Pyruvate dehydrogenase : its structure, function and interactions within the pyruvate dehydrogenase multienzyme complex

A.F. Hengeveld

Research output: Thesisinternal PhD, WU


<p>Pyruvate dehydrogenase multi-enzyme complex (PDHC) is member of a family of multienzyme complexes that catalyse the irreversible decarboxylation of various 2-oxoacid substrates to their corresponding acyl-CoA derivatives, NADH and C02. 2-oxoacid dehydrogenase complexes hold key points in primary energy metabolism: PDHC in glycolysis, the oxoglutarate dehydrogenase complex (OGDC) in the citric acid cycle, the branched-chain oxoacid dehydrogenase complex (BCDC) in amino acid catabolism, the glycine dehydrogenase complex (GDHC) in the glycine cleavage system and acetoin dehydrogenase complex (ADHC) in acetoin metabolism. Malfunctioning of a 2-oxo acid dehydrogenase complex in man leads to a broad variety of clinical manifestations, e.g. lactic acidosis (PDHC-deficiency) or maple syrup urine disease (BCDC-deficiency).<br/>PDHC consists of multiple copies of three enzymes: 2-oxoacid dehydrogenase or Elp-component, dihydrolipoyl acyltransferase (E2p) and dihydrolipoamide dehydrogenase (E3). The E2 component plays a central role in the complex, both catalytically and structurally. It consists of multiple domains (from N- to C-terminus, 1-3 lipoyl domains, an EI/E3-binding domain and a catalytic domain) connected by flexible linkers, allowing a high degree of flexibility of the individual domains. In gram-negative bacteria, the C-terminal catalytic domain forms a cubic core of 24 subunits. Multiple copies of the peripheral components Elp and E3 are non-covalently attached to this core. Three-dimensional structures of the different components and domains of PDHC have been solved by X-ray crystallography or NMR.<br/>E1 catalyses the rate limiting step in the overall complex reaction; the reductive acylation of the lipoyl groups of E2 utilising thiamin diphosphate (ThDP). The El-component exists either as a homodimer (α <sub>2</sub> or heterotetramer (α <sub>2</sub> β <sub>2</sub> ), depending on the type and source of the complex. There is strikingly little sequence similarity between homodimeric and heterotetranieric E1 or even between homodimeric E1o and homodimeric E1p. An exception to this is the so-called "ThDP-binding motif', that has so far been found in all known ThDP dependent enzymes. Until quite recently EI was by far the least characterised component of the complex. This lack of (structural) information was largely due to the lack of a stable form of the enzyme: when resolved from the complex, E 1 is unstable. To obtain a better insight into the structure and functioning of the El-component of the pyruvate dehydrogenase multienzyme complex from A. <em>vinelandii</em> and its interactions within the complex, a PhD project was started in 1995. The results of this project are presented in this thesis.
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • Wageningen University
  • Veeger, C., Promotor
  • de Kok, A., Promotor, External person
Award date24 Apr 2002
Place of PublicationS.l.
Print ISBNs9789058086204
Publication statusPublished - 2002


  • pyruvate dehydrogenase (lipoamide)
  • biochemistry


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