Reconstitution of ThiC in thiamine pyrimidine biosynthesis expands the radical SAM superfamily |
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Authors: | Chatterjee Abhishek Li Yue Zhang Yang Grove Tyler L Lee Michael Krebs Carsten Booker Squire J Begley Tadhg P Ealick Steven E |
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Affiliation: | Department of Chemistry and Chemical Biology, 120 Baker Laboratory, Cornell University, Ithaca, New York 14853-1301, USA. |
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Abstract: | 4-Amino-5-hydroxymethyl-2-methylpyrimidine phosphate (HMP-P) synthase catalyzes a complex rearrangement of 5-aminoimidazole ribonucleotide (AIR) to form HMP-P, the pyrimidine moiety of thiamine phosphate. We determined the three-dimensional structures of HMP-P synthase and its complexes with the product HMP-P and a substrate analog imidazole ribotide. The structure of HMP-P synthase reveals a homodimer in which each protomer comprises three domains: an N-terminal domain with a novel fold, a central (betaalpha)(8) barrel and a disordered C-terminal domain that contains a conserved CX(2)CX(4)C motif, which is suggestive of a [4Fe-4S] cluster. Biochemical studies have confirmed that HMP-P synthase is iron sulfur cluster-dependent, that it is a new member of the radical SAM superfamily and that HMP-P and 5'-deoxyadenosine are products of the reaction. M?ssbauer and EPR spectroscopy confirm the presence of one [4Fe-4S] cluster. Structural comparisons reveal that HMP-P synthase is homologous to a group of adenosylcobalamin radical enzymes. This similarity supports an evolutionary relationship between these two superfamilies. |
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