A New Class of Xanthine Oxidase Inhibitors Isolated from Guanidinium Salts<sup>*</sup>

Fridovich, Irwin

doi:10.1021/bi00882a018

Cited by 24 publications

(7 citation statements)

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“…The inhibitory power of guanidinium salts was found to vary markedly from lot to lot. I then isolated the symmetrical triazine that was responsible for this variability (16). While working with triazines I found some that were powerful inhibitors of uricase (17) and was pleased to see this information applied to raising the urate level of mice by feeding them my uricase inhibitor (18).…”

Section: Reflections: Reflections Of a Fortunate Biochemistmentioning

confidence: 99%

Reflections of a Fortunate Biochemist

Fridovich

2001

Journal of Biological Chemistry

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While contemplating the writing of this article I reread some of my early publications and in so doing was appalled at my profound ignorance. That, of course, is the advantage of hindsight. It is also an indication of how much has been learned by me and by others during the intervening half-century. That is the beauty of science; it is a collaborative work in progress that builds knowledge and understanding of the real world. I hope it may be interesting (for readers concerned with the process as well as with the results) to recount how we progressed from abysmal naiveté to our current informed view of the biology of oxidation stress. The goal of modesty is served by allowing for the probability that our successors 5 decades hence will consider the knowledge we have achieved pitifully incomplete. Sulfite OxidationAbraham Mazur introduced me to the wonders of biochemistry in an undergraduate course and then during a year spent working in his laboratory at Cornell Medical School. At the end of that year he recommended graduate work and sent me to Duke Medical School to work with Philip Handler, the chairman of the Department of Biochemistry. Handler was the most impressive person I have ever met. He was blessed with a photographic memory, an incomparable mastery of language, and excellent judgment. He assigned me to work with Murray Heimberg, who was then a senior graduate student. He was older than the usual graduate student, having devoted several years to fighting World War II. At one time during this conflict Murray had lost half of his body weight because of malnutrition while a prisoner of war, but he had entirely recovered when I knew him.We worked long hours, measuring O 2 uptake with Warburg microrespirometers and methylene blue bleaching in evacuated Thunberg tubes with a Coleman colorimeter. We found that ␣-hydroxysulfonic acids dissociated to carbonyl compounds plus sulfite and that sulfite was then oxidized to sulfate in the liver extracts we were studying (1). Thus began my long infatuation with sulfite oxidation.It had already been established that sulfite was readily oxidized by a free radical chain mechanism, but I did not know this and had to discover it for myself. Thus I found that sulfite could reduce cytochrome c and, of course, at the same time cytochrome c could oxidize sulfite. When this was done anaerobically the stoichiometry was 2 cytochrome c reduced per sulfite oxidized, as expected. However, in the presence of dissolved O 2 thousands of sulfites were oxidized per cytochrome c reduced. This could be rationalized by assuming that each time sulfite transferred an electron to cytochrome c, the resulting sulfur trioxyradical started a chain reaction between sulfite and O 2 as follows.

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Section: Reflections: Reflections Of a Fortunate Biochemistmentioning

confidence: 99%

Reflections of a Fortunate Biochemist

Fridovich

2001

Journal of Biological Chemistry

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“…The enzyme concentrations were 100, 100 and 200 ,ug/ml for the bovine liver (0), baker's yeast (A) and C. symbosium (O) enzymes respectively. possible effects on enzymes have been discussed previously (Fridovich, 1965;Nozaki, 1972).…”

Section: Effect Of Gdnhci On Enzyme Activitymentioning

confidence: 99%

The unfolding and refolding of glutamate dehydrogenases from bovine liver, baker's yeast and Clostridium symbosium

West

Price

1988

Biochemical Journal

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The unfolding behaviour of the hexameric glutamate dehydrogenases from bovine liver, Clostridium symbosium and baker's yeast in solutions of guanidinium chloride (GdnHCl) was studied. Changes in Mr studied by light-scattering indicate that, in each case, the hexamer dissociates to form trimers, which then dissociate to monomers at higher concentrations of GdnHCl. Dissociation to trimers is accompanied by a reversible loss of enzyme activity, but no gross structural changes can be detected by fluorescence or c.d. Dissociation to monomers is accompanied by large structural changes, and the loss of activity cannot be reversed by dilution. The parallel behaviour of all three enzymes shows that the previously noted inability of the isolated subunits of the bovine liver enzyme to refold [Bell & Bell (1984) Biochem. J. 217, 327-330] is not a result of any modification of the enzyme as a result of import into mitochondria, since the C. symbosium and baker's-yeast enzymes do not undergo any such post-translational translocation.

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“…Indeed, Fridovich has shown that certain s-triazines are potent competitive inhibitors of uricase ( 1 ) and of xanthine oxidase ( 2 ) in vitro. But unlike uric acid, the s-triazines do not serve as substrates for uricase and hence their destruction by this enzyme is prevented.…”

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confidence: 99%