex, so the breakdown of pyruvate to form acetyl CoA is impaired. The pyruvate dehydrogenase complex consists of three separate enzymes: E1 – pyruvate decarboxylaseE2 – dihydrolipoyl transacetylaseE3 – dihydrolipoyl dehydrogenase.
The Reaction Mechanism
Published in D. B. Keech, J. C. Wallace, Pyruvate Carboxylase, 2018
Probably one of the most important steps forward in understanding the mechanism of action of biotin-dependent enzymes in general, came from the studies of Northrop606 and Northrop and Wood.607 They carried out a detailed kinetic study on the biotin-dependent methyl-malonyl-CoA transcarboxylase [EC 2.1.3.1] which catalyzes the reversible transfer of carboxyl groups between methyl-malonyl-CoA and pyruvate. Their data were interpreted to suggest that transcarboxylase catalyzed a reaction involving a modified Ping-Pong mechanism where the active center consisted of two separate subsites. Northrop and Wood then introduced the concept that the two separate subsites were linked together by the covalently bound biotin acting as a mobile carboxyl-group carrier, shifting the activated carboxyl group from one subsite to the other. The idea of a flexible, covalently bound residue providing a shuttle system had not previously been considered to apply to the biotin-containing group of enzymes. A similar function had been postulated for lipoic acid, the prosthetic group of dihydrolipoyl transacetylase [EC 2.3.1.12], to transfer acetyl groups in the pyruvate dehydrogenase complex. Pantetheine was assigned a similar function in the acyl-carrier protein complex of the fatty-acid-synthesizing complex in yeast. However, the difference here is that in the latter two examples the carrier system is acting between enzymes, whereas the biotin is postulated to be acting within a single active center.
Targeting glucose metabolism to develop anticancer treatments and therapeutic patents
Published in Expert Opinion on Therapeutic Patents, 2022
Yan Zhou, Yizhen Guo, Kin Yip Tam
Pyruvate dehydrogenase complex (PDC) is a 9.5 million Da multi-enzyme complex located in mitochondrial matrix and consisting of four major enzyme components: pyruvate dehydrogenase (E1), dihydrolipoyl transacetylase (E2), dihydrolipoamide dehydrogenase (E3), and E3-binding protein (E3BP), as well as the two kinds of dedicated regulatory enzymes: PDKs and pyruvate dehydrogenase phosphatase [47]. The detailed structure and function of PDC have been well reviewed [48]. As an important gatekeeper enzyme that links pyruvate to the TCA cycle, PDC catalyzes the conversion of pyruvate to acetyl-CoA coupled with the reduction of NAD+ to NADH. The modulation of PDC activities depends on the reversible phosphorylation and dephosphorylation [49]. Phosphorylation of E1α component, regardless of which one of the three serine residues, is enough to switch off PDC activity. Thus, phosphorylation of PDC by PDKs will downregulate its activity, and subsequently reduce the flux of pyruvate into the TCA cycle. In human, phosphorylation of PDC is catalyzed by any of four isoforms of pyruvate dehydrogenase kinase (PDK1-4) which are expressed differently in specific tissues. In particular, PDK1 is closely associated with cancer malignancy and serves as the only PDK isoform that could phosphorylate all serine sites of PDC [50]. To sum up, inhibiting PDKs has been one of the recognized strategies to fight against cancer by increasing OXPHOS and reversing Warburg effect.