Dismantling and Rebuilding the Trisulfide Cofactor Demonstrates Its Essential Role in Human Sulfide Quinone Oxidoreductase

• DOI: 10.1021/jacs.0c06066
• Publication Date: 2020-07-31T14:49:27Z
• Authors: Aaron P. Landry; Sojin Moon; Jenner Bonanata; Uhn Soo Cho; E. Laura Coitiño; Ruma Banerjee
• Keywords: Dimethyl trisulfide; Rhodanese; Dimethyl sulfide

Sulfide quinone oxidoreductase (SQOR) catalyzes the first step in sulfide clearance, coupling H2S oxidation to coenzyme Q reduction. Recent structures of human SQOR revealed a sulfur atom bridging active site cysteines trisulfide configuration. Here, we assessed importance this cofactor using kinetic, crystallographic, and computational modeling approaches. Cyanolysis proceeds via formation an intense charge transfer complex that subsequently decays eliminate thiocyanate. We captured disulfanyl-methanimido thioate intermediate crystal structure, revealing how cyanolysis leads reversible loss activity is restored presence sulfide. Computational MD simulations ∼105-fold rate enhancement for nucleophilic addition into versus disulfide cofactor. The cysteine thus critical provides significant catalytic advantage over disulfide.