Molecular Mechanism of Allosteric Substrate Activation in a Thiamine Diphosphate-dependent Decarboxylase

Thiamine diphosphate-dependent enzymes are involved in a wide variety of metabolic pathways. The molecular mechanism behind active site communication and substrate activation, observed in some of these enzymes, has since long been an area of debate. Here, we report the crystal structures of a phenyl...

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Bibliographic Details
Published in:The Journal of biological chemistry 2007-11, Vol.282 (48), p.35269-35278
Main Authors: Versées, Wim, Spaepen, Stijn, Wood, Martin D.H., Leeper, Finian J., Vanderleyden, Jos, Steyaert, Jan
Format: Article
Language:English
Subjects:
Allosteric Site
Binding Sites
Carboxy-Lyases - chemistry
Carboxy-Lyases - metabolism
Catalysis
Crystallography, X-Ray - methods
Models, Biological
Models, Molecular
Molecular Conformation
Plant Roots - metabolism
Protein Binding
Protein Structure, Quaternary
Protein Structure, Tertiary
Signal Transduction
Substrate Specificity
Thiamine Pyrophosphate - chemistry
X-Ray Diffraction
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Summary:Thiamine diphosphate-dependent enzymes are involved in a wide variety of metabolic pathways. The molecular mechanism behind active site communication and substrate activation, observed in some of these enzymes, has since long been an area of debate. Here, we report the crystal structures of a phenylpyruvate decarboxylase in complex with its substrates and a covalent reaction intermediate analogue. These structures reveal the regulatory site and unveil the mechanism of allosteric substrate activation. This signal transduction relies on quaternary structure reorganizations, domain rotations, and a pathway of local conformational changes that are relayed from the regulatory site to the active site. The current findings thus uncover the molecular mechanism by which the binding of a substrate in the regulatory site is linked to the mounting of the catalytic machinery in the active site in this thiamine diphosphate-dependent enzyme.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M706048200