Open AccessStructural basis for substrate activation and regulation by cystathionine beta-synthase (CBS) domains in cystathionine β-synthase
Author(s) -
Markos Koutmos,
Ömer Kabil,
Janet L. Smith,
Ruma Banerjee
Publication year - 2010
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.1011448107
Subject(s) - cystathionine beta synthase , chemistry , active site , homocysteine , tryptophan synthase , stereochemistry , cysteine , homocystinuria , atp synthase , pyridoxal , serine , allosteric regulation , biochemistry , enzyme , methionine , amino acid , tryptophan
The catalytic potential for H2 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 H2 S, respectively. In this study, high-resolution structures of the full-length enzyme fromDrosophila 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 byS -adenosylmethionine.