IMP CYCLOHYDROLASE

The enzymatic activity of amido phosphoribosyltransferase (P-Rib-PP— PR A) is low and flux through the de novo pathway in vivo is regulated by the end-products, AMP, IMP and GMP. Inhibition of reaction 1 by dihydrofolate polyglutamates would signal the unavailability of /V1()-formyl tetrahydrofolate, required as a substrate at reactions 3 and 9 of the pathway. The purine pathway is subject to further regulation at the branch point from IMP XMP is a potent inhibitor of IMP cyclohydrolase (FAICAR—> IMP), AMP inhibits adenylosuccinate synthetase (IMP—> sAMP) and GMP inhibits IMP dehydrogenase (IMP— XMP). 

A bifunctional enzyme, comprising the activities of AIR carboxylase and SAICAR synthetase, catalyzes reactions 6 and 7 of the purine pathway (AIR—> CAIR— SAICAR Fig. 15-16). A second bifunctional enzyme, IMP synthase, containing the activities of AICAR transformylase and IMP cyclohydrolase, catalyzes reactions 9 and 10 of the pathway (AICAR — FAICAR— IMP Fig. 15-16). Human IMP synthase has a subunit molecular weight of 62.1 kDa and associates as a dimer. A... 

Fig. 15-16 The de novo purine biosynthetic pathway. Rib-5-P, ribose 5-phosphate P-Rib-PP, 5-phosphoribosyl 1-pyrophosphate PRA, 5-phosphoribosylamine IO-CHO-FH4, /Vl0-formyl tetrahydrofolate GAR, glycineamide ribotide FGAR. /V-formylglycineamide ribotide FGAM, /V-formylglycineamidine ribotide AIR, 5-aminoimidazole ribotide CAIR, 4-carboxy-5-aminoimidazole ribotide SAICAR, iV-succino-5-aminoimidazole-4-carboxamide ribotide AICAR, 5-aminoimidazole-4-carboxamide ribotide FAICAR, 5-formamidoimidazole-4-carboxamide ribotide sAMP, /V-succino-AMP. Enzymes (1) amido phosphoribosyltransferase (2) GAR synthetase (3) GAR transformylase (4) FGAM synthetase (5) AIR synthetase (6) AIR carboxylase (7) SAICAR synthetase (8) adenylosuecinase (9) AICAR transformylase (10) IMP cyclohydrolase (11) sAMP synthetase (12) adenylosuecinasc (13) IMP dehydrogenase (14) GMP synthetase.

Fig. 3. The pathway of de novo purine ribonucleotide biosynthesis. The pathway includes the synthesis of PRPP, which is also used in the synthesis of pyrimidines, pyridine nucleotides, histidine, and tryptophan in plants. The enzymes catalyzing the numbered reactions are (1) PRPP synthetase, (2) PRPP amidotransferase, (3) GAR synthetase, (4) GAR transformylase, (5) FGAR amidotransferase, (6) AIR synthetase, (7) AIR carboxylase, (8) succino-AICAR synthetase, (9) adenylosuccinase, (10) AICAR transformylase, and (11) IMP cyclohydrolase.

Human IMP synthase has a subunit molecular weight of 62.1 kDa and associates as a dimer. A trifunctional enzyme, Cj-THF synthase, containing (V °-methenyl tetrahydrofolate (5,10-CH-THF) cyclohydrolase and A °-formyl tetrahydrofolate (lO-CHO-THF) synthetase, catalyzes the reactions 5,10-CH2-THF 5,10-CH-THF and THF —> lO-CHO-THF. The A °-CH-THF produced is a substrate for GAR and AICAR transformylases catalyzing reactions 3 and 9 of the pathway. In higher eukaryotes, the dehydrogenase and cyclohydrolase activities are located in one domain of the protein, which is fused to a larger synthetase domain, forming a trifunctional enzyme. 

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