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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
Component X binds to E3 and is also referred to as the E3-binding protein [75]. In two unrelated patients with homozygous splice-site mutations and neonatal lactic acidosis, the mutations were a G>A mutation at the donor splice site of intron 5 leading to exon 5 deletion, and a G>A transition of the splice acceptor site of intron 8. Neonatal lactic acidosis, severe encephalopathy, and death at 35 days was reported in a girl with a homozygous deletion (620 delC) in the PDX1 gene [76]. In a girl with a large 3913-bp deletion of the PDX1 gene involving introns 9 and 10 and exon 10, the patient had developmental delay and spastic paraparesis, but her disease was static until 14 years of age when she developed status epilepticus and was treated with valproate, which was followed by severe metabolic and neurologic decompensation [77]. A novel mechanism for the causation of human disease was found in a 25-year-old man with psychomotor delay and spastic diplegia. He developed recurrent dystonia, which disappeared with institution of a ketogenic diet [78]. He had a p.Q248X mutation on the paternal allele. On the maternal side, there was a 46-kb deletion combined with the integration of a full-length LINE-1 element. A model of template jumping was suggested as the mechanism of retropositional insertion of the full-length element.
Primary Biliary Cirrhosis Bench to Bedside
Published in Gianfranco Alpini, Domenico Alvaro, Marco Marzioni, Gene LeSage, Nicholas LaRusso, The Pathophysiology of Biliary Epithelia, 2020
Shinji Shimoda, Akiyoshi Nishio, Hiromi Ishibashi, M. Eric Gershwin
AMA are highly specific for PBC,32 but there is no clear relationship of AMA titer with prognosis or the progression of disease. The predominant AMA reactivity is directed to five autoantigens of the 2-OADC complexes; the E1α subunit of PDC, the E2 subunits of PDC, OGDC and BCOADC, and E3 binding protein (E3BP)33–38 (Table 4). Serum autoantibodies from more than 90% of patients with PBC react with PDC-E2 by immunoblotting, whereas the frequency of reactivity against the E2 subunits of OGDC and BCOADC is lower, around 50–70%. Antibodies to PDC-E1α are present in lower titers. Approximately 10% of patients react only to OGDC-E2 and/or BCOADC-E2. Antimitochondrial reactivity is usually observed against some, or even all of the 2-OADC, but serologic cross-reactivity is only found between PDC-E2 and E3BP.
Metabolic Diseases
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Stephanie Grünewald, Alex Broomfield, Callum Wilson
PDHC is a multi-subunit enzyme complex, governing the conversion of pyruvate into acetyl CoA. Its four main subunits are E1 – the decarboxylase that is a heterodimer of an α (PDHA1) and β (PDHB) subunit; E2 – the dihydrolipoamide acetyltransferase (DLAT); E3 – dihydroliopamide dehydrogenase(DLD), which is also a component of branched chain α-ketoacid dehydrogenase complex; and E3BP – the E3 binding protein. PDHC uses thiamine as a cofactor. Only the E1 α subunit is encoded on the X chromosome, but defects are typically the result of new mutations.
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.