Adenine, 8- , xanthine oxidase inhibition

The similarity in the pyrimidine ring of pteridines and pterins, especially to the purines adenine and guanosine, undoubtedly makes them good templates for inhibitor design as these examples show. Another enzyme for which inhibition by pteridines has been established is xanthine oxidase <1999BBA387>. In this case, the limitation on structure for inhibitors in the pteridine series was that there should be no substituent on C-7 and that the pteridines should be fully conjugated. The best inhibitors (ICso 0.1 xM) were 6-formylpterin and 6-hydroxylumazine. 

The inhibition of enzyme systems dues nut necessarily cause unwarned effects. Consider the enzyme xanthine oxidase. It contains two atoms of molybdenum, four Fe2S2, and two FAD (flavin adenine dinucleotidei moieties, and it has a molecular weight of 275.000-300.000. There is no evidence that the two units (Mo/SFe Sj/FAD) are near each other or interact in any way. It is believed that the immediate environment of each molybdenum atom consists of one oxygen and three sulfur atoms (additional ligands may be present) 12... 

As indicated in Fig. 25-18, free adenine released from catabolism of nucleic acids can be deaminated hydrolytically to hypoxanthine, and guanine can be deaminated to xanthine.328 The molybdenum-containing xanthine oxidase (Chapter 16) oxidizes hypoxanthine to xanthine and the latter on to uric acid. Some Clostridia convert purine or hypoxanthine to xanthine by the action of a selenium-containing purine hydroxylase.3283 Another reaction of xanthine occurring in some plants is conversion to the trimethylated derivative caffeine. 328b One of the physiological effects of caffeine in animals is inhibition of pyrimidine synthesis.329 However, the effect most sought by coffee drinkers may be an increase in blood pressure caused by occupancy of adenosine receptors by caffeine.330... 

Xanthine oxidase is a rather nonspecific enzyme it not only catalyzes the oxidation of hypoxanthine and xanthine, but also the conversion of adenine to 2,8-dihydroxyadenine (B23, K9) as well as the oxidation of many unusual purines, such as 2-azaadenine (S14). It also acts on xanthopterin (K4), and catalyzes the oxidation of a variety of aldehydes and NADH. Several pterins, notably 2-amino-4-hydroxy-6-formyl- (K3), 2-amino-4-hydroxy-6-carboxy-, 2-amino-4-hydroxy-, and 6-hydroxymethyl- (P3) pterins, inhibit xanthine oxidase. A variety of purines are both substrate and inhibitor of the enzyme. Antabuse (tetraethylthiuram disulfide) has a considerable inhibitory effect on xanthine oxidase in rat... 

Further in vitro studies using a lung cancer cell line (A549) demonslrated that febuxostat (16 xM for 3h) completely inhibited xanthine oxidase activity without affecting the activities of adenosine deaminase, purine nucleoside phosphorylase, adenine phosphoribosyltransferase, hypoxanthine-guanine phosphoribosyltransferase, pyrimidine -nucleoside phosphorylase, or guanase. ... 

---