IspH is an [Fe4S4] enzyme in isoprenoid biosynthesis in many bacteria and malaria parasites. It is an important drug target. X-ray crystal structure of a very potent pyridine inhibitor suggests a unique η2 coordination mode. However, the resolution is not high enough to clear some uncertainties. A systematic quantum chemical investigation of the active site models using both reduced and oxidized clusters, both neutral pyridine and positively charged pyridinium, and both the original X-ray conformation and ring-flipped conformation, provide strong evidence that the active site structure has a reduced cluster with a side-on η2 coordination of pyridine. This structure enables excellent predictions of experimental HYSCORE spectroscopic data. A major barrier to understanding the mechanism of nitric oxide reductases (NORs) is the lack of a selective probe of NO binding to the nonheme FeB center. A recent experimental advance is the construction of a structurally and functionally similar NOR biosynthetic model. Quantum chemical calculations show that the NO bound non-heme iron center enables excellent predictions of experimental Mössbauer properties, sensitive probes of the iron nitrosyl complex. Computational results also show a radical nature of the bound NO, which may facilitate N-N bond formation by radical coupling with the heme-bound NO as proposed previously. Overall, these results show that quantum chemical studies together with experimental spectroscopic data may provide useful structural information to investigate metalloprotein complexes with inhibitors and ligands.

Binding of a potent pyridine inhibitor in an iron-sulfur enzyme IspH and NO in the non-heme center of a biosynthetic nitric oxide reductase model

251st National Meeting (2016)

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