title: Structural basis for substrate activation and regulation by cystathionine beta-synthase (CBS) domains in cystathionine {beta}-synthase.
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.
authors.affiliation: Department of Biological Chemistry and the Life Sciences Institute, University of Michigan Medical Center, Ann Arbor, MI 48109-5606, USA.
authors.forename: Markos
authors.initials: M
authors.lastname: Koutmos
authors.forename: Omer
authors.initials: O
authors.lastname: Kabil
authors.forename: Janet L
authors.initials: JL
authors.lastname: Smith
authors.forename: Ruma
authors.initials: R
authors.lastname: Banerjee
mesh_terms: D000818:Animals; D002384:Catalysis; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D003541:Cystathionine beta-Synthase / Q000737:chemistry* / Q000378:metabolism; D029721:Drosophila Proteins / Q000737:chemistry*; D008239:Lysine; D017434:Protein Structure, Tertiary; D012436:S-Adenosylmethionine; D055672:Static Electricity
chemical_list: D029721:Drosophila Proteins; D012436:S-Adenosylmethionine; D003541:Cystathionine beta-Synthase; D008239:Lysine