Xanthine 5 -monophosphate

IMP is the key intermediate of purine nucleotide biosynthesis. IMP can react along two pathways that yield either GMP or AMP. Oxidation of the 2 position makes xanthine monophosphate, which is transamidated to GMP. Alternatively, the a-amino group of aspartate can replace the ring oxygen of IMP to make AMP. (Note again how this reaction is similar to the synthesis of arginine fromcitrulline.)... 

In addition to salvaging purines, most cells interconvert adenine and guanine nucleotides. Inosine monophosphate (IMP), is the common intermediate. IMP is converted into AMP by a two-step reaction catalyzed by adenylosuccinate synthetase and adenylosuccinate lyase. Guanine nucleotides are formed in a two-step reaction in which IMP is converted into xanthine monophosphate (XMP) and then aminated to GMP. Both GMP and AMP can be reconverted into IMP. Mammalian cells can also deaminate adenosine to inosine and guanine to xanthine (Fig. 6.1). 

Abbreviations GPC, 5 -glycerol 3-phosphorylcholine GPE, i/i-glycerol 3-phosphoryleth-anolamine PCr, phosphocreatine SP, sugar phosphates XMP, xanthine monophosphate DN, dinucleotides NS, nucleoside diphospho sugars PCA, perchloric acid NC, noncollage-nous CSF, cerebrospinal fluid T, spin-lattice relaxation time NOE, nuclear Overhauser enhancement. 

Figure 12 Gradient separation of bases, nucleosides and nucleoside mono- and polyphosphates. Column 0.6 x 45 cm. Aminex A-14 (20 3 p) in the chloride form. Eluent 0.1 M 2-methyl-2-amino-l-propanol delivered in a gradient from pH 9.9-100 mM NaCl to pH 10.0-400 mM NaCl. Flow rate 100 ml/hr. Temperature 55°C. Detection UV at 254 nm. Abbreviations (Cyt) cytosine, (Cyd) cytidine, (Ado) adenosine, (Urd) uridine, (Thyd) thymidine, (Ura) uracil, (CMP) cytidine monophosphate, (Gua) guanine, (Guo) guanosine, (Xan) xanthine, (Hyp) hypoxanthine, (Ino) inosine, (Ade) adenosine, (UMP) uridine monophosphate, (CDP) cytidine diphosphate, (AMP) adenosine monophosphate, (GMP) guanosine monophosphate, (IMP) inosine monophosphate, (CTP) cytidine triphosphate, (ADP) adenosine diphosphate, (UDP) uridine monophosphate, (GDP) guanosine diphosphate, (UTP) uridine triphosphate, (ATP) adenosine triphosphate, (GTP), guanosine triphosphate. (Reproduced with permission of Elsevier Science from Floridi, A., Palmerini, C. A., and Fini, C., /. Chromatogr., 138, 203, 1977.)...

Answer C. The child most likely has severe combined immunodeficiency caused by adenosine deaminase defidency. This enzyme deaminates adenosine (a nudeoside) to form inosine (another nucleoside). Hypoxanthine and xanthine are both purine bases, and the monophosphates are nucleotides. 

Fig. 14.2 Scheme of thiopurine drug metabolism. HPRT, hypoxanthine phosphoribosyl transferase 6-MMP, 6-methylmercaptopurine 6-TGN, 6-thioguanine nucleotides 6-TIMP, 6-thiosine monophosphate TPMT, thiopurine methyltransferase XO, xanthine oxidase... 

The reason for the selective toxicity of 6-mercaptopuiine remains to be established, but two factors may be of primary importance. 6-Mercaptopurine is anabolized primarily, if not exclusively, to the monophosphate level, and it is readily catabolized by xanthine oxidase, an enzyme that is low in most cancer cells compared to normal cells. Another factor that must be considered is the metabolic state of the target cells. Actively proliferating leukaemia cells are more sensitive to 6-mercaptopurine, as they are to all antimetabolites, than cells in the so-called Gq or stationary phase. Although this does not explain the difference between 6-mercaptopurine and other purine analogues, it may explain the ineffectiveness of 6-mercaptopurine against solid tumours, most of the cells of which are in the non-dividing state. 

Purine (left). The purine nucleotide guano-sine monophosphate (CMP, 1) is degraded in two steps—first to the guanosine and then to guanine (Gua). Guanine is converted by deamination into another purine base, xanthine. 

In the most important degradative pathway for adenosine monophosphate (AMP), it is the nucleotide that deaminated, and inosine monophosphate (IMP) arises. In the same way as in GMP, the purine base hypoxanthine is released from IMP. A single enzyme, xanthine oxidase [3], then both converts hypoxanthine into xanthine and xanthine into uric acid. An 0X0 group is introduced into the substrate in each of these reaction steps. The oxo group is derived from molecular oxygen another reaction product is hydrogen peroxide (H2O2), which is toxic and has to be removed by peroxidases. 

Clarke H, Cushley MJ, Persson CG, Holgate ST (1989) The protective effects of intravenous theophylline and enprofylline against histamine- and adenosine 50-monophosphate-provoked bronchoconstriction implications for the mechanisms of action of xanthine derivatives in asthma. Pulm Pharmacol 2(3) 147-154... 

In 1932 Levene and Harris128 showed that the hydrolysis of xanthylic acid gave rise to the formation of a D-ribose phosphate which was not identical with the known D-ribose 5-phosphate. Since xanthylic acid is the monophosphate derivative of a ribofuranoside of xanthine it followed that the new phosphate was either D-ribose 2-phosphate or the 3-isomer (L). Shortly thereafter the same authors129 succeeded in reducing the new D-ribose phosphate with hydrogen in the presence of platinum oxide to a ribitol phosphoric acid (LI) which was completely... 

Figure 2.3(D). Uricogenesis during alanine catabolism and gluconeogenesis in avian liver. Some abbreviations are as in figure 2.3(C). 1 C refers to one-carbon units MDH, malate dehydrogenase XDH, xanthine dehydrogenase PRPP, phosphoribosylpyrophosphate IMP, inosoine monophosphate ino, inosine hyp, hypoxanthine xan, xanthine.

Xanthine Ribose Xanthosine Xanthosine monophosphate (XMP) xanthinylic acid Xanthosine diphosphate Xanthosine triphosphate... 

The determination of the purine-nucleotide metabolites xanthine, hypox-an thine, and inosine by biosensors is of special interest for the estimation of meat or fish freshness. After the death of a fish, adenosine triphosphate (ATP) in the fish tissue is quickly degraded to inosine monophosphate (IMP). Further enzymatic decomposition of IMP leads to the accumulation of hypoxan thine (Hx), which is used as an indicator of fish freshness. To quantify these compounds with biosensors, it is possible to perform amperometric measurements of the generated hydrogen peroxide or the consumed oxygen according to the following enzymatic reactions ... 

Although some steps remain to be fully elucidated, caffeine is probably derived though a pathway beginning with inosine 5 -monophosphate and proceeds through xanthosine, 7-methylxanthosine, 7-methyl-xanthine, 3,7-dimethylxanthine (theobromine) to caffeine (Fig. 45). The final methyltransferase has been characterized in coffee and tea, whereas the methyla-tion of xanthosine has only been studied in tea. 

Enz5une sensors or assays exist for the determination of adenosine triphosphate (ATP) and its degradation products inosine 5 -monophosphate (IMP), inosine (HxR), hypoxanthine (Hx) and xanthine (X) as ATP is used as an indicator of the presence of microorganisms and the concentrations of its degradation products are used as indicators for fish and meat freshness in food industry [118]. 

Inosine monophosphate (IMP), which contains the base hypo-xanthine, is generated. 

Fig. 2 Scheme of thiopurine drug metabolism. 77Wthiopurine methyltransfer-ase, XO xanthine oxidase, HPRT hypoxanthine phosphoribosyl transferase, 6-TIMP 6-thiosine monophosphate, 6-MMP 6-methylmercaptopurine, 6-TGN 6-thioguanine nucleotides, AZA Azathioprine, 6-/WP6-Mercaptopurine... 

Fig. 2 Metabolism of 6-mercaptopurine (6-MP) via xanthine oxidase (XO) to the inactive metabolite 6-thiouric acid (6-TU), thiopurine S-methyltransferase (TPMT) to the inactive metabolite 6-methylmercaptopurine (6-MMP), and hypoxanthine guanine phosphoribosyl transferase (HPRT) to 6-thioinosine monophosphate (6-TIMP) which is then further metabolized to thioguanine nucleotides (6-TGN), 6-methylmercaptopurine ribonucleotides (6-MMPR) or 6-thio-inosine triphosphate (6-thio-ITP), these all being active metabolites...

In 2010, a baby girl was diagnosed with molybdenum cofactor deficiency at 6 days old. After treatment with purified cyclic pyranopterin monophosphate (cPMP), the precursor of MoCo whose synthesis was defective, starting at 36 days old, all urinary metabolites of sulfite oxidase and xanthine oxidase deficiency returned to almost normal values and has remained constant for more than one year. 

Fig. 7. (A) Pyrimidine metabolism m vitro in human epidermis. C, eytidine U, uracil T, thymine O, orotic acid R, ribose dR, deoxyribose MP, monophosphate. (B) Purine metabolism in vitro in human epidermis. A, adenine G, guanine H, hypoxanthine X, xanthine UA, uric acid I, inosine R, ribose dR, deoxyribose MP, monophosphate. In (A) and (B), dotted line indicates reaction not found. Adapted from de Bersaques (B15).

Cyclic AMP is catabolized to 5 -adenosine monophosphate by the enzyme cyclic nucleotide phosphodiesterase, which terminates any further cAMP-initiated reactions. This enzyme also requires Mg + for activity. Calcium, again in consort with calmodulin, can stimulate phosphodiesterase activity. Phosphodiesterase appears to exist in multiple forms, each with specificity toward different substrates. Calcium and calmodulin activate only one form of the enzyme. The enzyme is potently inhibited by methyl xanthines, such as caffeine, theophylline, and theobromine. It is believed that at least part of the pharmacological effects of such compounds can be explained through their inhibition of phosphodiesterase and the consequent reduction in the catabolism of cAMP. 

---