Pyrimidine metabolites

Table 7.1.3 Concentration of purine and pyrimidine metabolites in urine from controls (n = 104)...

Table 7.1.4 Concentration range of purine and pyrimidine metabolites in urine (pmol/mmol creatinine) from patients. ADA Adenosine deaminase, APRT adenine phosphoribosyltransferase, ASA adenylosuccinate lyase, DHP dihydropyrimidinase, DPD dihydropyrimidine dehydrogenase, HGPRT hypoxanthine-guanine phosphoribosyltransferase, PNP purine nucleoside phosphorylase, TP thymidine phosphorylase, UMPS uridine monophosphate synthase, / -UP fi-ureidopropionase... 

Acid sellable extracts (trioctyl-amine freon method) were frozen at -70°C until measurements were made. In those samples in which deoxycytidine was measured tetrahydrouridine (THU) was added to the tube in which the blood was collected to diminish the catabolism of deoxycytidine by deoxycytidine deaminase which is competitively inhibited by THU. Purine and pyrimidine metabolites were measured using high-pressure liquid chromatography as previously reported (Cohen et al., 1978). 

At regular intervals the immune status of the patient was assessed as well as the serum content and the urinary excretion of purine- and pyrimidine metabolites according to methods described in detail previously (6,8,10). The (deoxy)ribonucleotide content of the erythrocytes was analyzed by HPLC Ul)- Perchloric acid extracts of freshly withdrawn blood were made according to Cohen et al. (2) with minor modifications. In order to analyze deoxyribo-nucleotides the neutralized perchloric acid extracts were treated with sodium periodate according to Garret and Santi (12). 2,3 Di-phosphoglycerate (2,3-DPG) in the erythrocytes was determined as previously described (13). Ecto-5 -nucleotidase on intact lymphocytes was determined as described(14). Adenosine deaminase activity of the lymphocytes was determined essentially according to van Laar-hoven et al. (15). 

Likewise, in most other tissues, there is very little free thiamin and it is mostly present as TDP (90%) in coenzymes bound to respective enzymes and a smaller amount of TTP (10%) in nervous tissues. The concentration of thiamin in specific tissues is on the order of 2-3 pg/g for heart muscle 1 pg/g for brain, liver, and kidney and 0.5 pg/g in skeletal muscle. Thiamin supplements can increase these concentrations slightly and prolonged febrile illnesses are likely to reduce them. Thiamin is mainly excreted intact in the urine but there are small amounts of thiochrome (Figure 2) and other thiazole and pyrimidine metabolites. A linear relationship exists between intake and excretion of thiamin until intake falls to an amount approaching minimum requirements when excretion decreases rapidly indicating a renal conservation mechanism. 

Fluorouracil (5-fluorouracil, 5-FU, Fig. 5) represents an early example of rational drag design in that it originated from the observation that tumor cells, especially from gut, incorporate radiolabeled uracil more efficiently into DNA than normal cells. 5-FU is a fluorinated pyrimidine analog that must be activated metabolically. In the cells 5-FU is converted to 5-fluoro-2>deoxyuridine-monophosphate (FdUMP). This metabolite inhibits thymidilate synthase which catalyses the conversion of uridylate (dUMP) to thymidilate (dTMP) whereby methylenetetrahydrofo-late plays the role of the carbon-donating cofactor. The reduced folate cofactor occupies an allosteric site of... 

The active metabolite of leflunomide, the ring-opened drug A771726, inhibits dihydroorotate dehydrogenase (DHOD) which is the key enzyme of the de novo pyrimidine synthesis. Inhibition of synthesis stops proliferation of activated lymphocytes. The leflunomide derivative FK778 which shows similar therapeutic efficacy but shorter half-life is investigated in clinical trials. 

CATABOLISM OF PYRIMIDINES PRODUCES WATER-SOLUBLE METABOLITES... 

Although pyridines and quinolines were first produced during the carbonization of coal, they are now available by synthesis in quantities that far exceed those by the former. Phosphorylated ribosides of hydroxylated and aminated pyrimidines and purines make up the basic structure of ribonucleic and deoxyribonucleic acids. The polycyclic oxaarenes are plant metabolites, while thiaarenes are primarily important components of high-sulfur petroleum that must be removed. 

Wetzstein H-G, N Schmeer, W Karl (1997) Degradation of the fluoroquinolone enrofloxacin by the brown-rot fungus Gleophyllum striatum identification of metabolites. Appl Environ Microbiol 63 4272-4281. Wondrack LM, C-A Hsu, MT Abbott (1978) Thymine-7-hydroxylase and pyrimidine deoxyribonucleoside 2 -hydroxylase activities in Rhodotorula glutinis. J Biol Chem 253 6511-6515. 

Fluorouracil (5-FU) acts as a false pyrimidine, inhibiting the formation of the DNA base thymidine.26,35 The main mechanism by which it accomplishes this is by inhibiting the enzyme thymidylate synthase, the rate-limiting step in thymidine formation. 5-FU first must be metabolized to its active metabolite (F-dUMP). Additionally, metabolites of 5-FU may incorporate into RNA, inhibiting its synthesis. 

T3 M 75.1% after 15 days 4-(6-Imino-2, 4-dimethoxy pyrimidin-l-yl) aniline additional metabolites were preliminary assigned but not confirmed [22]... 

The answer is a. (Hardman, p 1302.) Cyclophosphamide, an alkylating agent, reacts with purine and pyrimidine bases of DNA to form bridges and dimers. These products interfere with DNA replication. 5-FU, methotrexate, and 6-thioguanine are anti metabolites, and the steroid prednisone has some tumor-suppressive effects. 

Figure 5.10 The interconversion of folate metabolites. /V5,/V10-methenylTHFis required for purine synthesis. /V5,/V10-methylene THF and /V10-formylTHF are required for deoxythymidylate (pyrimidine) synthesis...

Actinomycetes can metabolize a wide variety of organic substrates, including organic compounds that are generally not metabolized, such as phenols and steroids. They are also important in the metabolism of heterocyclic compounds such as complex nitrogen compounds and pyrimidines [42,49]. The breakdown products of their metabolites are frequently aromatic, and these metabolites are important in the formation of humic substances and soil humus [42,49]. 

Serine (Ser or S) ((S)-2-amino-3-hydroxypropanoic acid) is a polar, neutral, uncharged amino acid with the formula H00CCH(NH2)CH20H. It has an aliphatic hydroxyl side chain and can be seen as a hydroxylated version of Ala. Ser participates in the biosynthesis of purines and pyrimidines and is also the precursor to several amino acids including Gly, Cys, and Trp (in bacteria). In addition, it is the precursor to numerous other metabolites, including sphingolipids and is present in enzymes such as a-chymotrypsin. Ser, Asn, and aspartate disrupt a helices. 

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