Structural basis for substrate activation and regulation by cystathionine beta-synthase (CBS) domains in cystathionine β-synthase
- 16 November 2010
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 107 (49), 20958-20963
- https://doi.org/10.1073/pnas.1011448107
Abstract
The catalytic potential for H(2)S biogenesis and homocysteine clearance converge at the active site of cystathionine β-synthase (CBS), a pyridoxal phosphate-dependent enzyme. CBS catalyzes β-replacement reactions of either serine or cysteine by homocysteine to give cystathionine and water or H(2)S, respectively. In this study, high-resolution structures of the full-length enzyme from Drosophila in which a carbanion (1.70 Å) and an aminoacrylate intermediate (1.55 Å) have been captured are reported. Electrostatic stabilization of the zwitterionic carbanion intermediate is afforded by the close positioning of an active site lysine residue that is initially used for Schiff base formation in the internal aldimine and later as a general base. Additional stabilizing interactions between active site residues and the catalytic intermediates are observed. Furthermore, the structure of the regulatory "energy-sensing" CBS domains, named after this protein, suggests a mechanism for allosteric activation by S-adenosylmethionine.This publication has 46 references indexed in Scilit:
- Redox Biochemistry of Hydrogen SulfideOnline Journal of Public Health Informatics, 2010
- Relative Contributions of Cystathionine β-Synthase and γ-Cystathionase to H2S Biogenesis via Alternative Trans-sulfuration ReactionsOnline Journal of Public Health Informatics, 2009
- Heme Regulation of Human Cystathionine β-Synthase Activity: Insights from Fluorescence and Raman SpectroscopyJournal of the American Chemical Society, 2009
- Modulation of the heme electronic structure and cystathionine β-synthase activity by second coordination sphere ligands: The role of heme ligand switching in redox regulationJournal of Inorganic Biochemistry, 2009
- Insights into the Catalytic Mechanism of Tyrosine Phenol-lyase from X-ray Structures of Quinonoid IntermediatesOnline Journal of Public Health Informatics, 2008
- Hydrogen sulphide and its therapeutic potentialNature Reviews Drug Discovery, 2007
- Inference of Macromolecular Assemblies from Crystalline StateJournal of Molecular Biology, 2007
- MolProbity: all-atom contacts and structure validation for proteins and nucleic acidsNucleic Acids Research, 2007
- A Pathogenic Linked Mutation in the Catalytic Core of Human Cystathionine β-Synthase Disrupts Allosteric Regulation and Allows Kinetic Characterization of a Full-Length DimerBiochemistry, 2007
- Coot: model-building tools for molecular graphicsActa crystallographica. Section D, Structural biology, 2004