Imidazoleglycerol phosphate

Analogously, ethyl 4-fluoro-3-methylcrotonate is brominated with NBS in the presence of AIBN and then reacted with triethyl phosphite to produce good yields (72-78%) of a-fluorophosphonate, a key intermediate in the synthesis of fluorinated vitamin A esters (Scheme 3.3)7 Following a similar procedure (radical bromination and Michaelis-Arbuzov rearrangement), ( )-l-fluoro-3-(l-trityl-l,2,4-triazol-3-yl)-2-propenylphosphonate, a good inhibitor of imidazoleglycerol phosphate dehydratase, has been prepared in 25% overall yield. ... 

The D-erythro configuration of imidazoleglycerol suggests that a pentose such as ribose 5 -phosphate might be concerned in the formation of the above intermediates of histidine synthesis. Qualitative evidence has been obtained of an enzyme that converts imidazoleglycerol phosphate to imidazoleacetol phosphate ( SS, 84). The further characterization of this enzyme has not been reported. 

Subsequently Moyed and Magasanik ( 88) obtained the synthesis of D-er ro-imidazoleglycerol phosphate ester in cell-free preparations from three enteric bacterial species. This compound is a precursor of histidine. Evidence was also obtained that the imidazoleglycerol phosphate was formed from ribose 5-phosphate, the amide nitrogen of glutamine, and the N-1 and C-2 portion of the adenine ring of ATP. The residue of the ATP appears as 5-amino-l-ribosyl-4-imidazolecarboxamide 5 -phosphate. The latter is a well-known intermediate in purine biosynthesis and can be reconverted to ATP. This provides a cyclic process for the i thesis of the imidazole ring of histidine. 

Since aminoribosylimidazolecarboxamide phosphate is not a known precursor for purine biosynthesis and various experimental results were obtained which indicated that this compound was not being utilized for purine formation by the bacterial preparations, Moyed and Magasanik were led to suspect that this compound was involved in the biosynthesis of the imidazole ring of histidine. This suggestion was supported by the finding of the accumulation of D-erj/ffiro-imidazoleglycerol phosphate ester as a product of these reactions. 

The C-1 of ribose 5-P was incoiporated into imidazoleglycerol phosphate without dilution. When AMP-8-C was employed, the aminoribosyl-imidazolecarbnxamide phosphate had the same radioactivity as the reisolated adenosine 5-phosphate (AMP) the imidazol ycerol phosphate had no detectable activity. The C-2 of adenine, on the contrary, was incorporated into imidazoleglycerol ph q>hate without dilution, but was not incorporated into the aminoribosylimidazolecarboxamide phosphate. 

The results support the assumption that the adenine ring is cleaved into two moieties one containing the C-2 of adenine combined with ribose 5-P to form imidazoleglycerol phosphate, and a residual moiety, containing C-8, that is converted to the arylamine. 

Studies with histidine auxotrophs of Salmonella typhimurium showed that mixing extracts of a strain unable to produce compound III with that of a strain capable of producing III, but unable to convert it to the aminoribosylimidazolecarboxamide phosphate and imidazoleglycerol phosphate, carried the reaction to completion with the formation of both of these compounds. 

Cox JM, Hawkes TR, Bellini P et al (1997) The design and synthesis of inhibitors of imidazoleglycerol phosphate dehydratase as potential herbicides. Pestic Sci 50 297-311... 

Figure 2.6. The reaction catalyzed by imidazoleglycerol-phosphate dehydratase.

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