Aminoimidazole carboxamide ribotide

Equation 1 is catalyzed by glycinamide ribotide (GAR) trans-formylase and Equation 2 is catalyzed by aminoimidazole-carboxamide ribotide (AICAR) transformylase. 

The biosynthesis of histidine. The 5-aminoimidazole-4-carboxamide ribotide formed during the course of histidine biosynthesis is also an intermediate in purine nucleotide biosynthesis. Therefore it can be readily regenerated to an ATP, thus replenishing the ATP consumed in the first step in the histidine biosynthetic pathway (see fig. 23.13). 

Fig. 15-16 The de novo purine biosynthetic pathway. Rib-5-P, ribose 5-phosphate P-Rib-PP, 5-phosphoribosyl 1-pyrophosphate PRA, 5-phosphoribosylamine IO-CHO-FH4, /Vl0-formyl tetrahydrofolate GAR, glycineamide ribotide FGAR. /V-formylglycineamide ribotide FGAM, /V-formylglycineamidine ribotide AIR, 5-aminoimidazole ribotide CAIR, 4-carboxy-5-aminoimidazole ribotide SAICAR, iV-succino-5-aminoimidazole-4-carboxamide ribotide AICAR, 5-aminoimidazole-4-carboxamide ribotide FAICAR, 5-formamidoimidazole-4-carboxamide ribotide sAMP, /V-succino-AMP. Enzymes (1) amido phosphoribosyltransferase (2) GAR synthetase (3) GAR transformylase (4) FGAM synthetase (5) AIR synthetase (6) AIR carboxylase (7) SAICAR synthetase (8) adenylosuecinase (9) AICAR transformylase (10) IMP cyclohydrolase (11) sAMP synthetase (12) adenylosuecinasc (13) IMP dehydrogenase (14) GMP synthetase.

As indicated above, derivatives of folic acid play a key role in the biosynthesis of purines and pyrimidines. These pteridines are the coenzymes responsible for inserting the carbon atoms into both positions 2 and 8 of purines, and they also insert the methyl-group into thymine (4.7 ). When bacteria are treated with low concentrations of sulfonamides, 4-aminoimidazole-5-carboxamide ribotide 9.22) accumulates in the culture media. This substance is an intermediate in the biosynthesis of inosinic acid 9.23) from which all purines are derived. 

EC 4.3.2.21 9. AICAR formyltransferase 5-Aminoimidazole-4-carboxamide ribotide (ACAIRl 1 ... 

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 first pharmacological agent shown to activate AMPK was 5-aminoimidazole-4-carboxamide (AICA) riboside, also known as acadesine. This adenosine analogue is taken up into cells by adenosine transporters and phosphoiylated by adenosine kinase to the mono-phosphorylated form, AICA ribotide or ZMP. ZMP accumulates inside cells to higher concentrations than the concentration of AICA riboside present in the medium, and it mimics both effects of AMP on AMPK system (allosteric activation and inhibition of... 

Then as shown in Scheme 13.67 (a reproduction of Scheme 12.96), 5-aminoimidazole ribose 5-phosphate is carboxylated (either with CO2 or with bicarbonate) to 5-carboxyamino-l-(5 -phosphoribosyl)imidazole, which rearranges to 5-aminoimidazole ribotide-4-carboxylate, and the latter undergoes amination from aspartate (Asp, D) to yield 5-amino-l-(5-phosphoribosyl)imidazole-4-carboxamide after the loss of fumarate. Finally (Scheme 13.8), A-formylation is effected with lO-CHO-H, folate to yield the A-formyl derivative (5-formamido-l-(5 -phosphoribosyl)imidaz-ole-4-carboxyamide) and cyclization yields inosine 5 -phosphate (IMP). 

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