This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.1. The de novo purine biosynthetic pathway is ubiquitous in most organisms. In vertebrates, it is a ten-step synthesis of inosine 5'-monophosphate (IMP) from phosphoribosyl pyrophosphate. We undertook a structural investigation of several enzymes involved in the pathway to elucidate their catalytic mechanisms. Formyl glycinamidine ribonucleotide (FGAM) synthetase (PurL) catalyzes the fourth step: an ATP dependent conversion of formyl glycinamide ribonucleotide (FGAR) to FGAM. PurL exists in two forms; large PurL found in eukaryotes and gram-negative bacteria consists of a single polypeptide chain of 140 kDa; small PurL of 80 kDa is found in archaea and gram-positive bacteria and requires two additional gene products, PurQ and PurS, for activity. In the fifth step, aminoimidazole ribonucleotide (AIR) synthetase (PurM) utilizes ATP to convert FGAM to AIR. Class I PurE is an unusual mutase that catalyzes the sixth step, synthesis of carboxyaminoimidazole ribonucleotide (CAIR) from N5-CAIR. PurP is an archaeal signature gene that has been recently identified to catalyze the ninth step; it utilizes ATP to incorporate formate into 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) and form formaminoimidazole-4-carboxamide ribonucleotide (FAICAR). In the final step of the de novo purine biosynthesis, IMP cyclohydrolase catalyzes the cyclization of FAICAR to IMP. Two major types of this enzyme have been discovered to date: PurH in bacteria and eukarya, and PurO in archaea. 2. We determined structures
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