The [FeFe] hydrogenase catalyzes the redox interconversion of protons and H2 with a H-cluster employing CO, CN and azadithiolate ligands to two Fe centers. The biosynthesis of the H-cluster relies on a set of Fe-S maturase enzymes namely HydE, HydF and HydG. Among these three maturases, HydE and HydG are both members of the radical S-adenosylmethionine protein family. HydG can convert the tyrosine into diatomic ligands CO and CN with the help of the radical SAM. In addition, the auxiliary Fe-S cluster in HydG further incorporates CO and CN into an organometallic Fe(II)(CO)2(CN)cysteine “synthon”, which serves as the substrate for HydE. HydE is proposed to decompose the cysteine in the synthon and dimerize the left into a H-cluster analogue, which can be transferred by HydF to HydA. Although the overall synthetic mechanism of the H-cluster has been experimentally determined, there are still many mechanistic questions that have eluded experiments. Herein, QM/MM simulations were utilized to investigate the reaction mechanism of the H-cluster synthesis, particularly the catalytic reactions of HydG and HydE. We propose a radical relay mechanism of the tyrosine decomposition in HydG and a possible cysteine decomposition pathway in HydE

Theoretical study of the biosynthetic mechanism of the H-cluster in [FeFe] hydrogenase

ACS Spring 2022

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