Distinct regulatory properties of pyruvate dehydrogenase kinase and phosphatase isoforms

Thomas E. Roche, Jason C. Baker, Xiaohua Yan, Yasuaki Hiromasa, Xiaoming Gong, Tao Peng, Jianchun Dong, Ali Turkan, Shane A. Kasten

Research output: Chapter in Book/Report/Conference proceedingChapter

167 Citations (Scopus)

Abstract

The mammalian pyruvate dehydrogenase complex (PDC) plays central and strategic roles in the control of the use of glucose-linked substrates as sources of oxidative energy or as precursors in the biosynthesis of fatty acids. The activity of this mitochondrial complex is regulated by the contnuous operation of competing pyruvate dehydrogenase kinase (PDK) and pyruvate dehydrogenase phosphatase (PDP) reactions. The resulting interconversion cycle determines the fraction of active (nonphosphorylated) pyruvate dehydrogenase (E1) component. Tissue-specific and metabolic state-specific control is achieved by the selective expression and distinct regulatory properties of at least four PDK isozymes and two PDP isozymes. The PDK isoforms are members of a family of serine kinases that are not structurally related to cytoplasmic Ser/Thr/Tyr kinases. The catalytic subunits of the PDP isoforms are Mg2+-dependent members of the phosphatase 2C family that has binuclear metal-binding sites within the active site. The dihydrolipoyl acetyltransferase (E2) and the dihydrolipoyl dehydrogenase-binding protein (E3BP) are multidomain proteins that form the oligomeric core of the complex. One or more of their three lipoyl domains (two in E2) selectively bind each PDK and PDP1. These adaptive interactions predominantly influence the catalytic efficiencies and effector control of these regulatory enzymes. When fatty acids are the preferred source of acetyl-CoA and NADH, feedback inactivation of PDC is acomplished by the activity of certain kinase isoforms being stimulated upon preferentially binding a lipoyl domain containing a reductively acetylated lipoyl group. PDC activity is increased in Ca2+-sensitive tissues by elevating PDP1 activity via the Ca2+-dependent binding of PDP1 to a lipoyl domain of E2. During starvation, the irrecoverable loss of glucose carbons is restricted by minimizing PDC activity due to high kinase activity that results from the overexpression of specific kinase isoforms. Overexpression of the same PDK isoforms deleteriously hinders glucose consumption in unregulated diabetes.

Original languageEnglish
Title of host publicationProgress in Nucleic Acid Research and Molecular Biology
PublisherAcademic Press Inc.
Pages33-54,IN1-IN2,55-75
ISBN (Print)0125400705, 9780125400701
Publication statusPublished - Jan 1 2001

Publication series

NameProgress in Nucleic Acid Research and Molecular Biology
Volume70
ISSN (Print)0079-6603

Fingerprint

Pyruvate Dehydrogenase (Lipoamide)-Phosphatase
Pyruvate Dehydrogenase Complex
Protein Isoforms
Phosphotransferases
Glucose
Isoenzymes
Pyruvate Dehydrogenase (Lipoamide)
Catalytic Domain
Fatty Acids
Dihydrolipoyllysine-Residue Acetyltransferase
Dihydrolipoamide Dehydrogenase
Acetyl Coenzyme A
Protein-Serine-Threonine Kinases
Starvation
Phosphoric Monoester Hydrolases
NAD
Carrier Proteins
Carbon
Metals
Binding Sites

All Science Journal Classification (ASJC) codes

  • Molecular Biology

Cite this

Roche, T. E., Baker, J. C., Yan, X., Hiromasa, Y., Gong, X., Peng, T., ... Kasten, S. A. (2001). Distinct regulatory properties of pyruvate dehydrogenase kinase and phosphatase isoforms. In Progress in Nucleic Acid Research and Molecular Biology (pp. 33-54,IN1-IN2,55-75). (Progress in Nucleic Acid Research and Molecular Biology; Vol. 70). Academic Press Inc..

Distinct regulatory properties of pyruvate dehydrogenase kinase and phosphatase isoforms. / Roche, Thomas E.; Baker, Jason C.; Yan, Xiaohua; Hiromasa, Yasuaki; Gong, Xiaoming; Peng, Tao; Dong, Jianchun; Turkan, Ali; Kasten, Shane A.

Progress in Nucleic Acid Research and Molecular Biology. Academic Press Inc., 2001. p. 33-54,IN1-IN2,55-75 (Progress in Nucleic Acid Research and Molecular Biology; Vol. 70).

Research output: Chapter in Book/Report/Conference proceedingChapter

Roche, TE, Baker, JC, Yan, X, Hiromasa, Y, Gong, X, Peng, T, Dong, J, Turkan, A & Kasten, SA 2001, Distinct regulatory properties of pyruvate dehydrogenase kinase and phosphatase isoforms. in Progress in Nucleic Acid Research and Molecular Biology. Progress in Nucleic Acid Research and Molecular Biology, vol. 70, Academic Press Inc., pp. 33-54,IN1-IN2,55-75.
Roche TE, Baker JC, Yan X, Hiromasa Y, Gong X, Peng T et al. Distinct regulatory properties of pyruvate dehydrogenase kinase and phosphatase isoforms. In Progress in Nucleic Acid Research and Molecular Biology. Academic Press Inc. 2001. p. 33-54,IN1-IN2,55-75. (Progress in Nucleic Acid Research and Molecular Biology).
Roche, Thomas E. ; Baker, Jason C. ; Yan, Xiaohua ; Hiromasa, Yasuaki ; Gong, Xiaoming ; Peng, Tao ; Dong, Jianchun ; Turkan, Ali ; Kasten, Shane A. / Distinct regulatory properties of pyruvate dehydrogenase kinase and phosphatase isoforms. Progress in Nucleic Acid Research and Molecular Biology. Academic Press Inc., 2001. pp. 33-54,IN1-IN2,55-75 (Progress in Nucleic Acid Research and Molecular Biology).
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