Regulation of pyruvate dehydrogenase complex activity by reversible phosphorylation
Abstract
PDC (pyruvate dehydrogenase complex) catalyses the oxidative decarboxylation of pyruvate, linking glycolysis to the tricarboxylic acid cycle. Regulation of PDC determines and reflects substrate preference and is critical to the 'glucose-fatty acid cycle', a concept of reciprocal regulation of lipid and glucose oxidation to maintain glucose homoeostasis developed by Philip Randle. Mammalian PDC activity is inactivated by phosphorylation by the PDKs (pyruvate dehydrogenase kinases). PDK inhibition by pyruvate facilitates PDC activation, favouring glucose oxidation and malonyl-CoA formation: the latter suppresses LCFA (long-chain fatty acid) oxidation. PDK activation by the high mitochondrial acetyl-CoA/CoA and NADH/NAD(+) concentration ratios that reflect high rates of LCFA oxidation causes blockade of glucose oxidation. Complementing glucose homoeostasis in health, fuel allostasis, i.e. adaptation to maintain homoeostasis, is an essential component of the response to chronic changes in glycaemia and lipidaemia in insulin resistance. We develop the concept that the PDKs act as tissue homoeostats and suggest that long-term modulation of expression of individual PDKs, particularly PDK4, is an essential component of allostasis to maintain homoeostasis. We also describe the intracellular signals that govern the expression of the various PDK isoforms, including the roles of the peroxisome proliferator-activated receptors and lipids, as effectors within the context of allostasis.
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Glucose catabolism in cancer cells is partially uncoupled from the TCA cycle and OXPHOS because increased activity of PDK dampens glucose metabolism through negative feedback on PDH.
“Interestingly, glucose catabolism in cancer cells is partially uncoupled from the TCA cycle and OXPHOS because increased activity of PDK dampens glucose metabolism through negative feedback on PDH (210, 211).”
From Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease (2018) · cites this paper as [210]
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- Authors
- Holness, M. J., & Sugden, M. C.
- Affiliations
- University of London (GB)
- ORCID
- Sugden, M.C.
- Venue
- Biochemical Society Transactions
- Publisher
- Portland Press Ltd.
- Published
- 2003-12-01
- Volume
- 31
- Issue
- 6
- Pages
- 1143-1151
- ISSN
- 0300-5127 (ISSN-L)
- 1470-8752
- OpenAlex
- W2053291546
- Cited by
- 479
- References
- 3
- Citations by year
- 2026: 19 · 2025: 28 · 2024: 20 · 2023: 14 · 2022: 16 · 2021: 36 · 2020: 33 · 2019: 24 · 2018: 25 · 2017: 25 · 2016: 26 · 2015: 31 · 2014: 22 · 2013: 24 · 2012: 17
- FWCI
- 3.95
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical Society Transactions (publishedVersion)
- PubMed (publishedVersion)
- 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 complex, reversible phosphorylation, pyruvate dehydrogenase kinase, PDK4, glucose-fatty acid cycle, glucose oxidation, long-chain fatty acid oxidation, malonyl-CoA, NAD+/NADH ratio, allostasis, insulin resistance, peroxisome proliferator-activated receptors, lipid signaling, glucose homeostasis
- MeSH terms
- Animals, Diabetes Mellitus, Type 2, Homeostasis, Insulin, Phosphorylation, Pyruvate Dehydrogenase Complex, Transcription Factors, Receptors, Cytoplasmic and Nuclear
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