Enzyme Catalysis that Paves the Way for S‑Sulfhydration via Sulfur Atom Transfer

S-sulfhydration is
generally anticipated to proceed through the
transfer of the SH group (Nu–SH···–S–R → Nu–···HS–S–R).
The other route involves the sulfur atom (S0) transfer
between two sulfhydryl anions (Nu–S–···–S–R → Nu–···–S–S–R) and is considered electrostatically
unfavorable. Mercaptopyruvate sulfurtransferase (MST, PDB code: 4JGT) catalyzes sulfur
transfer from mercaptopyruvate to sulfur acceptors, and the first
step of the reaction is the formation of cysteine (Cys248) persulfide
via S-sulfhydration. Mechanistic studies on S-sulfhydration in MST
using QM/MM methods show that the sulfur atom transfer initialized
by the deprotonation of the Ser250/His74/Asp63 triad is kinetically
preferred to the SH-promoted sulfur transfer. The calculated barrier
of approximately 16 kcal mol–1 for the S0 transfer agrees well with experimental results. The electrostatic
repulsion during the S0 transfer can be sophisticatedly
reduced by the aid of the Cys248-Gly249-Ser250-Gly251-Val252-Thr253
(CGSGVT) loop. Electrostatic potentials and frontier orbitals are
also analyzed for the persulfide anion surrounded by the loop. The
sulfur atom transfer which is seldom regarded possible is therefore
facilitated with the assistance of the triad and the loop in the enzyme.