The Reduction of Thioketones by a Model for a Coenzyme

Abeles, Robert H.; Hutton, Robert F.; Westheimer, F. H.

doi:10.1021/ja01560a058

Cited by 161 publications

(46 citation statements)

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“…References to both opposing views are presented in several stimulating publications but differences in interpretation still persist [27][28][29][30][31][32][33][34][35].…”

Section: Methodsmentioning

confidence: 99%

“…Still, we believed that evidence of semiquinone radical formation in biochemical reactions was insufficient. It seemed that the investigation of a relevant redox process such as the reaction of naturally occuring quinones with NAD(P)H models under conditions aimed to mimic those in biological systems, might be an adequate reaction although earlier examinations led to contradictiory conclusions (see above, [27][28][29][30][31][32][33][34][35]). …”

Section: Dna Damagementioning

confidence: 99%

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Reactivity and Biological Activity of the Marine Sesquiterpene Hydroquinone Avarol and Related Compounds from Sponges of the Order Dictyoceratida

Sladić

Gašić

2006

Molecules

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A review of results of bioactivity and reactivity examinations of marine sesquiterpene (hydro)quinones is presented. The article is focused mostly on friedorearranged drimane structural types, isolated from sponges of the order Dictyoceratida. Examples of structural correlations are outlined. Available results on the mechanism of redox processes and examinations of chemo-and regioselectivity in addition reactions are presented and, where possible, analyzed in relation to established bioactivities. Most of the bioactivity examinations are concerned with antitumor activities and the mechanism thereof, such as DNA damage, arylation of nucleophiles, tubulin assembly inhibition, protein kinase inhibition, inhibition of the arachidonic cascade, etc. Perspectives on marine drug development are discussed with respect to biotechnological methods and synthesis. Examples of the recognition of validated core structures and synthesis of structurally simplified compounds retaining modes of activity are analyzed.

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“…References to both opposing views are presented in several stimulating publications but differences in interpretation still persist [27][28][29][30][31][32][33][34][35].…”

Section: Methodsmentioning

confidence: 99%

Section: Dna Damagementioning

confidence: 99%

Reactivity and Biological Activity of the Marine Sesquiterpene Hydroquinone Avarol and Related Compounds from Sponges of the Order Dictyoceratida

Sladić

Gašić

2006

Molecules

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“…The involvement of the active-site zinc ion as a Lewis acid catalyst of ternary-complex interconversion has been suggested by several authors [6,[22][23][24][25][26][27][28][29][30]. Most proposals in that direction have focused on the process of aldehyde reduction and emphasized the polarizing effect of the zinc ion on the metal-bound substrate.…”

Section: Tlzc Cntcilytic Functioti O F Thc Active-site Zinc Ionmentioning

confidence: 99%

Substituent Effects on the Ionization Step Regulating Desorption and Catalytic Oxidation of Alcohols Bound to Liver Alcohol Dehydrogenase

Kvassman¹,

Larsson²,

Pettersson³

1981

Eur J Biochem

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1. Transient-state kinetic methods, based on the use of pyrazole as a displacing reagent and reporter ligand, have been applied to examine the pH dependence of rate and equilibrium constants for 2-chloroethanol and 2,2-dichloroethanol binding to the binary complex formed between liver alcohol dehydrogenase and NAD' .2. The apparent affinity of the enzyme . NAD' complex for the examined alcohols is dependent on two proton dissociation equilibria. One of these equilibria affects the rate of alcohol association to the binary complex with a ligand-independent pKa value of 7.6, attributable to ionization of zinc-bound water in the enzyme. NAD' complex. The second proton dissociation equilibrium regulates the rate of alcohol desorption from the enzyme . NAD' . alcohol complex and exhibits a pK, value of 5.4 and 4.5, respectively, with 2-chloroethanol and 2,2'-dichloroethanol as the ligand. Steady-state kinetic data are reported which indicate that the pK,-5.4-equilibrium controls also the apparent rate of enzymic hydride transfer from 2-chloroethanol to NAD '. 3. These results lend strong support to the mechanism of enzyme action proposed by Kvassman andPettersson according to which the enzyme . NAD' . alcohol complex participates in an obligatory proton dissociation step which regulates both desorption and catalytic oxidation of the alcohol ligand. The corresponding pKa value is shown to be lineary dependent on the pK, of the free alcohol ligand with a regression coefficient (Bronstedt a value) of about 0.6. The latter observation provides direct evidence that the effect of pH on the reactivity of the enzyme . NAD' . alcohol complex reflects an alcohol/alcoholate ion equilibration of the enzyme-bound substrate. 4. The particular mode of binding and properties of the active-site zinc ion in liver alcohol dehydrogenase suggest that the catalytic function of the metal ion can be related primarily to facilitation of the process of alcohol oxidation through facilitation of the alcoholate ion formation step now established to precede hydride transfer to NAD' Liver alcohol dehydrogenase catalyzes the oxidation of alcohols by NAD'. The enzyme operates by an effectively ordered ternary-complex mechanism (Scheme l), coenzyme binding preceding binding of the alcohol substrate [l]. Investigations of the effect of pH on the catalytic steps of alcohol binding [2,3] and ternary-complex interconversion [4,5] have shown that the enzyme . NAD' . alcohol complex participates in a proton dissociation equilibrium which regulates the reactivity of this reaction intermediate. Alcohol desorption occurs exclusively from the protonated form of the ternary complex, while hydride transfer from the alcohol substrate to NAD' requires the unprotonated form of the complex.It has been suggested in previous reports from our laboratory [3,5] that the effect of pH on the reactivity of the enzyme . NAD+ . alcohol complex derives from an alcohol/ alcoholate ion equilibration of the enzyme-bound substrate (Scheme 2). Determinations of the corresponding ac...

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“…from dihydronicotinamides to flavin was later formulated to involve preequilibrium complex formation along the reaction path. This was based on the lack of correlation of log(kr te) for the redox reaction with the E112 potentials for a series of flavins and the good correlation between log(krale) with log(Ke) for complex formation ofthe flavins with tryptophan (7,8 (19)(20)(21)(22)(23)(24). A multistep rather than a single-step Htransfer has been suggested in order.…”

mentioning

confidence: 99%

Concerning 1e- transfer in reduction by dihydronicotinamide: reaction of oxidized flavin and flavin radical with N-benzyl-1,5-dihydronicotinamide.

Powell¹,

Wong²,

Bruice³

1982

Proc. Natl. Acad. Sci. U.S.A.

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The rates of reaction of 5-ethyl-3-methyllumiflavinium perchlorate and.5-ethyl-3-methyllumiflavinyl radical with a NADH analogue, N-benzyl-1,4-dihydronicotinamide, were measured anaerobically in tert-butanol and .5% acetonitrile/ 95% tert-butanol-solutions at 30C. The biphasic kinetics observed for the reaction of flavin radical with dihydronicotinamide were interpreted in terms.of both a leC and a 2e-mechanism; the former was found to be inadequate based on experimental requirements of the mechanism. The dihydronicotinamide reacts preferentially with oxidized flavin rather than flavin radicals even when the concentration of oxidized flavin. is at a concentration 5 orders of magnitude less than that of radical. These studies show that the "hydride" reduction of oxidized flavin by BNAH is more facile than is the le-reduction of flavin radical by BNAH.The oxidation of reduced pyridine nucleotides and their analogues is far from completely understood, especially when a flavin moiety is used as the oxidant as it is in the flavin coenzymes ofthe respiratory chain (1). Suelter and Metzler (2) studied the nonenzymatic reduction of several flavin analogues by 1-propyl-1,4-dihydronicotinamide and concluded that hydride transfer was occurring. Their deduction was based on the observations that: (i) electron-withdrawing.substituents on the. nicotinamide decreased the oxidation rate; (ii) the 4,4-dideutero-1,4-dihydronicotinamide reacted slower than its protio analogue by a factor of 0.31; and (iii) the oxidation rate increased with increasing solvent polarity. Radda and Calvin (3) pointed out that radical detection by ESR is not a useful. observation because the comproportionation reaction between oxidized flavinmononucleotide and reduced flavinmononucleotide (FMN and FMNH2, respectively) provides the flavin radical, FMNHF-.[1]Thus, the presence ofa flavin radical does not provide evidence for a le-transfer mechanism. In further studies (4-6), these results were confirmed and the N5 of the flavin. moiety was proposed to be the position accepting the hydride ion. The reaction mechanism for net hydride transfer. from dihydronicotinamides to flavin was later formulated to involve preequilibrium complex formation along the reaction path. This was based on the lack of correlation of log(kr te) for the redox reaction with the E112 potentials for a series of flavins and the good correlation between log(krale) with log(Ke) for complex formation ofthe flavins with tryptophan (7,8 (19)(20)(21)(22)(23)(24). A multistep rather than a single-step Htransfer has been suggested in order. to account for. the observations that product isotope effects have been found to be significantly larger than the kinetic ones. This observation-can be explained if an intermediate is formed along the reaction path for "hydride. transfer. " In most cases a pyridinyl radical was invoked. The direct determination of isotope ratios of products is inherently more difficult in the dihydronicotinamide reduction of flavins because of the exchangable nat...

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The Reduction of Thioketones by a Model for a Coenzyme

Cited by 161 publications

References 0 publications

Reactivity and Biological Activity of the Marine Sesquiterpene Hydroquinone Avarol and Related Compounds from Sponges of the Order Dictyoceratida

Reactivity and Biological Activity of the Marine Sesquiterpene Hydroquinone Avarol and Related Compounds from Sponges of the Order Dictyoceratida

Substituent Effects on the Ionization Step Regulating Desorption and Catalytic Oxidation of Alcohols Bound to Liver Alcohol Dehydrogenase

Concerning 1e- transfer in reduction by dihydronicotinamide: reaction of oxidized flavin and flavin radical with N-benzyl-1,5-dihydronicotinamide.

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