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 Ras proteins. However, we have discovered that Man A inhibits mammalian cytosolic thioredoxin reductase 1 (TrxR-1) in a time-dependent manner, with an IC₅₀ 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 (O₂^–•).

中文翻译：

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Manumycin A是哺乳动物硫氧还蛋白还原酶-1（TrxR-1）的有效抑制剂。

Manumycin A（Man A）的抗癌作用归因于法呢基转移酶（FTase）的抑制，该酶负责Ras蛋白的翻译后修饰。但是，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），其IC _50为预孵育时为272 nM，未预孵育时为1586 nM。Man A对TrxR-1的抑制是不可逆的，并且是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与硒代半胱氨酸残基形成Michael加合物，该残基位于TrxR-1的C端氧化还原中心。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将氧还原为超氧自由基阴离子（O ₂ ^–•）。