NYMC Faculty Publications

Title

Metabolism of the Cysteine S-Conjugate of Busulfan Involves a Beta-Lyase Reaction

Document Type

Article

Publication Date

8-1-2008

Department

Biochemistry and Molecular Biology

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.

Publisher's Statement

Originally published in Drug Metabolism and Disposition: The Biological Fate of Chemicals. https://doi.org/10.1124/dmd.108.020768