Glutamine inosinic acid

The second step in the conversion of inosinic acid to guanylic acid is the aminolysis of xanthylic acid with glutamine by xanthosine-5 -phosphate aminase [65]. This aminase, isolated fromf. coli B, is inhibited allosterically by adenosine and adenylic acid [320], and it is also inhibited by psicofuranine (9-0-D-psicofuranosyladenine) (LXXIV) [284, 321-326], which apparently is not... 

When injected, azathioprine (Imuran) is rapidly converted to 6-mercaptopurine. The half-life of azathioprine after intravenous injection is 10 to 20 min, and that of 6-mercaptopurine is somewhat longer. The cytotoxic activity of these thiopurines is due to the conversion of mercaptopurine to 6-thiouric acid, a noncarcinostatic metabolite. This action is thought to block the excess synthesis of inosinic acid from its precursors, glutamine and phosphoribosylpyrophosphate. In addition, unlike cyclophosphamide, azathioprine is a potent anti-inflammatory substance that can cause a reduction in the number of monocytes and neutrophils at inflammatory sites. Antibody responses are also inhibited by azathioprine. Studies in humans have shown that azathioprine decreases the y-globulin and antibody levels, thus influencing IgG rather than IgM production. This makes azathioprine an effective immunosuppressant in the early phases of immune responses. It is less effective or completely ineffective in altering either the effector phase or already established reactivities. 

Purine nucleotides can be produced by two different pathways. The salvage pathway utilizes free purine bases and converts them to their respective ribonucleotides by appropriate phosphoribosyltransferases. The de novo pathway utilizes glutamine, glycine, aspartate, N -formyl FH4, bicarbonate, and PRPP in the synthesis of inosinic acid (IMP), which is then converted to AMP and GMP. 

HGPRT is responsible for the conversion of guanine to guanylic acid and hypoxanthine to inosinic acid. These two conversions require PRPP as the cosubstrate and are important reutilization reactions involved in the synthesis of nucleic acids. A deficiency in the HGPRT enzyme leads to increased metabolism of guanine and hypoxanthine to uric acid, and more PRPP to interact with glutamine in the first step of the purine pathway." Complete absence of HGPRT results in the childhood Lesch-Nyhan syndrome, characterized by choreoathetosis, spasticity, mental retardation, and markedly excessive production of uric acid. A partial deficiency of the enzyme may be responsible for marked hyperuricemia in otherwise normal, healthy individuals. 

Two of the more important purine analogs in use clinically are 6-mercaptopurine and 6-thioguanine. These purine antagonists and glutamine antagonists such as azaserine (Table 4-6) are major antagonists in the biosynthesis of purine bases. Before understanding the mechanism of their action, it is necessary to look at the biosynthesis of inosinic acid, the purine ribonucleotide that is the precursor to both purine bases found in DNA and RNA... 

Next, a glycine moiety aaivated by ATP is introduced as an amide, and an ammonia moiety derived from glutamine is introduced to form an imidazole ring. In addition, carbon dioxide and a nitrogen atom derived from an aspartic acid moiety are introduced, and the biosynthesis of inosinic acid (IMP) is completed. 

Glutamine is then involved in a series of reactions with ribose-5-phosphate, glycine and aspartate to give inosinic acid, which contains a purine nucleus. This series of reactions may be represented as follows ... 

Ammonia (NHj) is found in foods mainly as a product of free nucleotide deamination, such as deamination of adenosine 5 -monophosphate (AMP) to inosine 5 -monophosphate, and as a product of deamination of the amino acid amides asparagine and glutamine. In acidic foods, ammonia is present almost exclusively in the form of ammonium salts. 

The nucleotides that are constituents of nucleic acids, guanylic acid and adenylic acid, were formed from inosinic acid. Inosinic acid was oxidized by a DPN-enz3une to xanthosine 5 -phosphate, which was then ami-nated by glutamine to form guanosine 5 -phosphate. Adenylic acid was produced by the cleavage of adenylosuccinic acid which was formed by the reaction of inosinic acid with aspartic acid. 

The glutamine analogue, diazo-oxo-norleucine, and the aspartate analogue, hadacidin (iV-formyl hydroxyaminoacetic acid), inhibit guanylate synthetase and adenylosuccinate synthetase, respectively. Alanosine (2-amino-3-nitrohydroxylaminopropionic acid) is also an inhibitor of adenylate synthesis from inosinate, but its mechanism of inhibition is not yet clear (52). 

The formation of GMP has been observed in extracts of rabbit bone marrow (148,162) and of pigeon liver (163,164). In this process, IMP was oxidized to xanthylic acid (XMP) (Fig. 1) by a DPN-dependent enzsune, inosine 5 -phosphate dehydrogenase [Eq. (17)] and XMP was subsequently aminated by glutamine amide N to form GMP (Eq. (18)]. 

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