Cooper Arthur J L, Younis Islam R, Niatsetskaya Zoya V, Krasnikov Boris F, Pinto John T, Petros William P, Callery Patrick S
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, New York, USA.
Drug Metab Dispos. 2008 Aug;36(8):1546-52. doi: 10.1124/dmd.108.020768. Epub 2008 May 12.
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.
本研究记录了首例酶催化从锍半胱氨酸S-共轭物中β-消除硫醚的实例。β-(S-四氢噻吩鎓)-L-丙氨酸(THT-A)是白消安的半胱氨酸S-共轭物。在pH 7.4和37℃条件下,THT-A缓慢进行非酶β-消除反应,生成四氢噻吩、丙酮酸和氨。该反应可被以下物质加速:1)大鼠肝脏、肾脏和脑匀浆;2)分离的大鼠肝脏线粒体;3)磷酸吡哆醛(PLP)。大鼠肝细胞溶质中一种依赖PLP且催化THT-A发生β-裂解反应的酶被鉴定为胱硫醚γ-裂解酶。这种不寻常的药物代谢途径代表了巯基尿酸途径中中间体的另一条途径。