Aminoimidazole carboxamide ribonucleotide

MTX also has several effects on the purine synthetic pathway. MTXPGs inhibit the enzyme aminoimidazole carboxamide ribonucleotide (AlCAR) transformylase, which in turn causes intracellular accumulation of AICAR. AICAR and its metabolites can then inhibit two enzymes in the adenosine pathway adenosine deaminase and adenosine monophosphate (AMP) deaminase, which leads to intracellnlar accumulation of adenosine and adenine nucleotides. Subsequent dephosphorylation of these nucleotides results in increased extracellular concentrations of adenosine, which is a powerful anti-inflammatory agent (11). 

Fig. 14.1 Cellular pathway of methotrexate. ABCBl, ABCCl-4, ABC transporters ADA, adenosine deaminase ADP, adenosine diphosphate AICAR, aminoimidazole carboxamide ribonucleotide AMP, adenosine monophosphate ATIC, AICAR transformylase ATP, adenosine triphosphate SjlO-CH -THF, 5,10-methylene tetrahydrofolate 5-CHj-THF, 5-methyl tetrahydro-folate DHFR, dihydrofolate reductase dTMP, deoxythymidine monophosphate dUMP, deoxy-uridine monophosphate FAICAR, 10-formyl AICAR FH, dihydrofolate FPGS, folylpolyglutamyl synthase GGH, y-glutamyl hydrolase IMP, inosine monophosphate MTHFR, methylene tetrahydrofolate reductase MTR, methyl tetrahydrofolate reductase MTX-PG, methotrexate polyglutamate RFCl, reduced folate carrier 1 TYMS, thymidylate synthase. Italicized genes have been targets of pharmacogenetic analyses in studies published so far. (Reproduced from ref. 73 by permission of John Wiley and Sons Inc.)...

Dervieux, T., Eurst, D., Lein, D. O., et al. (2004) Polyglutamation of methotrexate with common polymorphisms in reduced folate carrier, aminoimidazole carboxamide ribonucleotide transformylase, and thymidylate synthase are associated with methotrexate effects in rheumatoid arthritis. Arthritis and Rheumatism. 50, 2766-2774. 

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],... 

Figure 44.1 Folate-mediated one carbon metabolism network. Enzymes and transport proteins are enclosed in rectangular boxes. AHCY S-adenosyDiomocys-teine hydrolase AICART 5-aminoimidazole carboxamide ribonucleotide transferase BHMT betaine homocysteine methyltransferase CBS cystathionine beta-synthase DHFR dihydrofolate reductase FR folate receptor FTCD formimidoyltransferase cyclodeaminase GART glycinamide ribonucleotide transformylase MATs (MATI/MATIII) adenosylmethionine transferase enzyme I/III MS methionine synthase MSR methionine synthase reductase MT methyltransferase MTHFD methylenetetrahydrofolate dehydrogenase MTHFR 5,10-methylenete-trahydrofolate reductase MTHFS 5,10-methylenetetrahydrofolate synthase. RFC reduced folate AdoMet 5-adenosylmethionine AdoHcy S-adenosylhomocysteine Hey homocysteine SHMT serine hydroxymethyltransferase TS thymidylate synthase.

Aminoimidazole-4-Carboxamide Ribonucleotide Transformylase Carbonic Anhydrase II DNA Gyrase... 

Aminoimidazole-4-carboxamide ribonucleotide (AlCAR) transformylase inhibitor, Ki = 154 nM, IC50 = 600 nM... 

Li C, Xu L, Wolan DW, Wilson lA, Olson AJ. Virtual screening of human 5-aminoimidazole-4-carboxamide ribonucleotide transformylase against the NCI diversity set by use of AutoDock to identify novel nonfolate inhibitors. J Med Chem 2004 47 6681-90. 

Til. Mode of Action of Sulfa Drugs Some bacteria require p-aminobenzoate in the culture medium for normal growth, and their growth is severely inhibited by the addition of sulfanilamide, one of the earliest sulfa drugs. Moreover, in the presence of this drug, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR see Fig. 22-33) accumulates in the culture medium. These effects are reversed by addition of excess p-aminobenzoate. 

PFACRI N -[(5 -phosphoribosyl)formimino]-5-aminoimidazole-4-carboxamide ribonucleotide isomerase ImGPS imidazole 3-glycerol phosphate synthase OMPDC orotidine 5 -phosphate decarboxylase R5PE ribulose 5-phosphate epimerase HUMPS hex-3-ulose monophosphate... 

Fig. 11.6. Interconversions of tetrahydrofolate derivatives. FH2 = dihydrofolic acid FH4 = tetrahydrofolic acid AICAR -= 5 aminoimidazole 4-carboxamide ribonucleotide FAICAR = formyl AICAR GAR = glycinamide ribonucleotide FGAR = formyl GAR Glu = glutamic acid FIGLU = formimino glutamic acid. (Modified from Mudd and Cantoni, 1964.)...

Sulfa action. Bacterial growth is inhibited by sulfanilamide and related sulfa drugs, and there is a concomitant accumulation of 5-aminoimidazole-4-carboxamide ribonucleotide. This inhibition is reversed by the addition ofp-aminobenzoate. 

ATP phosphoribosyl transferase ( ) pyropbospbohydrolase ( ) pbospboribosyl-AMP cyclohydrolase ( phosphoribosylfornumino-5-aminoimidazole-4-carboxamide ribonucleotide isomerase... 

Another enzyme recently shown [62] to be competitively inhibited by lAHQ is aminoimidazole-4-carboxamide ribonucleotide transferase (AICAR TFase), which catalyzes the final step in the biosynthesis of purine nucleo-... 

FIGURE 51—4 Sites of action of methotrexate and its pofyglutamates. AICAR, aminoimidazole carboxamide TMR thymidine monophosphate dUMP, deoxyuridine monophosphate FH Glu, dihydrofolate polyglutamate FH Glu, tetrahydrofolate polyglutamate GAR, glycinamide ribonucleotide IMP, inosine monophosphate PRPP, 5-phosphoribosyl-1 -pyrophosphate. 

It is not known exactly how methotrexate produces its effects in rheumatoid arthritis, but one theory is that it possibly increases levels of adenosine by blocking a step in purine biosynthesis, leading to accumulation of adenosine, which results in anti-inflammatory effects. It also inhibits the enzyme 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) trans-formylase, raising levels of AICAR, which in turn increases adenosine levels. It may also contribute to the phosphorylation of adenosine nucleotides creating an accumulation of adenosine in tissues. Caffeine is an adenosine receptor antagonist and therefore could reverse the effects of methotrexate. 

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.

Adenylosuccinate formed by adenylosuccinate synthetase is cleaved by adenylosuccinate lyase to form AMP. The reaction steps are illustrated in Fig. 1. Included in the sequence is the additional reaction catalyzed by AMP deaminase. These three enzymes have been suggested to function in a cyclic process termed the purine nucleotide cycle 7,8). The two-step conversion of IMP to AMP is very similar to both the conversion of citrulline to arginine, which involves formation of argininosuccinate as an intermediate, and formation of 5-amino-imidazole 4-carboxamide ribonucleotide from 5-aminoimidazole 4-carboxylate ribonucleotide as part of IMP biosynthesis. Adenylosuccinate lyase is a dual function enzyme catalyzing the cleavage of both adenylosuccinate and 5-aminoimidazole 4-N-succinocarboxamide ribonucleotide. 

It was subsequently shown that radioactive aminoimidazole carboxamide was converted to inosinate by pigeon liver extracts, and it seemed logical to assume that a ribose phosphate derivative of aminoimidazole carboxamide must be an intermediate. The ribonucleotide, phosphoribosyl aminoimidazole carboxamide, was synthesized enzymatically and was indeed converted to inosinate by pigeon liver fractions. 

F ormyltransferases 5,10-Methenyltetra-hydrofolate, 10-formyltetrahy dro-folate ( activated formic acid ) Glycineamide ribonucleotide transformylase (D 10.4) 5-Aminoimidazole-4-carboxamide ribonucleotide transformylase (D 10.4)... 

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