Purine carbon sources

Adenosine serves as a carbon source for mammalian cells by its deamination to inosine in the presence of ADA, the cleavage of inosine to hypoxanthine and ribose-l-P in the presence of purine nucleoside phosphorylase, the conversion of ribose-l-P to ribose-5-P in the presence of phosphopentomutase and then the entrance of ribose-5-P into the glycolytic cycle. To insure that adenosine utilization is mediated by ADA and to avoid the inhibitory effects of adenosine on cell growth, a tubercidin resistant mutant (tub ) deficient in adenosine kinase activity was selected initially. 

Besides the energy and carbon sources, microorganisms also need the so-called supplementary materials. These are bound nitrogen, phosphoric and sulfuric compounds, potassium, calcium, magnesium, and iron, as well as trace elements (sodium, chlorine, manganese, molybdenum, zinc, copper, cobalt, nickel, vanadium, boron, selenium, tungsten, etc.) and eventually aminoacids, vitamins, purines, pyrimidines, etc. [for identification, see Ehrlich (1996)]. 

Figure 34-1. Sources of the nitrogen and carbon atoms of the purine ring. Atoms 4,5, and 7 (shaded) derive from glycine.

Figure 20.7 Sources of carbon and nitrogen atoms in pyrimidine and purine bases. The dotted lines represent the bonds between the atoms. The shaded areas represent atoms or groups of atoms from precursor molecules.

Dietary purines are not an important source of uric acid. Quantitatively important amounts of purine are formed from amino acids, formate, and carbon dioxide in the body. Those purine ribonucleotides not incorporated into nucleic acids and derived from nucleic acid degradation are converted to xanthine or hypoxanthine and oxidized to uric acid (Figure 36-7). Allopurinol inhibits this last step, resulting in a fall in the plasma urate level and a decrease in the size of the urate pool. The more soluble xanthine and hypoxanthine are increased. 

The imidazole ring of histidine (30) arises by a quite different route to that used for the formation of the imidazole ring in purine biosynthesis. The sources of the carbon and nitrogen atoms of histidine were established as a result of a series of labelling experiments with T4C and 15N substrates coupled with degradation of the labelled histidines. A summary of these results is given in Scheme 7 (59JBQ234)586). 

The related 1,2,6-thiadiazine (96) is also readily brominated at C-4 simply by treatment with bromine in carbon tetrachloride (80JHC977). The resulting bromide (97) is a source of Br+, although it has not yet been developed as a brominating agent. 1,2,6-Thiadiazine (98) is oximated at C-4 by reaction with nitrous acid. The oxime is a useful precursor to the purine isostere (99) (76MI22800). 

A5-Methyltetrahydrofolate is the methyl-group donor substrate for methionine synthase, which catalyzes the transfer of the five-methyl group to the sulfhydryl group of homocysteine. This and selected reactions of the other folate derivatives are outlined in figure 10.15, which emphasizes the important role tetrahydrofolate plays in nucleic acid biosynthesis by serving as the immediate source of one-carbon units in purine and pyrimidine biosynthesis. 

Serine Hydroxymethyltransferase Serinehydroxymethyltrans-ferase is a pyridoxed phosphate-dependent aldolase that catalyzes the cleavage of serine to glycine and methylene-tetrahydrofolate (as shown in Figure 10.5). Serine is the major source of one-carbon substituted folates for biosynthetic reactions. At times of increeised cell proliferation, the activities of serine hydroxymethyltransferase emd the enzymes of the serine biosynthetic pathway cue increased. The other product of the reaction, glycine, is also required in increased cimounts under these conditions (for de novo synthesis of purines). 

Substituted purines may arise in mixtures with 9-substituted derivatives from direct alkylation of purine anions. They are best prepared however by Traube syntheses. Thus formylation of 4,5-diamino-6-benzylthiopyrimidine and ethylation of the formyl derivatives gave a formamidopyrimidine which readily cyclized to 6-benzylthio-7-ethylpurine in the presence of potassium carbonate (B-68MI40901, p. 31). The derivative is clearly a ready source of 7-substituted adenines by reaction with ammonia or amines, or of 7-substituted purines by dethiation with Raney nickel. 7-Methylguanine has also been obtained from 7-methyl-guanosine, sodium borohydride and aniline at pH 4.5 (B-78MI40903, p. 615). 

FIGURE 9.5 SimplifiKl version of folate nnetaboUsm. Serine is the source of most of the 1-carbon units carried by folates. These 1-carbon units pre used in the synthesis of thymidy-late (a pyrimidine nucleotide), purine nucleotides, and methionine. 

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