Metabolism of the Cysteine S-Conjugate of Busulfan Involves a Beta-Lyase Reaction
Biochemistry and Molecular Biology
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.
Cooper, A. J., Younis, I. R., Niatsetskaya, Z. V., Krasnikov, B. F., Pinto, J. T., Petros, W. P., et al. (2008). Metabolism of the cysteine S-conjugate of busulfan involves a beta-lyase reaction. Drug Metabolism and Disposition: The Biological Fate of Chemicals, 36(8), 1546-1552. doi:10.1124/dmd.108.020768
Originally published in Drug Metabolism and Disposition: The Biological Fate of Chemicals. https://doi.org/10.1124/dmd.108.020768