Uric acid discovery

Since the discovery of hydantoin in 1861, when Baeyer isolated it in his uric acid studies, that system has been an important precursor of a-amino acids owing to its lability toward alkali, especially for those acids that are difficult to prepare by other methods.300 Furthermore, the stereochemical courses of the Bucherer-Bergs and Read methods of synthesis for hydantoins (Section II,E), permit the preparation of epimeric amino acids.301-305 Some of these amino acids have been tested as possible tumor growth inhibitors,306,307 as metabolism-resistant amino acid analogues for transport system studies,72,308... 

Researchers at the University of Florida have proposed targeting ketohexokinase (fructokinase), one of the main enzymes responsible for fructose metabolism, as a therapy for cardiovascular disease, metabolic syndrome and renal diseases.15 They propose that the rise in serum uric acid levels following fructose intake induces metabolic syndrome by inhibiting endothelial NO. The authors suggest that metabolic syndrome and cardiovascular disease can be controlled by inhibiting the enzymes responsible for fructose metabolism. No further drug discovery efforts have been described. 

This enzyme, as well as nicotinic acid hydroxylase was recently reported by Andreesan to be a selenoenzyme. The discovery of both these enzymes was based on the clever assumption that selenium might well be a component of multisubunit enzymes containing redox centers such as iron-sulfur, flavin, molybdenum, etc. When Clostridium acidiurici was cultured in media with supplemental selenium, an elevated activity of xanthine dehydrogenase was observed. The clostridial enzyme is comparable to mammalian xanthine oxidases in that it contains flavin adeninedinucleotide (FAD), molybdenum and nonheme iron. This enzyme functions in vivo under anaerobic conditions and appears to catalyze the reduction of uric acid to xanthine. Again it will be interesting to learn the form of selenium in this enzyme. 

In the past uric acid has been recognized as significant for the genesis of Ca oxalate stones. The main mechanism discussed is a blockade of acidic mucopolysaccharides, which are considered to inhibit Ca oxalate precipitation (Robertson). The discovery of uric acid microliths (Berg) or sodium urate (Bellanato) in Ca oxalate stones has not been uncommon. 

Benziodarone has been largely used for the treatment of gout since the discovery of its action to reduce plasma uric acid level, in 1965 its uricosuric effect have been proved later (3-4). 

Based on the United States Renal Data System, which reported their retrospective records of 42,096 renal transplant recipients between 1994 and 1998, the incidence of urolithiasis was 0.11% for males and 0.15% for females (Abbott et al. 2003). At the time of calculus discovery, 67% had kidney stones and 33% ureteral stones. Uric acid stones are much less common than calcium calculi. The stones can be transplanted from cadaveric or living donors or develop de novo, favored either by metabolic disorders (tertiary hyperparathyroidism, hypercalciuria, hypocitraturia) or infection (Proteus tnirabilis), or the presence of a foreign body in the urinary tract (double-J stent) (Crook and Keoghane 2005). 

Recent advances in the understanding of human purine metabolism have been stimulated by the discovery of specific inborn errors of this pathway in man. In particular, the demonstration of the deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) in the Lesch-Nyhan syndrome and in some patients with gout has contributed essential information on the regulation of purine biosynthesis novo and on the critical role of this reutilization pathway in central nervous system function in man. The search for other disorders led to the description of a partial deficiency of adenine phosphoribosyltransferase (APRT) in four members in three generations of one family. Each of the subjects partially deficient in APRT exhibited a normal serum urate concentration and the propositus had a normal excretion of uric acid (Kelley, et al., 1968). We have investigated a second family partially deficient in APRT (Fox and Kelley, in press). 

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