Inosine, biosynthesis

Li, H., et al. (2011). De novo engineering and metabolic flux analysis of inosine biosynthesis in Bacillus subtilis. Biotechnol. Lett., 33 (8), 1575—1580. 

Inosine, 6-benzyloxy-9- -D-ribofuranosyl-2-dimethylamino-hydrogenolysis, 5, 558 Inosine, 2 -deoxy-alkylation, 5, 538 Inosine, 6-phenacylthio-dethiation, S, 559 Inosine 5 -monophosphate biosynthesis, 1, 88 Inosines, thio-synthesis, 5, 584 Inositol, D-l,4-anhydro-synthesis, 1, 416 Inositols synthesis, 1, 416 Insecticides... 

One of the steps in the biosynthesis of a nucleotide called inosine monophosphate is the formation of aminoimidazole ribonucleotide from formyjglycin-amidine ribonucleotide. Propose a mechanism. 

Inosine monophosphate dehydrogenase (EVDPDH) is a key enzyme of purine nucleotide biosynthesis. Purine synthesis in lymphocytes exclusively depends on the de novo synthesis, whereas other cells can generate purines via the so-called salvage pathway. Therefore, IMPDH inhibitors preferentially suppress DNA synthesis in activated lymphocytes. 

Inosine monophosphate dehydrogenase (IMPDH) is the key enzyme of purine nucleotide biosynthesis. Proliferation of activated lymphocytes dq ends on rapid de novo production of purine nucleotides for DNA synthesis. 

The biosynthesis of adenosine is theoretically controlled by several processes namely (1) the biosynthesis of adenosine from AMP by 5 -nucleotidase [EC 3.1.3.5], (2) from S-adenosyl homocysteine by S-adenosyl homocystine hydrolase [EC 3.3.1.1], (3) the metabolism of adenosine to AMP by adenosine kinase [EC 2.7.1.20], and (4) to inosine by adenosine deaminase (ADA) [EC 3.5.4.2], Interestingly, both 5 -nucleotidase and ADA activities were found to be highest in the leptomeninges of rat brain in contrast, the adenosine kinase activity was widely distributed throughout the brain parenchyma, which has negligible ADA activity... 

The major intermediates in the biosynthesis of nucleic acid components are the mononucleotides uridine monophosphate (UMP) in the pyrimidine series and inosine monophosphate (IMP, base hypoxanthine) in the purines. The synthetic pathways for pyrimidines and purines are fundamentally different. For the pyrimidines, the pyrimidine ring is first constructed and then linked to ribose 5 -phosphate to form a nucleotide. By contrast, synthesis of the purines starts directly from ribose 5 -phosphate. The ring is then built up step by step on this carrier molecule. 

In the second control mechanism, exerted at a later stage, an excess of GMP in the cell inhibits formation of xanthylate from inosinate by IMP dehydrogenase, without affecting the formation of AMP (Fig. 22-35). Conversely, an accumulation of adenylate inhibits formation of adenylosuccinate by adenylosuccinate synthetase, without affecting the biosynthesis of GMP. In the third mechanism, GTP is required in the conversion of IMP to AMP (Fig. 22-34, step (T)), whereas ATP is required for conversion of IMP to GMP (step (4)), a reciprocal arrangement that tends to balance the synthesis of the two ribonucleotides. 

Scheme 5 Biosynthesis of inosine 5 -phosphate the nature of the Cj donors is described in the text (P = P03H2)...

All biosynthetic pathways are under regulatory control by key allosteric enzymes that are influenced by the end products of the pathways. For example, the first step in the pathway for purine biosynthesis is inhibited in a concerted fashion by nucleotides of either adenine or guanine. In addition, the nucleoside monophosphate of each of these bases inhibits its own formation from inosine monophosphate (IMP). On the other hand, adenine nucleotides stimulate the conversion of IMP into GMP, and GTP is needed for AMP formation. 

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. 

Inosinic acid (hypoxanthine ribonucleoside phosphate) is the end product of purine biosynthesis. It then gives rise to GMP and AMP. 

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 Monophosphate Dehydrogenase. Proliferative cells such as lymphocytes have high demands for the rapid supply of nucleotides to support DNA and RNA synthesis, as do viruses during their proliferative phase. The first dedicated step in the de novo biosynthesis of guanine nucleotides is conversion of inosinate to XMP, catalyzed by inosine monophosphate dehydrogenase (IMPDH). 

B Mycophenoiate mofetil and other antiproiiferative agents fre-quentiy cause leukopenia and thrombocytopenia. Mycophenoiic acid (active form of mycophenoiate mofetil) inhibits the enzyme inosine monophosphate dehydrogenase, the key enzyme in the de novo pathway for purine biosynthesis. Activated T-lymphocytes cannot use the salvage pathway for purine biosynthesis, and therefore are sensitive to the effects of mycophenoiic acid. The caicineurin inhibitors, IL-2 receptor antagonists, and corticosteroids do not cause bone marrow suppression. 

Biosynthesis of inosinic acid. The reactions are numbered. Enzymes (1) amidophosphoribosyltransferase ... 

L13. Levenberg, B., Melnick, I., and Buchanan, J. M., Biosynthesis of the purines. XV. The effect of aza-L-serine and 6-diazo-5-oxo-Lrnorleucine on inosinic acid biosynthesis de novo. J. Biol. Chem. 226, 163-167 (1957). 

M2. Magasanik, B., Moyed, H. S., and Gehring, L. B., Enzymes essential for the biosynthesis of nucleic acid guanine inosine 5 -phosphate dehydrogenase of Aerobacler aerogenes. J. Biol. Chem. 226, 339-350 (1957). 

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