Manumycin A Is a Potent Inhibitor of Mammalian Thioredoxin Reductase-1 (TrxR-1)

Anupama Tuladhar; Kathleen S Rein

doi:10.1021/acsmedchemlett.7b00489

Manumycin A Is a Potent Inhibitor of Mammalian Thioredoxin Reductase-1 (TrxR-1)

ACS Med Chem Lett. 2018 Mar 5;9(4):318-322. doi: 10.1021/acsmedchemlett.7b00489. eCollection 2018 Apr 12.

Authors

Anupama Tuladhar¹, Kathleen S Rein¹

Affiliation

¹ Department of Chemistry and Biochemistry, Florida International University, 11200 SW Eighth Street, Miami, Florida 33199, United States.

Abstract

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^-•).