Role of quinone-iron(III) interaction in NADPH-dependent enzymic generation of hydroxyl radicals

Dikalov, Sergey; Rumyantseva, G V; Пискунов, А. В.; Weiner, Lev

doi:10.1021/bi00152a034

Cited by 48 publications

(35 citation statements)

References 34 publications

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“…The sequence of reactions in electron transport chains in which quinones stimulate the production of hydroxyl radicals is discussed elsewhere (12,25). Briefly these reactions involve the production of a semiquinone radical (Q ⅐Ϫ ) in the presence of dioxygen, leading to the formation of superoxide (O 2 ⅐Ϫ ) anion which spontaneously dismutates to H 2 O 2 .…”

Section: Discussionmentioning

confidence: 99%

Aerobic inactivation of fumarate reductase from Escherichia coli by mutation of the [3Fe-4S]-quinone binding domain

Cecchini¹,

Sices²,

Schröder³

et al. 1995

J Bacteriol

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Fumarate reductase from Escherichia coli functions both as an anaerobic fumarate reductase and as an aerobic succinate dehydrogenase. A site-directed mutation of E. coli fumarate reductase in which FrdB Pro-159 was replaced with a glutamine or histidine residue was constructed and overexpressed in a strain of E. coli lacking a functional copy of the fumarate reductase or succinate dehydrogenase complex. The consequences of these mutations on bacterial growth, assembly of the enzyme complex, and enzymatic activity were investigated. Both mutations were found to have no effect on anaerobic bacterial growth or on the ability of the enzyme to reduce fumarate compared with the wild-type enzyme. The FrdB Pro-159-to-histidine substitution was normal in its ability to oxidize succinate. In contrast, however, the FrdB Pro-159-to-Gln substitution was found to inhibit aerobic growth of E. coli under conditions requiring a functional succinate dehydrogenase, and furthermore, the aerobic activity of the enzyme was severely inhibited upon incubation in the presence of its substrate, succinate. This inactivation could be prevented by incubating the mutant enzyme complex in an anaerobic environment, separating the catalytic subunits of the fumarate reductase complex from their membrane anchors, or blocking the transfer of electrons from the enzyme to quinones. The results of these studies suggest that the succinate-induced inactivation occurs by the production of hydroxyl radicals generated by a Fenton-type reaction following introduction of this mutation into the [3Fe-4S] binding domain. Additional evidence shows that the substrate-induced inactivation requires quinones, which are the membrane-bound electron acceptors and donors for the succinate dehydrogenase and fumarate reductase activities. These data suggest that the [3Fe-4S] cluster is intimately associated with one of the quinone binding sites found in fumarate reductase and succinate dehydrogenase.During anaerobic respiration in Escherichia coli, the fumarate reductase (FRD) complex catalyzes the fumarate-dependent oxidation of menaquinol, thereby allowing production of a transmembrane proton gradient that can be used by the organism to support metabolism (19). The FRD complex is composed of four nonidentical subunits, FrdA, FrdB, FrdC, and FrdD, arranged into two domains: the FrdAB catalytic domain and the FrdCD membrane anchor domain (2, 22). FrdA (66 kDa) contains covalently bound flavin adenine dinucleotide and the active site of the enzyme (38), and the 27-kDa FrdB subunit contains the three distinct iron-sulfur centers present in the enzyme (23). The iron-sulfur clusters, center 1 ([2Fe-2S] ), are similar in structure and function in all membranebound succinate dehydrogenases (SDHs) and FRDs examined to date (2). The FrdC (15 kDa) and FrdD (13 kDa) subunits are essential for attachment of the catalytic subunits to the inner surface of the cytoplasmic membrane (22) and are also essential for electron transfer reactions involving menaquinol and ubiquinone (8).The p...

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Section: Discussionmentioning

confidence: 99%

Aerobic inactivation of fumarate reductase from Escherichia coli by mutation of the [3Fe-4S]-quinone binding domain

Cecchini¹,

Sices²,

Schröder³

et al. 1995

J Bacteriol

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“…Semiquinones are known to react with molecular oxygen to produce superoxide radicals that can cause toxicity or even cell death in a mechanism completely independent of Hsp90 inhibition. 88 In order to stabilize the quinone and reduce its redox-active potential, investigators incorporated stronger electron-donating groups into the 17-position of GDA. Derivatives of GDA were prepared and evaluated in several murine xenograft models to determine that 17-allylamino-17-desmethoxygeldanamycin (17-AAG, Fig.…”

Section: B Geldanamycin Derivativesmentioning

confidence: 99%

Hsp90 inhibitors: Small molecules that transform the Hsp90 protein folding machinery into a catalyst for protein degradation

Blagg

Kerr

2005

Medicinal Research Reviews

175

119

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The 90 kDa heat shock proteins (Hsp90) are responsible for the conformational maturation of nascent polypeptides and the renaturation of denatured proteins. In transformed cells, numerous mutated and overexpressed proteins rely on the Hsp90 protein folding machinery for tumor progression. The Hsp90-mediated protein folding process is dependent upon ATP, and when inhibitors of ATP are present, the Hsp90 machinery is unable to fold client proteins into their biologically active form, which results in the degradation of protein substrates via the ubiquitin-proteasome pathway. Consequently, Hsp90 has evolved into a promising anti-cancer target because multiple oncogenic proteins can be simultaneously degraded as a consequence of Hsp90 inhibition. This review serves to explain the Hsp90 protein folding process, the impact of Hsp90 inhibition, the identification of natural product inhibitors, and the development of rationally designed inhibitors of the Hsp90 protein folding machinery.

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“…Quinones react with flavin-containing reductases and ascorbate to form semiquinone radicals that can in-turn reduce oxygen to form superoxide (O 2 . ) (8,9). Of note, the cytotoxicity of the ansamycin antibiotics has been attributed to radical generation (10).…”

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confidence: 99%

Geldanamycin Leads to Superoxide Formation by Enzymatic and Non-enzymatic Redox Cycling

Dikalov

Landmesser

Harrison

2002

Journal of Biological Chemistry

116

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The ansamycin antibiotic geldanamycin has frequently been used as an inhibitor of heat shock protein 90 (Hsp90), and this agent has been widely employed as a probe to examine the interactions of Hsp90 with endothelial nitric-oxide synthase. Geldanamycin contains a quinone group, which may participate in redox cycling. When geldanamycin was exposed to the flavin-containing enzyme cytochrome P-450 reductase, both semiquinone and superoxide (O 2 . ) radicals were detected using electron spin resonance. . , which scavenges nitric oxide, leading to loss of its bioavailability. This effect is independent of the inhibition of Hsp90 and indicates that geldanamycin cannot be used as a specific inhibitor of Hsp90. In light of these findings, the studies using geldanamycin as an inhibitor of Hsp90 should be interpreted with caution.

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Role of quinone-iron(III) interaction in NADPH-dependent enzymic generation of hydroxyl radicals

Cited by 48 publications

References 34 publications

Aerobic inactivation of fumarate reductase from Escherichia coli by mutation of the [3Fe-4S]-quinone binding domain

Aerobic inactivation of fumarate reductase from Escherichia coli by mutation of the [3Fe-4S]-quinone binding domain

Hsp90 inhibitors: Small molecules that transform the Hsp90 protein folding machinery into a catalyst for protein degradation

Geldanamycin Leads to Superoxide Formation by Enzymatic and Non-enzymatic Redox Cycling

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