D.G. Johns

The relative toxicities of methotrexate and aminopterin

Abstract Hepatic aldehyde oxidases from rabbit, mouse, rat, and guinea pig have been purified 10-fold to 15-fold and shown to catalyze the oxidation of methotrexate to 7-hydroxymethotrexate. The mouse and rat liver enzymes, however, were unable to catalyze the oxidation of the related compound aminopterin, and the aminopterinoxidizing ability of the rabbit liver enzyme was much inferior to its methoxtrexateoxidizing ability. The oxidase from all four species was stimulated by ammonium ion and inhibited by menadione; species differences were noted, however, in pH optima and susceptibility to inhibition by Triton X-100. The results support the hypothesis that, in some species, the greater toxicity of aminopterin (as compared with that of methotrexate) is attributable to the lesser ability of aminopterin to serve as a substrate for hepatic aldehyde oxidase.

Studies on the mode of oxidation of pyrazolo(3,4-d)pyrimidine by aldehyde oxidase and xanthine oxidase

Abstract Enzymic oxidation of the purine isomer pyrazolo(3,4- d )pyrimidine to the xanthine isomer 4,6-dihydroxypyrazolo(3,4- d )pyrimidine is catalyzed by the metalloflavoproteins xanthine oxidase and aldehyde oxidase. The aldehyde oxidase-satalyzed reaction proceeds conventionally, utilizing molecular oxygen as electron acceptor. The xanthine oxidase-catalyzed reaction is anomalous in type, proceeding rapidly in the presence of artificial electron acceptors for the enzyme (phenazine methosulfate, 2, 6-dichlorophenolindophenol, ferricyanide), but extremely slowly with the acceptors molecular oxygen and cytochrome c . Anaerobic incubation of pyrazolo ((3,4- d ) pyrimidine with enzyme results in substrate-induced reduction of the flavin moiety of aldehyde oxidase, but not in reduction of the flavin moiety of xanthine oxidase. The latter observation, together with the anomalous acceptor requirements, support the possibility that the xanthine oxidase-catalyzed reaction occurs by direct electron transfer to an external acceptor, by-passing the internal electrontransport chain of the enzyme.

4-Hydroxypyrazolo(3,4-d)pyrimidine as a substrate for xanthine oxidase: Loss of conventional substrate activity with catalytic cycling of the enzyme

Abstract The 6-hydroxylation of 4-hydroxypyrazolo(3,4-d)pyrimidine (4-HPP) by xanthine oxidase takes place by a mechanism which, initially, utilizes the complete internal electron transport chain of the enzyme; electron transfer to molecular oxygen and to cytochrome c can be demonstrated, together with spectrophotometrically detectable reduction of the enzyme flavin by substrate. Conventional substrate activity is rapidly lost, however, the rate of aerobic oxidation of 4-HPP showing an exponential decline with a half-time of 18 sec at 25°. The anomalous behavior of 4-HPP as a xanthine oxidase substrate becomes manifest only on catalytic cycling of the enzyme.

Dihydrofolate reductase from guinea pig liver and small intestine

Abstract Dihydrofolate reductase has been purified 2000-fold from guinea pig liver, and 450-fold from guinea pig small intestine. The chromatographic properties, pH optima, and substrate and cofactor requirements of the two enzymes have been compared; the susceptibility of the enzymes to a series of activators and inhibitors also has been determined. No differences were noted between dihydrofolate reductases from the two sources; it is concluded that the unusually high resistance of the guinea pig to folate antagonists cannot be attributed to differences in the properties of small intestine and liver dihydrofolate reductase, or to differences between guinea pig dihydrofolate reductase and the analogous enzyme from other mammalian species.

Antineoplastic and Immunosuppressive Agents Part I

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