Imidazole-4-carboxamide, 5-amino

Imidazole-4-catbonitrile, 5-amino-synthesis, 5, 463 Imidazolecarboxamide, cyano-reactions, 5, 436 Imidazole-4-carboxamide Hofmann reaction, 5, 435 Imidazole-4-carboxamide, 5-amino-in histidine biosynthesis, 1, 90 reactions... 

Therapeutic Function Cardiotonic, Platelet aggregation inhibitor Chemical Name lH-Imidazole-4-carboxamide, 5-amino-l(5-D-ribofuranosyl-Common Name Acadesine AICA riboside Arasine Structural Formula ... 

IMP, is synthesised with mutants of Bacillus subtilis or Corynehacterium am-moniagenes. Xanthosine 5 -monophosphate is produced with Corynebacte-rium or Bacillus and subsequently converted into GMF by Bacillus and other strains [6]. Alternatively, another related compound, 5 -amino-4-imidazole carboxamide-l-riboside-5 -phosphate, is produced by Bacillus megaterium and chemically converted into GMP [22, 36],... 

Small quantities of the 5-amino-4-imidazolecarboxamide nucleotide were also isolated from the culture medium of Escherichia coli grown under sulfonamide bacteriostasis.i i This substance is considered to be an intermediate in purine biosynthesis, both in micro-organisms and in mammalian cells. In sulfonamide-inhibited cells and in the purine-requiring mutant of Escherichia coli, there is a block in the conversion of 5-amino-4-imidazole-carboxamide n-ribonucleotide to inosinic acid. The accumulated nucleotide in the bacterial cell is probably attacked by phosphatases this would explain why the nucleoside is the main metabolite. 

Inosine can be converted directly to inosinate by inosine kinase. This enzyme has been shown to exist in human cells, but at a low level (P2). It undoubtedly does not play a major role. Inosine phosphorylase cleaves inosine to hypoxanthine and ribose I-phosphate (Kl). Inosine is formed by the deamination of adenosine catalyzed by adenosine deaminase, an enzyme found in varying concentrations in essentially all normal mammalian cells examined. Studies with an inhibitor of adenosine deaminase, ribosyl-4-amino-5-imidazole carboxamide, on several strains of Escherichia coli revealed a major role for the enzyme. In cells with a block in purine synthesis a condition of guanine deprivation occurred after growth with adenine as purine source, and there was a derepression of the enzymes that convert IMP to XMP and XMP to GMP (K17). 

Phosphoribosyl formimino-5-amino imidazole carboxamide ribonucleotide... 

Fig. 2. The pathway of histidine biosynthesis. Enzymes a, ribosephosphate pyrophos-phokinase E.C. 2.7.6.1 b, ATP-phosphoribosyltransferase, E.C. 2.4.2.17 c, phosphoribosyl-AMP cyclohydrolase, E.C. 3.5.4.19 d, N-(5 -phospho-D-ribosylforminino)5-amino-l-(5"-phos-phoribo yl)-4-imidazole carboxamide isomerase, E.C. 5.3.1.16 e, glutamine amidotransferase f, imidazolglycerolphosphate dehydratase E.C. 4.2.1.19 g, histidinol-phosphate aminotransferase E.C. 2.6.1.9 h, histidinol phosphatase, E.C. 3.1.3.15 i, histidinol dehydrogenase, E.C. 1.1.1.23.

K64 Kubonoya, J., Kimura, M. and Kongo, A. Clinical effectiveness of 4-amino-5-imidazole carboxamide orotate (Aica-min) on liver disease. Asian Med. J., 7, 196-198 (1964)... 

The heterocyclic base, 5-amino-4-imidazole carboxamide, was isolated in 1945 from sulfonamide-inhibited cultures of Escherichia coli, but its possible role as a precursor of purines was suggested only somewhat later. This re-... 

Under physiological conditions the pathway of purine biosynthesis de novo is believed to be irreversible. Reversibility of some reactions can, however, be demonstrated under some conditions of incubation in vitro. If Ehrlich ascites tumor cells are incubated with formate- C in the absence of glucose, for example, the 2-position of the purine ring may contain 8 to 10 times as much C as does the 8-position (SO), although these two positions should be equally labeled if net synthesis only had occurred. Apparently inosinate can be reversibly converted to phosphoribosyl amino-imidazole carboxamide, which in reforming inosinate incorporates radioactive formate. 

As mentioned in Chapter 7, adenylosuccinate lyase not only functions in purine ribonucleotide interconversion, but also converts phosphori-bosyl aminoimidazole succinocarboxamide to phosphoribosyl amino-imidazole carboxamide. Kinetic studies show that these compounds are alternative substrates and products, respectively, with adenylosuccinate and adenylate, and attempts physically to separate the two activities have consistently failed. Genetic studies have shown that both activities are governed by the same locus and that mutant enzymes behave similarly in both reactions 20, 21). 

Amino-4-imidazole carboxamide ribotide is converted to 5-formamido-4-imidazole carboxamide ribotide in a formylation reaction using N -formyltetra-hydrofolic acid. The formylation is catalyzed by 5-aminoimidazole-4-carboxamide ribotide transformy-lase. Isonicase then closes the purine ring, forming inosinic acid in the absence of ATP. Fig. 3-59 illustrates the origin of each atom of the purine ring. 

Amino-4-imidazole carboxamide ribotide, a precursor only two steps removed (formylation and cycli-zation) from inosinic acid, can be synthesized by the direct condensation of the imidazole with 5-phosphori-bosyl pyrophosphate. The enzyme catalyzing this reaction was purified from an acetone powder of beef liver. The same enzyme (AMP pyrophosphorylase) catalyzes the condensation of adenine, guanine, and hypoxan-thine. Nucleoside phosphorylase is an enzyme that catalyzes the formation of a ribose nucleoside from a purine base and ribose-1-phosphate. Guanine, adenine, xanthine, hypoxanthine, 2,6-diaminopurine, and aminoimidazole carboxamide are known to be converted to their respective nucleosides by such a mechanism. In the presence of a specific kinase and ATP, the nucleoside is then phosphorylated to the corresponding nucleotide. 

The 5-amino-4-imidazole carboxamide ribonucleotide transformylase and the glycinamide ribonucleotide transformylase reactions have been studied in chicken liver preparations by Hartman and Buchanan. 

Amino-5-imidazole-carboxamide ribotide CoF + HCOOH C -formyl-CoF O... 

Many similar reactions have been demonstrated and several hitherto unknown desoxyribosides have been enzymatically S5uithesized. The desoxyriboside of 6-methylcytosine can be formed in this way. 6-Methyl-cytosine is a component of the desoxyribonucleic acid of several animal and plant species.5-Amino-4-imidazole carboxamide also participates in reactions of this type to yield a desoxyriboside. This compound contains an incomplete purine ring and accumulates in sulfonamide-treated E. coli. It is discussed in detail elsewhere (page 229). 

Chlorobenzyl)amino)-l-(3-ethylureido)-iV, iV,5 -trimethyl- l//-imidazole -carboxamide (5c) White powder, mp 192-194 °C reaction time 7 h yield 88%... 

Bochner B R, Ames B N 1982 ZTP (5-amino 4-imidazole carboxamide riboside 5 -triphosphate) A proposed alarmone for 10-formyltetrahydrofolate deficiency. Cell 29 929-937... 

Trifluoromethylpurines have been prepared mainly through formation of the pyrimidine ring starting from highly functionalised imidazoles. 5-Amino-4-(cyanoformimidoyl)imidazole 29 reacted rapidly with neat trifluoroacetic anhydride to give the 6-cyano-2-trifluoromethylpurine 30 (20 °C, 10 min, 52 %) [55] (Scheme 13). However, hydrolysis to the 6-carboxamidopurine 31 was observed when the reaction was carried out over several days [55,56]. This latter transformation has been applied to prepare 9-(3-hydroxy-propyl)-2-trifluoromethyl-9H-purine-6-carboxamide [57]. 

Fig. 5. Effect of preincubation with adenine and amino-imidazole-carboxamide on heat stability of HGPRT activity in erythrocytes from a patient with the Lesch-Nyhan syndrome. Control, - 0.1 mM adenine or AIC,CM3 0.01 mM adenine or AIC,CIHII.

In summary, the biochemical function of folate coenzymes is to transfer and use these one-carbon units in a variety of essential reactions (Figure 2), including de novo purine biosynthesis (formylation of glycinamide ribonucleotide and 5-amino-4-imidazole carboxamide ribonucleotide), pyrimidine nucleotide biosynthesis (methylation of deoxyuridylic acid to thy-midylic acid), amino-acid interconversions (the interconversion of serine to glycine, catabolism of histidine to glutamic acid, and conversion of homocysteine to methionine (which also requires vitamin B12)), and the generation and use of formate. 

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).

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