Inosine Inosinic acid

The 5 -nucleotide of inosine, inosinic acid (C10H13N4O8P) is added to foods as a flavor enhancer. What is the structure of inosinic acid (The structure of inosine is given in Problem 28.21). 

Hypoxanthine Ribose Inosine Inosinic acid inosine monophosphate (IMP) Inosine diphosphate (IDP) Inosine triphosphate (ITP)... 

Inisone. See 4-(2,6,6-Trimethyl-2-cyclohexen-1-yl)-3-buten-2-one Ink blue. See Acid blue 93 Inosine 5 -disodium phosphate lnosine-5 -monophosphate disodium. See Disodium inosinate Inosinic acid CAS 131-99-7 INS630 E630... 

The synthesis of inosinic acid (123) from AIR (106) using soluble avian liver enzymes has been shown to proceed in several steps. The first step involves the formation of C-AIR (107) by carboxylation of the aminoimid-azole (106) (Scheme 15) (57JA1511). 

Tipson devoted most of his years in Levene s laboratory accomplishing seminal work on the components of nucleic acids. To determine the ring forms of the ribose component of the ribonucleosides he applied Haworth s methylation technique and established the furanoid structure for the sugar in adenosine, guanosine, uridine, and thymidine. He showed that formation of a monotrityl ether is not a reliable proof for the presence of a primary alcohol group in a nucleoside, whereas a tosyl ester that is readily displaced by iodide affords clear evidence that the ester is at the 5-position of the pentofuranose. Acetonation of ribonucleosides was shown to give the 2, 3 -C -isopropyl-idene derivatives, which were to become extensively used in nucleoside and nucleotide chemistry, and were utilized by Tipson in the first chemical preparation of a ribonucleotide, inosinic acid. 

The de novo synthesis of inosinic acid The salvage pathways Purine nucleotide interconversions Other enzymes... 

Inosinic acid dehydrogenase converts inosinic acid to xanthylic acid which in... 

The elucidation of the steps by which cells synthesize inosinic acid de novo for purine nucleotide interconversions is largely due to the brilliant work of Buchanan and his co-workers [65]. The biosynthetic scheme as it is currently envisioned is shown in Figure 2.4. 

The conversion of inosinic acid to adenylic acid is a two-step process [65] The first step, the conversion of inosinic acid to adenylosuccinic acid, is mediated by adenylosuccinate synthetase [65], which is inhibited by 6-mercaptopurine ribonucleotide [309-311] in a non-competitive manner, although the exact nature of this inhibition is not known [67]. The second step of the sequence, the conversion of adenylosuccinic acid to adenylic acid, is also inhibited by 6-mercaptopurine ribonucleotide [66, 311], and in this case the inhibition is competitive with respect to the substrate [67]. 

Although tumour growth inhibition by 6-mercaptopurine has been attributed to the inhibition of the conversion of inosinic acid to adenylic acid [309, 310, 312], probably at the first step, this conversion by cell-free extracts from the exquisitely sensitive tumour adenocarcinoma 755 was inhibited only at high levels of 6-mercaptopurine ribonucleotide [313]. Furthermore, hadacidin (A -formylhydroxyaminoacetic acid) is an excellent inhibitor of adenylosuccinate synthetase [314, 315], and yet it has little antitumour activity and is not cytotoxic, showing that this inhibition may be relatively unimportant to cells. 

Chloropurine ribonucleotide and thioinosinic acid also react covalently with GMP reductase, the enzyme that converts guanylic acid to inosinic acid and ammonia [318]. 

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... 

Azathioprine is a cytotoxic inhibitor of purine synthesis effective for the control of tissue rejection in organ transplantation. It is also used in the treatment of autoimmune diseases. Its biologically active metabolite, mercaptopurine, is an inhibitor of DNA synthesis. Mercaptopurine undergoes further metabolism to the active antitumour and immunosuppressive thioinosinic acid. This inhibits the conversion of purines to the corresponding phosphoribosyl-5 phosphates and hypoxanthine to inosinic acid, leading to inhibition of cell division and this is the mechanism of the immunosuppression by azathioprine and mercaptopurine. Humans are more sensitive than other species to the toxic effects of the thiopurines, in particular those involving the haematopoietic system. The major limiting toxicity of the thiopurines is bone marrow suppression, with leucopenia and thrombocytopenia. Liver toxicity is another common toxic effect. 

Azathioprine acts through its major metabolite, 6-thioguanine. 6-Thioguanine suppresses inosinic acid synthesis, -cell and T-cell function, immunoglobulin production, and interleukin-2 secretion (see Chapter 55). 

The nucleoside formed from hypoxanthine and ribose is known as inosine (Ino or I) and the corresponding nucleotide as inosinic acid. Further substitution at C-2 of -H by -OH and tautomerization yields xanthine (Xan). Its nucleoside is xanthosine (Xao, X). A similar hydroxylation at C-7 converts xanthine to uric acid, an important human urinary excretion product derived from nucleic acid bases. 

The 5 -Nucleotides. Also dating back many years in the Far East was the knowledge that bonita tuna possesses a substance that very effectively enhances the flavor of foods. However, it was not until 1913 dial S. Kodama (Tokyo University) commenced a serious investigation directed toward identifying and isolating the substance from tuna. Initially. Kodama believed that the substance was the histidine salt of 5 -inosinic acid, but later found that the substance was actually 5 -inosinic acid itself. This nucleotide was found to be many more times as effective as MSG. Further research by Kodama and others has shown that these nucleotides are present in many natural foods. 

The existence of two separate enzymes in animal tissues responsible for the liberation of ammonia from each of the two aminopurines, adenine and guanine, the latter specific for the free purine and the former for the nucleosides, was initially presented by Jones and his colleagues 11, 12). In 1928, Schmidt 13-15) demonstrated that AMP aminohy-drolase was responsible for the appearance of inosinic acid in muscle and for at least a portion of ammonia liberated during contraction. He showed not only a marked specificity for deamination of 5 -AMP but also provided the first clue that muscle adenylic acid (5 -AMP) and yeast adenylic acid (3 -AMP) were different compounds. Initial evidence for guanine and adenosine aminohydrolase including aspects of the specificity were also described by Schmidt 16). Additional details regarding development of interest in purine aminohydrolases are available in several excellent reviews 17-20). 

The phosphodiester bonds of xanthylic acid in deaminated RNA were scarcely split by RNase U2 (30). The susceptibility of purine nucleotide residues to RNase U2 decreases in the order of A>G>I X, indicating that the phosphodiester bonds of adenylic acid and inosinic acid without a keto group at the position of purine base are more sensitive to RNase U2 than those of guanylic acid and xanthylic acid. The resistance of TNP-RNA to RNase U2 may be also attributed to the steric hindrance by a larger substituent at 2-amino groups of guanylyl residues, as with RNase T, (SO). 

Kakiuchi, N., Marck, C., Rousseau, N., Leng, M., De Clerq, E. and Guschlbauer, W. (1982) Polynucleotide helix geometry and stability. Spectroscopic, antigenic and interferon-inducing properties of deoxyribose-, ribose-, or 2 -deoxy-2 -fluororibose-containing duplexes of poly(inosinic acid), poly(cytidylic acid). J. Biol. Chem., 257, 1924-1928. 

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