Tuladhar Anupama, Rein Kathleen S
Department of Chemistry and Biochemistry, Florida International University, 11200 SW Eighth Street, Miami, Florida 33199, United States.
ACS Med Chem Lett. 2018 Mar 5;9(4):318-322. doi: 10.1021/acsmedchemlett.7b00489. eCollection 2018 Apr 12.
The anticancer effect of manumycin A (Man A) has been attributed to the inhibition of farnesyl transferase (FTase), an enzyme that is responsible for post-translational modification of proteins. However, we have discovered that Man A inhibits mammalian cytosolic thioredoxin reductase 1 (TrxR-1) in a time-dependent manner, with an IC of 272 nM with preincubation and 1586 nM without preincubation. The inhibition of TrxR-1 by Man A is irreversible and is the result of a covalent interaction between Man A and TrxR-1. Evidence presented herein demonstrates that Man A forms a Michael adduct with the selenocysteine residue, which is located in the C-terminal redox center of TrxR-1. Inhibitors of TrxR-1, which act through this mechanism, convert TrxR-1 into a SecTRAP, which utilizes NADPH to reduce oxygen to superoxide radical anion (O).
马马霉素A（Man A）的抗癌作用归因于对法尼基转移酶（FTase）的抑制，该酶负责蛋白质的翻译后修饰。然而，我们发现Man A以时间依赖性方式抑制哺乳动物胞质硫氧还蛋白还原酶1（TrxR-1），预温育时IC为272 nM，未预温育时为1586 nM。Man A对TrxR-1的抑制是不可逆的，是Man A与TrxR-1之间共价相互作用的结果。本文提供的证据表明，Man A与位于TrxR-1 C端氧化还原中心的硒代半胱氨酸残基形成迈克尔加合物。通过这种机制起作用的TrxR-1抑制剂将TrxR-1转化为SecTRAP，后者利用NADPH将氧气还原为超氧阴离子自由基（O）。
