This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The recent publication of the crystal structure of the biotin synthase at 3 resolution allowed for structural models to understand the molecular mechanism of the final step in the biotin biosynthetic pathway. This is the conversion of dethiobiotin (DTB) to biotin via a unique, radical mechanism. The crystal structure revealed a highly unusual coordination environment for the 4Fe- and the 2Fe-clusters. The S-adenosylmethionine (SAM) is coordinated to the 4Fe cluster through the aminoacid end, while the 2Fe cluster has an Arg ligand in addition to three normal cysteines in both. Electronic structure calculations using the crystal coordinates already started to provide exciting insights into the mechanism as the mechanistically important sulfonium-carbon antibonding orbital of the SAM becomes the redox active orbital upon initial electron transfer into the 4Fe active site. However, these computational studies are strongly dependent on the employed 4Fe geometric structure. Therefore, a systematic EXAFS study would provide independent and more accurate radial coordinates relative to the crystal structure and could validate many of the mechanistic ideas we are developing.
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