Article abstract
Nature Chemical Biology 4, 758 - 765 (2008)
Published online: 26 October 2008 | doi:10.1038/nchembio.121
Reconstitution of ThiC in thiamine pyrimidine biosynthesis expands the radical SAM superfamily
Abhishek Chatterjee1,4, Yue Li1,4, Yang Zhang1, Tyler L Grove2, Michael Lee3, Carsten Krebs2,3, Squire J Booker2,3, Tadhg P Begley1 & Steven E Ealick1
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 (
)8 barrel and a disordered C-terminal domain that contains a conserved CX2CX4C 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. Mössbauer 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.
- Department of Chemistry and Chemical Biology, 120 Baker Laboratory, Cornell University, Ithaca, New York 14853-1301, USA.
- Department of Chemistry, 104 Chemistry Building, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
- Department of Biochemistry and Molecular Biology, 108 Althouse Laboratory, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
- These authors contributed equally to this work.
Correspondence to: Tadhg P Begley1 e-mail: tpb2@cornell.edu
Correspondence to: Steven E Ealick1 e-mail: see3@cornell.edu
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