Guanine excretion

For birds, insects, and reptiles, which have an egg stage during development, so that water availability is severely restricted, the synthesis of a highly soluble excretory product would have serious osmotic consequences therefore most of the ammonia is converted to the virtually insoluble uric acid (urate). This product can be safely retained in the egg or excreted as a slurry of fine crystals by the adult. In birds that nest colonially this can accumulate in massive amounts on islands off the coast of Peru cormorants have deposited so much that this guano (hence the name guanine) is collected for use as a fertiliser. Uric acid is less effective as an excretory product, since it has a lower nitrogen content than urea (33%) and is more expensive to synthesise (2.25 molecules ATP per atom of nitrogen). Mammals do produce uric acid but as a product of purine catabolism (see above). 

Nucleic acid degradation in humans and many other animals leads to production of uric acid, which is then excreted. The process initially involves purine nucleotides, adenosine and guanosine, which are combinations of adenine or guanine with ribose (see Section 14.1). The purine bases are subsequently modified as shown. 

Mithramycin (also known as MIT and plicamy-cin) is an antibiotic that binds to DNA to regulate transcription. It attaches to specific regions of DNA that are rich in guanine and cytosine. It appears to lower serum calcium concentrations by blocking the hypercalcemic action of Vitamin D. After IV administration about 25% of the drug is excreted in the urine after 2 hours, and 40% after 15 hours. The main indications are treatment of testicular tumors and control of hypercalcemia and hypercalciuria. 

The role of hypoxanthine-guanine phosphoribosyltransferase in purine salvage has been confirmed by the abnormally high excretion of purines (as uric acid) in humans who lack hypoxanthine-guanine phosphoribosyltransferase. Studies of purine metabolism in cultures of cells from patients with this hereditary disorder also support this conclusion. 

The N7-guanine adduct (22) is a urinary excretion product derived from the reaction of sulfur mustard with DNA. It can be isolated from urine by SPE on C18. GC/MS analysis of the derivatized adduct was problematic. A sensitive method was developed for the underivatized compound using LC/ESI/MS/MS, monitoring the fragmentation MH+, m/z 256 —> [CH2CH2SCH2CH2OH]+, m/z 105 on a triple-sector quadrupole instrument (60). LC separation was on a C18 column eluted with water-acetonitrile-formic acid. The detection limit was 8pg injected (S/N 5 1), 0.2 ng/ml in urine. Rao et al. (61) also reported characterization by LC/ESI/MS but using 25 mM NH4HC03 in 20 % MeOH as eluent. 

Analytical methods have been reported for unchanged agent and six of the urinary excretion products described above. These are TDG, TDGO, the bis A-acetylcysteine conjugate (1), two 3-lyase metabolites (2) and (3), and the guanine adduct (6). These methods have been applied to animal and/or human exposures to sulfur mustard. 

Benzo(a)pyrene in cigarette smoke coats the lung surface and is absorbed into cells which oxidize benzo(a)pyrene to convert it into a more polar and hence water-soluble form for excretion. The oxidized form intercalates at GC base pairs and modifies guanine bases... 

Normally dietary NA is hydrolyzed by pancreatic ribonucleases and absorbed in the small intestine. Guanine and adenine are metabolized further to uric acid before urinary excretion (2). Increased consumption of NA increased the uric acid levels above the urinary excretion rate, resulting in an increased plasma uric acid level. Uric acid has a pKa near 5.4. In the acidic urine, as much as half of the excreted compound may be in the form of the undissociated acid, which has a low solubility... 

The most studied oxidative modification of DNA relates to direct oxidation of DNA, the 8-hydroxylation of guanine being the one most extensively studied, particularly regarding urinary excretion of the repair product 8-oxodG. 

Treatment the drug that most effectively inhibits the formation of uric acid is allopurinol, a competitive inhibitor of xanthine oxidase. Hypoxanthine and xanthine are excreted during allopurinol therapy. Allopurinol, as with guanine and hypoxanthine, can be converted to its ribonucleotide form by HGPRT. Reducing the formation of uric acid with allopurinol relieves the symptoms of gout and decreases the possibility that uric acid kidney stones will form. 

The purine catabolic pathway appears in Figure 8,31, The end-product of purine cataboiism in primates, and in some other vertebrates, is uric acid, Purine catabolism differs in other species. Urate oxidase catalyzes the breakdown of uric acid to allantoin. Allantoin can be further broken down to produce urea and glyoxyJate, Allantoin is the purine excretory pixiduct in some mammals and reptiles. Urea is the purine excretory product in fish. Guanine is the purine excretory product in pigs and spiders. Uric acid is used for the packaging and excretion of waste N from amino acids in birds and some reptiles. 

Recently it has been shown that patients with this disease excrete more hypoxanthine than xanthine in their urine. All other subjects studied excrete more xanthine than hypoxanthine (B7). Furthermore, although the administration of allopurinol reduces total oxypurine output in other patients, it does not do so in these children (B7, 02). These observations have been clarified by the demonstration that patients with juvenile hyperuricemia lack inosinate pyrophosphorylase, the enzyme that catalyses the conversion of hypoxanthine (and guanine) to inosinic acid (and guanylic acid) (SlOa). They, thus, excrete any hypoxanthine formed rather than reutilize it. This may identify the fundamental difference between this entity and gout, but offers no explanation of the neurological damage. 

The answer is d. (Murray, pp 375-401. Scriver, pp 2513-2570. Sack, pp 121-138. Wilson, pp 287-320.) Xanthine oxidase catalyzes the last two steps in the degradation of purines. Hypoxanthine is oxidized to xanthine, and xanthine is further oxidized to uric acid. Thus, xanthine is both product and substrate in this two-step reaction. In humans, uric acid is excreted via the urine. Allopurinol, an analogue of xanthine, is used in gout to block uric acid production and deposition of uric acid crystals in the kidneys and joints. It acts as a suicide inhibitor of xanthine oxidase after it is converted to alloxanthine. Guanine can also be a precursor of xanthine. 

X Uric acid contains two rings and is similar to the purines adenine and V y guanine (adenine is shown in Fig. 5.25). In fact, it is the urinary excretion product formed from the oxidation of these two purine bases. It is not very soluble in water, particularly if the pH is near the pK of its acidic OH group. If present in excess amounts, Na+ urate tends to precipitate in joints, causing the severe pain of gout experienced by Ms. Topaigne. 

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