Site specificity of four pyruvate dehydrogenase kinase isoenzymes toward the three phosphorylation sites of human pyruvate dehydrogenase
Open accessAbstract
Activity of the mammalian pyruvate dehydrogenase complex is regulated by phosphorylation-dephosphorylation of three specific serine residues (site 1, Ser-264; site 2, Ser-271; site 3, Ser-203) of the alpha subunit of the pyruvate dehydrogenase (E1) component. Phosphorylation is carried out by four pyruvate dehydrogenase kinase (PDK) isoenzymes. Specificity of the four mammalian PDKs toward the three phosphorylation sites of E1 was investigated using the recombinant E1 mutant proteins with only one functional phosphorylation site present. All four PDKs phosphorylated site 1 and site 2, however, with different rates in phosphate buffer (for site 1, PDK2 > PDK4 approximately PDK1 > PDK3; for site 2, PDK3 > PDK4 > PDK2 > PDK1). Site 3 was phosphorylated by PDK1 only. The maximum activation by dihydrolipoamide acetyltransferase was demonstrated by PDK3. In the free form, all PDKs phosphorylated site 1, and PDK4 had the highest activity toward site 2. The activity of the four PDKs was stimulated to a different extent by the reduction and acetylation state of the lipoyl moieties of dihydrolipoamide acetyltransferase with the maximum stimulation of PDK2. Substitution of the site 1 serine with glutamate, which mimics phosphorylation-dependent inactivation of E1, did not affect phosphorylation of site 2 by four PDKs and of site 3 by PDK1. Site specificity for phosphorylation of four PDKs with unique tissue distribution could contribute to the tissue-specific regulation of the pyruvate dehydrogenase complex in normal and pathophysiological states.
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The activity of mammalian PDHC is regulated by phosphorylation status of three serine residues on the pyruvate dehydrogenase E1 alpha subunit.
“The activity of the mammalian complex is regulated by the phosphorylation status of three serine residues on the pyruvate dehydrogenase E1 alpha subunit (139).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [139]
Four PDKs (PDK1-4) catalyze phosphorylation of the serine residues, each with different site specificities, and PDPs reverse this phosphorylation.
“Four pyruvate dehydrogenase kinases (PDKs; PDK1–4) catalyze phosphorylation of the serine residues, each with different site specificities (139).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [139]
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“Four pyruvate dehydrogenase kinases (PDKs; PDK1–4) catalyze phosphorylation of the serine residues, each with different site specificities (139).”
Background
- Authors
- Korotchkina, L. G., & Patel, M. S.
- Affiliations
- University at Buffalo, State University of New York (US)
- Corresponding author
- Patel, Mulchand S.
- ORCID
- Patel, Mulchand S.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2001-10
- Volume
- 276
- Issue
- 40
- Pages
- 37223-37229
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2127629715
- Cited by
- 246
- References
- 34
- Citations by year
- 2026: 12 · 2025: 17 · 2024: 7 · 2023: 12 · 2022: 12 · 2021: 19 · 2020: 11 · 2019: 9 · 2018: 12 · 2017: 15 · 2016: 13 · 2015: 8 · 2014: 7 · 2013: 9 · 2012: 13
- FWCI
- 2.95
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK020478, DK20478)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- pyruvate dehydrogenase kinase, pyruvate dehydrogenase complex, serine phosphorylation sites, E1 alpha subunit, PDK1, PDK2, PDK3, PDK4, dihydrolipoamide acetyltransferase, site 1, site 2, site 3, enzyme regulation, tissue-specific gene regulation
- MeSH terms
- Pyruvate Dehydrogenase Acetyl-Transferring Kinase, Acetylation, Humans, Isoenzymes, Mutation, Oxidation-Reduction, Phosphorylation, Protein Kinases, Pyruvate Dehydrogenase Complex, Recombinant Proteins, Substrate Specificity, Protein Serine-Threonine Kinases
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