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Biosynthesis of the catalytic H-cluster of [FeFe] hydrogenase: the roles of the Fe-S maturase proteins HydE, HydF, and HydG.

Abstract

[FeFe] hydrogenases carry out the redox interconversion of protons and molecular hydrogen (2H+ + 2e- ⇌ H2) at a complex Fe-S active site known as the H-cluster. The H-cluster consists of a [4Fe-4S] subcluster, denoted here as [4Fe]H, linked via a cysteine sulfur to an interesting organometallic [2Fe]H subcluster thought to be the subsite where the catalysis occurs. This [2Fe]H subcluster consists of two Fe atoms, linked with a bridging CO and a bridging SCH2NHCH2S azadithiolate (adt), with additional terminal CO and CN ligands bound to each Fe. Synthesizing such a complex organometallic unit is a fascinating problem in biochemistry, complicated by the toxic nature of both the CO and CN- species and the relative fragility of the azadithiolate bridge. It has been known for a number of years that this complex biosynthesis is carried out by a set of three essential Fe-S proteins, HydE, HydF, and HydG. HydF is a GTPase, while HydE and HydG are both members of the large family of radical S-adenosylmethionine (rSAM) enzymes. In this perspective we describe the history of research and discovery concerning these three Fe-S "maturase" proteins and describe recent evidence for a sequential biosynthetic pathway beginning with the synthesis of a mononuclear organometallic [Fe(ii)(CO)2CN(cysteine)] complex by the rSAM enzyme HydG and its subsequent activation by the second rSAM enzyme HydE to form a highly reactive Fe(i)(CO)2(CN)S species. In our model a pair of these Fe(i)(CO)2(CN)S units condense to form the [Fe(CO)2(CN)S]2 diamond core of the [2Fe]H cluster, requiring only the installation of the central CH2NHCH2 portion of the azadithiolate bridge, whose atoms are all sourced from the amino acid serine. This final step likely occurs with an interplay of HydE and HydF, the details of which yet remain to be elucidated.

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