Pyruvate Dehydrogenase Complex

Mulchand S Patel, State University of New York at Buffalo, Buffalo, New York, USA
Lioubov G Korotchkina, State University of New York at Buffalo, Buffalo, New York, USA

Published online: January 2006

DOI: 10.1038/npg.els.0003943

Pyruvate dehydrogenase complex (PDC) is a highly organized multienzyme complex that plays a key role in glucose metabolism providing a direct link between glycolysis and the tricarboxylic acid cycle. PDC is tightly regulated according to changing demands in glucose consumption in different tissues and under different nutritional and pathophysiological conditions.

Keywords: pyruvate dehydrogenase; regulation by phosphorylation/dephosphorylation; genetic defects; pyruvate dehydrogenase deficiency; glucose metabolism

Figure 1. Activity of PDC and its regulation in higher eukaryotes by phosphorylation/dephosphorylation catalysed by isoenzymes of PDKs and PDPs, respectively.
Figure 2. Sequence of reactions catalysed by PDC. The partial reactions (1 – 5) catalysed by three catalytic components are identified.
Figure 3. Two models of the mammalian PDC organization. (a) Cut-away model of a fully assembled PDC. E3 molecules (red) are bound inside the pentagonal dodecahedron core formed by 60 inner domains of E2 and 12 inner domains of BP (green). E1 (yellow) is bound to the E2-core through the inner linkers of E2 (blue) (Zhou et al., 2001). (b) A model of the inner core formed by E2 and BP. Twelve inner domains of BP (red) replace 12 inner domains of E2 and bind with 48 inner domains of E2 (blue) to form a 60-mer pentagonal dodecahedron (Hiromasa et al., 2004).
Figure 4. Structure of human E1. Subunits are coloured: , red, ’, green, , yellow, ’, blue. TPP is coloured black;  Mg2+ and  K+ are shown as dark blue and magenta spheres, respectively (Ciszak et al., 2003).
Figure 5. Effect of H15 mutation on the E1 structure. (a) Structure of the subunit of E1 in the region of H15. (b) Simulated structure of H15R. Residue in position 15 is shown in yellow. Hydrogen bonds are displayed (Korotchkina et al., 2004).
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 References
    Ciszak EM, Korotchkina LG, Dominiak PM et al. (2003) Structural basis for flip-flop action of thiamin pyrophosphate-dependent enzymes revealed by human pyruvate dehydrogenase. Journal of Biological Chemistry 278: 21240–21246.
    Frank RA, Titman CM, Pratap JV et al. (2004) A molecular switch and proton wire synchronize the active sites in thiamine enzymes. Science 306: 872–876.
    Harris RA, Huang B and Wu P (2001) Control of pyruvate dehydrogenase kinase gene expression. Advances in Enzyme Regulation 41: 269–288.
    Hiromasa Y, Fujisawa T, Aso Y et al. (2004) Organization of the cores of the mammalian pyruvate dehydrogenase complex formed by E2 and E2 plus the E3-binding protein and their capacities to bind the E1 and E3 components. Journal of Biological Chemistry 279: 6921–6933.
    Korotchkina LG, Ciszak EM and Patel MS (2004) Function of several critical amino acids in human pyruvate dehydrogenase revealed by its structure. Archives of Biochemistry & Biophysics 429: 171–179.
    Patel MS and Korotchkina LG (2003) The biochemistry of the pyruvate dehydrogenase complex. Biochemistry and Molecular Biology Education 31: 5–15.
    Perham RN (2000) Swinging arms and swinging domains in multifunctional enzymes: catalytic machines for multistep reactions. Annual Review in Biochemistry 69: 961–1004.
    Roche TE, Baker JC, Yan X et al. (2001) Distinct regulatory properties of pyruvate dehydrogenase kinase and phosphatase isoforms. Progress in Nucleic Acid Research and Molecular Biology 70: 33–75.
    Sugden MC and Holness MJ (2003) Recent advances in mechanisms regulating glucose oxidation at the level of the pyruvate dehydrogenase complex by PDKs. American Journal of Physiology and Endocrinology Metabolism 284: E855–E862.
    proceedings Zhou ZH, McCarthy DB, O'Connor CM et al. (2001) The remarkable structural and functional organization of the eukaryotic pyruvate dehydrogenase complexes. Proceedings of the National Academy of Sciences of the USA 98: 14802–14807.
 Further Reading
    Izard T, Aevarsson A, Allen MD et al. (1999) Principles of quasi-equivalence and Euclidean geometry govern the assembly of cubic and dodecahedral cores of pyruvate dehydrogenase complexes. Proceedings of the National Academy of Sciences of the USA 96: 1240–1245.
    book Jordan F and Patel MS (eds) (2004) "Thiamine". Catalytic Mechanisms in Normal and Disease States. Basel, NY: Marcel Dekker.
    book Kerr DS, Wexler ID, Tripatara A et al. (1996) "Human defects of the pyruvate dehydrogenase complex",. In: Patel MS, Roche TE and Harris RA (eds) Alpha-keto Acid Dehydrogenase Complexes, pp. 249–269. Boston, Berlin: Birkhauser Verlag, Basel.
    Kwon HS and Harris RA (2004) Mechanisms responsible for regulation of pyruvate dehydrogenase kinase 4 gene expression. Advances in Enzyme Regulation 44: 109–121.
    Mooney BP, Miernyk JA, Randall DD et al. (2002) The complex fate of alpha-ketoacids. Annual Review of Plant Biology 53: 357–375.
    Patel MS and Korotchkina LG (2001) Regulation of mammalian pyruvate dehydrogenase complex by phosphorylation: complexity of multiple phosphorylation sites and kinases. Experimental Molecular Medicine 33: 191–197.
    book Patel MS and Korotchkina LG (2002) "Pyruvate dehydrogenase complex". In: Wiley Encyclopedia of Molecular Medicine, vol. 5, pp. 2699–2703. New York: Wiley.
    Patel MS and Roche TE (1990) Molecular biology and biochemistry of pyruvate dehydrogenase complexes. FASEB Journal 4: 3224–3233.
    book Patel MS, Roche TE and Harris RA (eds) (1996) Alpha-keto Acid Dehydrogenase Complexes. Boston, Berlin: Birkhauser Verlag, Basel.
    Sugden MC and Holness M (2002) Therapeutic potential of the mammalian pyruvate dehydrogenase kinases in the prevention of hyperglycemia. Current Drug Targets 2: 151–165.

Related Sub-Topics:

Protein Structure | Enzymes: Structure and Action Mechanism
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Article Title: Pyruvate Dehydrogenase Complex
 
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Patel, Mulchand S, and Korotchkina, Lioubov G(Jan 2006) Pyruvate Dehydrogenase Complex. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1038/npg.els.0003943]