Guanylic acid synthesis

Azathioprine is converted in vivo to thioinosinic acid, which competitively inhibits the synthesis of in-osinic acid, the precursor to adenylic acid and guanylic acid. In this way, azathioprine inhibits DNA synthesis and therefore suppresses lymphocyte proliferation. This effectively inhibits both humoral and cell-mediated immune responses. 

ThiolMP and ThioGMP are feedback inhibitors of phosphoribosylpyrophosphate amido-transferase, which is the first, and rate-limiting step in the synthesis of purine. In addition, these analogs inhibit the de novo biosynthesis of purine and block the conversion of inosinic acid to adenylic acid or guanylic acid. The triphosphate nucleotides are incorporated into DNA, and this results in delayed toxicity after several cell divisions. 

P. falciparum Guanylate Kinase (PfGK). PfGK is involved in nucleic acid synthesis, specifically the conversion of dGMP to... 

Guanylic acid has been synthesized by direct phosphorylation of guanosine with phosphorus oxychloride in the presence of barium hydroxide solution, but this method of synthesis is valueless as regards confirming the above structure. 

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. 

Ribavirin [4.15) is of special interest because of its broad spectrum of attack. It is active against both DNA and RNA viruses. Also known as tribavirin and Virazole , this substance is l-)8-D-ribofuranosyl-l,2,4-triazole-3-carboxamide. In vivo, it is changed to the 5 -monophosphate which inhibits inosinate dehydrogenase, and hence prevents the formation of guanylic acid on which synthesis of both DNA and RNA depend. It is being used clinically for the treatment of viral pneumonia and measles although the results are not quite clear-cut (Smith and Kirkpatrick, 1980). 

Since mycophenolic acid is an inhibitor of the penultimate enzyme in guanyl nucleotide synthesis (10), the effects of mycophenolic acid on the guanine nucleotide levels in wild-type and mutant cells were examined. Figure 2. Whereas, a profound depletion of GTP occurred in wild-type cells incubated 4 hr with 1 uM mycophenolic acid, a similar GTP depletion was seen only at 5 jiM mycophenolic acid in MYCO-IA cells (Figure 2). No depletion of intracellular GTP was observed in MYCO-lA-20 cells incubated with exogenous mycophenolic acid at concentrations as high as 25 pM. 

The formation of guanyl azide (IV) at the first stage may account for the formation of tetrazene by the action of nitrous acid on aminoguanidine, i.e. by Hoffmann synthesis. 

A more convenient approach for the preparation of a protected Narg derivative is the synthesis of Fmoc-Narg(Boc)2-OH (95 in Scheme 43). The key step in this synthesis is the guanylation of Z-Norn-OMe 93 which can be prepared from a monoprotected diamino-propane with bromoacetate or by reductive amination with glyoxylic acid. 

The findings that inosinate was the end product of the pathway of de novo synthesis and that adenylate and guanylate were the first metabolites formed in the course of the incorporation into nucleic acids of adenine and guanine, were most consistent with interconversion at the ribonucleo-... 

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). 

Hadacidin (N-formyl hydroxy-aminoacetic acid), which is known to inhibit adenylosuccinate synthetase (7), blocked synthesis of adenosine nucleotides from IMP (Table 1). There was a significant decrease (83%, p <. 001 Student s T test for unpaired values) in newly synthesized ATP and in total adenylates (ZA). The concentration of ATP and the level of the adenylate pool were not decreased. There was a decrease in labelled guanylate in PRBC exposed to hadacidin. 

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