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  Enzyme-ligand complexes of pyridoxine 5 -phosphate synthase: Implications for substrate binding and catalysis

Garrido-Franco, M., Laber, B., Huber, R., & Clausen, T. (2002). Enzyme-ligand complexes of pyridoxine 5 -phosphate synthase: Implications for substrate binding and catalysis. Journal of Molecular Biology, 321(4), 601-612.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0010-6E72-E Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0010-6E73-C
Genre: Journal Article
Alternative Title : J. Mol. Biol.

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 Creators:
Garrido-Franco, M.1, Author              
Laber, B., Author
Huber, R.1, Author              
Clausen, T.1, Author              
Affiliations:
1Huber, Robert / Structure Research, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565155              

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Free keywords: enzyme-substrate complex; open-closed transition; PdxJ; PLP; vitamin B-6
 Abstract: Pyridoxine 5'-phosphate (PNP) synthase is the last enzyme in the de novo biosynthesis of vitamin B-6 catalyzing the complicated ring-closure reaction between 1-deOXy-D-xylulose-5- phosphate and 1-amino-acetone-3-phosphate. Here we present the crystal structures of four PNP synthase complexes with substrates and substrate analogs. While the overall fold of the enzyme is conserved in all complexes, characteristic readjustments were observed in the active site. The complementary structural information allowed us to postulate a detailed reaction mechanism. The observed binding mode of substrates indicates how the first reaction intermediate, the Schiff-base conjugate, is formed. The most important mechanistic features are the presence of two phosphate-binding sites with distinct affinities and the existence of a water relay system for the release of reaction water molecules. Furthermore, the complexes provide the basis to rationalize the open-closed transition of a flexible loop located on the C- terminal side of the TIM-barrel. Binding of both substrate molecules to the active site seems to be a prerequisite to trigger this transition. Highly conserved mechanistically important residues in the PNP synthase family imply a similar active site organization and reaction mechanism for all family members. Due to the exclusive presence of PNP synthase in a subset of eubacteria, including several well-known pathogens, and due to its outstanding physiological importance for these organisms, the enzyme appears to be a promising novel target for antibacterial drug design. (C) 2002 Elsevier Science Ltd. All rights reserved.

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Language(s): eng - English
 Dates: 2002-08-23
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: eDoc: 41456
ISI: 000178813900005
 Degree: -

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Title: Journal of Molecular Biology
  Alternative Title : J. Mol. Biol.
Source Genre: Journal
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Publ. Info: -
Pages: - Volume / Issue: 321 (4) Sequence Number: - Start / End Page: 601 - 612 Identifier: ISSN: 0022-2836