title: Metabolism of the cysteine S-conjugate of busulfan involves a beta-lyase reaction.
abstract: The present work documents the first example of an enzyme-catalyzed beta-elimination of a thioether from a sulfonium cysteine S-conjugate. beta-(S-Tetrahydrothiophenium)-L-alanine (THT-A) is the cysteine S-conjugate of busulfan. THT-A slowly undergoes a nonenzymatic beta-elimination reaction at pH 7.4 and 37 degrees C to yield tetrahydrothiophene, pyruvate, and ammonia. This reaction is accelerated by 1) rat liver, kidney, and brain homogenates, 2) isolated rat liver mitochondria, and 3) pyridoxal 5'-phosphate (PLP). A PLP-dependent enzyme in rat liver cytosol that catalyzes a beta-lyase reaction with THT-A was identified as cystathionine gamma-lyase. This unusual drug metabolism pathway represents an alternate route for intermediates in the mercapturate pathway.
authors.affiliation: Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, New York, USA.
authors.forename: Arthur J L
authors.initials: AJ
authors.lastname: Cooper
authors.forename: Islam R
authors.initials: IR
authors.lastname: Younis
authors.forename: Zoya V
authors.initials: ZV
authors.lastname: Niatsetskaya
authors.forename: Boris F
authors.initials: BF
authors.lastname: Krasnikov
authors.forename: John T
authors.initials: JT
authors.lastname: Pinto
authors.forename: William P
authors.initials: WP
authors.lastname: Petros
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Callery
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000493:pharmacokinetics*; D001921:Brain / Q000201:enzymology / Q000378:metabolism; D002066:Busulfan / Q000493:pharmacokinetics*; D003545:Cysteine / Q000378:metabolism*; D007668:Kidney / Q000201:enzymology / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008190:Lyases / Q000378:metabolism*; D011732:Pyridoxal Phosphate / Q000378:metabolism; D051381:Rats
chemical_list: D018906:Antineoplastic Agents, Alkylating; D011732:Pyridoxal Phosphate; D008190:Lyases; D002066:Busulfan; D003545:Cysteine