IMIDAZOLE GLYCEROL PHOSPHATE DEHYDRATASE

Norcross, R.D., Matt, P.v., Kolb, H.C., and Bellus, D., Synthesis of novel cyclobutylphosphonic acids as inhibitors of imidazole glycerol phosphate dehydratase. Tetrahedron, 53, 10289, 1997. 

Amlnotrlazole Histidine Imidazole glycerol phosphate dehydratase... 

ATP phosphoribosyltransferase 2 phosphoribosyl-ATP pyrophosphatase 3 phosphoribosyl-AMP cyclohydrolase 4 isomerase 5 formyltransferase, inosine monophosphate cyclohydrolase 6 adenylosuccinate synthetase 7 adenylosuccinate lyase 8 adenylate kinase 9 imidazole glycerol phosphate dehydratase 10 histidinol phosphate aminotransferase 11 histidinol phosphatase 12 histidinol dehydrogenase... 

Fig. 4. Histidine tnosynthess. Intermediates PRPP, phosphoribosyl pyrophosidiate PR-ATP, JV-phoqjhoribosyl-ATP PR-AMP, A/ -phosphoribosyl-AMP PR-FAIC-RN, phosphoribosyl for-mimino-S-amino imidazole carboxamide ribonucleotide PRu-FAIC-RN, phosphoribulosyl for-mimino-5-aniino imidazole carboxamide ribonucleotide IGP, imidazole glycerol phosphate lAP, imidazole acetol idrosphate HP, histidinol (dioqrhate HOL, histidinol. Enzymes (I) ATP phos-phoribosyltransferase (EC 2.4.2.17) (2) phosphoribosyl-ATP pyrophosphohydrolase (EC 3.6.1.31) (3) idiospharibosyl-AMP cyciohydrolase (EC 3.5. A19) (4) PR-FAIC-RN isomerase (EC S.3.1.16) (S) glutamine amidotransferase (6) cyclase (7) imidazole glycerol phosphate dehydratase (EC 4.2.1.19) (8) histidinol-phosphate aminotransferase (EC 2.6.1.9) (9) histidinol phosphatase (EC 3.1.3.15) (10) histidinol dehydrogenase (EC 1.1.1.23).

The herbicide Amitrole (455) has several documented effects on metabolism. In E. coli, histidine and adenine together reverse the inhibition of growth by Amitrole, whereas adenine alone, but not histidine alone, partially relieves the inhibition. In the yeast T. cremoris, histidine alone, but not adenine alone, completely reverses the inhibition.A metabolite, identified as a conjugate of alanine and Amitrole, has been shown to accumulate in the medium of E. coli cultured in the presence of Amitrole it apparently competes with histidine for incorporation into protein.Unlike Amitrole, this metabolite does not inhibit the conversion of imidazole glycerol phosphate (IGP) to imidazole acetol phosphate by IGP dehydratase in Salmonella the reaction is part of the biosynthesis of histidine. 

The enzyme imidazole glycerol-phosphate (IGP) dehydratase (EC 4.2.1.19, Figure 2.6) is inhibited by amitrole (Figure 2.4). The enzyme from S. typhimurium is competitively inhibited with a K, of 30 A similar... 

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