Imidazole glycerol

Independent of the actual mechanism, functional divergence between two proteins with a common ancestor is exemplified in the /la-barrel structures of N-(phosphor-ibosyl-formimino)-aminoimidazole-carboxamide ribonucleotide isomerase (HisA) and imidazole glycerol phosphate synthase (HisF) of the histidine biosynthetic pathway [16]. The hypothesis of a common origin of the two enzymes was formulated based on sequence comparison [17] and has recently found support by the identification of extensive structural similarities [18],... 

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. 

Association of domains or subunits carrying multiple active sites also allows coordination of various activities carried out by the protein. For example, in imidazole glycerol phosphate synthase, binding of phosphoribulosylformimino-amino imidazole ribonucleotide phosphate at one active site stimulates the hydrolysis of glutamate at another active site 30 A away by 4900-fold." This strategy prevents generation of NH3, an inconveniently volatile intermediate, until it is needed. 

Amlnotrlazole Histidine Imidazole glycerol phosphate dehydratase... 

Figure 5.82 Biosynthesis of histidine. PRPP, 5-phosphoribosyl-a-l-pyrophosphate PRATP, AT-5 -phosphoribosyl-ATP PRAMP, M-S -phosphoribosyl-AMP 5 -ProFAR, yV -[(5. phosphoribosyl)-formimino]-5-aminoiinidazole-4-carboxamide-ribonucleotide 5 -PRFAR, A/ -[(5 -phosphoribulosyl)-formimino]-5-aminoimidazole-4-carboxainide-ribonuc leotide IMGP, imidazole glycerol-phosphate AICAR, 5 -phosphoribosyl-4-carboxamide-5-aminoimidazole lAP, imidazoleacetol-phosphate HOL-P, L-histidinol-phosphate HOL, L-histidinol HAL, L-histidinal.

E. Amidotransferase and cyclase. Presumably an intermediate is produced by transfer of nitrogen from glutamine, followed by cyclization to form the imidazole ring of imidazole glycerol phosphate. The intermediate is not known, and the amidotransferase and cyclase activities have not been separated. 

Amlno-l, 2,4-triazole NH, Inhibits imidazole glycerol phosphate dehydrase 9... 

Formation of L-histidine is closely related to purine biosynthesis (D 10.4, Fig. 239). ATP is the actual precursor. It condenses with phosphoribosyl pyrophosphate at position 1 before the purine ring is splitted between the positions 1 and 6. An Amadori rearrangement in the two-prime-ribose unit yields the ribulose derivative l-(5 -phosphoribosyl)-4-carboxamido-5-iV-(N -5 -phospho-ribosyl)-formamidinoimidazole, which reacts with glutamine to D-erythro-imidazole glycerol phosphate (the precursor of histidine) and l-(5 -phospho-ribosyl)-4-carboxamido-5-aminoimidazole, which may be regenerated to ATP (D 10.4). 

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... 

The enzymes that catalyze these transformations have been partially purified from extracts of Neurospora. Imidazole glycerol phosphate is dehydrated by an enzyme named IGP dehydrase to form imidazole acetol phosphate. The dehydrase requires Mn++ and a sulfhydryl com-... 

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