The biosynthesis of the active site of the [FeFe]-hydrogenases (H-cluster) remains a tantalizing puzzle due to its unprecedented and complex ligand environment. It contains a [2Fe] cluster ([2Fe](H)) bearing cyanide and carbon monoxide ligands attached to low-valence Fe ions and an abiological dithiolate ligand (SCH(2)XCH(2)S)(2-) that bridges the two iron centers. Various experimentally testable hypotheses have already been put forward regarding the precursor molecule and the biosynthetic mechanism that leads to the formation of the dithiolate ligand. In this work, we report a density functional theory-based theoretical evaluation of these hypotheses. We find preference for a mechanistically simple and energetically favorable pathway that includes known radical-SAM (S-adenosylmethionine) catalyzed reactions. We modeled this pathway using a long alkyl chain precursor molecule that leads to the formation of pronanadithiolate (X = CH(2)). However, the same pathway can be readily adopted for the biosynthesis of the dithiomethylamine (X = NH) or the dithiomethylether (X = O) analog, provided that the proper precursor molecule is available.
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