Journal
ACS CATALYSIS
Volume 9, Issue 1, Pages 253-258Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acscatal.8b03903
Keywords
ovothiol; sulfur-containing natural products; kinetic isotope effect; unnatural amino acid; biosynthesis
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Funding
- National Science Foundation [CHE-1309148]
- National Natural Science Foundation of China [31670030, 31628004]
- China Postdoctoral Science Foundation [2018M642901]
- Young Talents Program of Wuhan University
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Ovothiols are thiol-histidines that play important roles in protecting cells against oxidative stresses. Because of challenges faced in their chemical synthesis, biosynthesis provides an alternative option. In ovothiol biosynthesis, a nonheme iron enzyme (OvoA) catalyzes a four-electron oxidative coupling between L-His and L-Cys. There are debates in the literature over whether oxidative C-S bond formation or sulfur oxidation is the first half of OvoA-catalysis. In this report, by incorporating a tyrosine analogue, 2-amino-3-(4-hydroxy-3-(methoxyl) phenyl) propanoic acid (MeOTyr), via an amber-suppressor method, we modulated the rate-limiting steps of OvoA-catalysis and observed an inverse deuterium KIE for [U-H-2(5)]-His. In conjunction with the reported quantum mechanics/molecular mechanics (QM/MM) studies, our results suggest that Y417 plays redox roles in OvoA-catalysis and imply that oxidative C-S bond formation is most likely the first half of the OvoA-catalysis.
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