Transition Structures of Hydride Transfer Reactions of Protonated Pyridinium Ion with 1,4-Dihydropyridine and Protonated Nicotinamide with 1,4-Dihydronicotinamide

Wu, Yun‐Dong; Lai, David K. W.; Houk, K. N.

doi:10.1021/ja00119a026

Cited by 63 publications

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“…2 The two interacting pairs of nicotinamide cofactors are shown in Figure 4(b) and (d), adjacent to the electron density for the dinucleotides (Figure 4(a) and (c)). In accord with the biochemical data, theoretical considerations, 44,45 and crystal structures of other nicotinamide-containing enzymes, 46,47 the NAD(H) nicotinamides are anti about the glycosyl torsion angle c, and the NADPH nicotinamides are syn. In the dI(B)-dIII(C) pair the C4 atoms are 10.9 Å apart; in the dI(H)-dIII(I) pair this distance is reduced to 4.6 Å .…”

Section: Hydride Transfer Complexmentioning

confidence: 78%

“…The nicotinamide side-chain torsion angle X am is w1208 for each NADPH, placing the carbonyl oxygen nearer C4, which is the trans conformation favored for hydride transfer. 44 However, the NAD(H) nicotinamides differ: in dI(B) X am is w908; in dI(H) it is w208, or essentially cis, with the amide nitrogen nearer C4, which is less favored for hydride transfer.…”

Section: Hydride Transfer Complexmentioning

confidence: 99%

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Conformational Diversity in NAD(H) and Interacting Transhydrogenase Nicotinamide Nucleotide Binding Domains

Sundaresan

Chartron

Yamaguchi

et al. 2005

Journal of Molecular Biology

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Section: Hydride Transfer Complexmentioning

confidence: 78%

Section: Hydride Transfer Complexmentioning

confidence: 99%

Conformational Diversity in NAD(H) and Interacting Transhydrogenase Nicotinamide Nucleotide Binding Domains

Sundaresan

Chartron

Yamaguchi

et al. 2005

Journal of Molecular Biology

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“…Molecular dynamics simulations on the native ADH-NADH-benzaldehyde complex show fluctuations of the protein cause the nicotinamide ring of NADH to bend, with angles for the C4 deviation being as large as 20° (39). Calculations show that puckering of the dihydronicotinamide ring, to form a quasi-boat conformation, decreases the transition state energy for hydrogen transfer of the pseudoaxial hydrogen at C4 (40,41). The structure of the complex with NADH and the formamide suggests that the ground state can have a puckered nicotinamide ring.…”

Section: Discussionmentioning

confidence: 99%

Formamides Mimic Aldehydes and Inhibit Liver Alcohol Dehydrogenases and Ethanol Metabolism

Venkataramaiah

Plapp

2003

Journal of Biological Chemistry

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Formamides are unreactive analogues of the aldehyde substrates of alcohol dehydrogenases and are useful for structure-function studies and for specific inhibition of alcohol metabolism. They bind to the enzyme-NADH complex and are uncompetitive inhibitors against varied concentrations of alcohol. Fourteen new branched chain and chiral formamides were prepared and tested as inhibitors of purified Class I liver alcohol dehydrogenases: horse (EqADH E), human (HsADH1C*2), and mouse (MmADH1). In general, larger, substituted formamides, such as N-1-ethylheptylformamide, are better inhibitors of HsADH1C*2 and MmADH1 than of EqADH, reflecting a few differences in amino acid residues that change the sizes of the active sites. In contrast, the linear, alkyl (n-propyl and n-butyl) formamides are better inhibitors of EqADH and MmADH1 than of HsADH1C*2, probably because water disrupts van der Waals interactions. These enzymes are also inhibited strongly by sulfoxides and 4-substituted pyrazoles. The structure of EqADH complexed with NADH and (R)-N-1-methylhexylformamide was determined by x-ray crystallography at 1.6 Å resolution. The structure resembles the expected Michaelis complex with NADH and aldehyde, and shows for the first time that the reduced nicotinamide ring of NADH is puckered, as predicted for the transition state for hydride transfer. Metabolism of ethanol in mice was inhibited by several formamides. The data were fitted with kinetic simulation to a mechanism that describes the non-linear progress curves and yields estimates of the in vivo inhibition constants and the rate constants for elimination of inhibitors. Some small formamides, such as N-isopropylformamide, may be useful inhibitors in vivo.Vertebrate alcohol dehydrogenases (EC 1.1.1.1, ADH) 1 are involved in the metabolism of relatively non-polar alcohols and aldehydes (1). The five different human enzymes have broad substrate specificity, oxidizing primary and secondary alcohols and reducing their corresponding carbonyl compounds. Specific inhibitors of these dehydrogenases would be useful for defining substrate specificity, for studying the physiological roles of the enzymes and for preventing the oxidation of methanol and ethylene glycol to toxic products (2-6).Formamides and sulfoxides are analogues of the carbonyl substrates, are bound preferentially to the enzyme-NADH complex, and are potent uncompetitive inhibitors against varied concentrations of alcohol (7-15). Uncompetitive inhibitors could be especially useful for controlling alcohol metabolism since they are effective even when the concentrations of alcohol are saturating. Previous studies identified some potent uncompetitive inhibitors for human (14, 15), horse (10,11,14,15), monkey (11), and rat (10, 11) liver alcohol dehydrogenases. We now extend the studies with 14 new branched-chain and chiral formamides in order to explore active site topologies and to make more effective inhibitors for the mouse (MmADH1) and human (HsADH1C*2) enzymes. For comparison, we also studied the potency of fi...

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“…6) and the dI 2 dIII 1 complex, and, according to the ab initio MO studies (52), this is the favored conformation for hydride transfer. However, conformational changes in this site are also expected during turnover, but on the basis that thio-NADP ϩ is a good substrate for transhydrogenase, these changes are not expected to involve equivalent rotations in the C-3-C-7 bond of the nucleotide.…”

mentioning

confidence: 85%

“…Note that the 3-carboxamide of NAD ϩ in polypeptides A and D of isolated dI (6), was arbitrarily set in the commonly observed trans position, although the hydrogen bonds to the carboxylate of Asp 135 in the former do not discriminate against a cis conformation, and there are no hydrogen bonds in the latter to determine an orientation (the electron density in polypeptides B and C, on the other hand, is too weak to define the nicotinamide position and conformation). The finding that the carboxamide is probably in the cis conformation in at least some of the transhydrogenase structures is all the more remarkable in view of the results of ab initio molecular orbital calculations on transition state models of hydride transfer between nicotinamide and dihydronicotinamide (52). It was shown that X am can affect the rate of reaction, notably with a trans organization lowering the energy of the transition state.…”

mentioning

confidence: 97%

Interactions between Transhydrogenase and Thio-nicotinamide Analogues of NAD(H) and NADP(H) Underline the Importance of Nucleotide Conformational Changes in Coupling to Proton Translocation

Singh

Venning

Quirk

et al. 2003

Journal of Biological Chemistry

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Transhydrogenase couples the reduction of NADP؉ by NADH to inward proton translocation across mitochondrial and bacterial membranes. The coupling reactions occur within the protein by long distance conformational changes. In intact transhydrogenase and in complexes formed from the isolated, nucleotide-binding components, thio-NADP(H) is a good analogue for NADP(H), but thio-NAD(H) is a poor analogue for NAD(H). Crystal structures of the nucleotide-binding components show that the twists of the 3-carbothiamide groups of thio-NADP ؉ and of thio-NAD ؉ (relative to the planes of the pyridine rings), which are defined by the dihedral, X am , are altered relative to the twists of the 3-carboxamide groups of the physiological nucleotides. The finding that thio-NADP ؉ is a good substrate despite an increased X am value shows that approach of the NADH prior to hydride transfer is not obstructed by the S atom in the analogue. That thio-NAD(H) is a poor substrate appears to be the result of failure in the conformational change that establishes the ground state for hydride transfer. This might be a consequence of restricted rotation of the 3-carbothiamide group during the conformational change.Transhydrogenase is found in the inner membrane of animal mitochondria and in the cytoplasmic membrane of bacteria. The enzyme provides NADPH for biosynthesis and for reduction of glutathione, and in some mammalian tissues, it probably participates in the regulation of flux through the tricarboxylic acid cycle (1, 2). Under most physiological conditions transhydrogenase is driven in the "forward" direction by the proton electrochemical gradient (⌬p) generated by respiratory (or photosynthetic) electron transport.There is general agreement that coupling between the redox reaction and proton translocation is mediated by changes in protein conformation, although the character of these conformational changes is not known (reviewed in Refs. 3-5). Coupling mechanisms that involve large conformational changes operating over considerable distances are emerging as a common feature in proteins that translocate solutes/ions across membranes, and the amenable properties of transhydrogenase make it an attractive model in the search for fundamental principles. The enzyme has three components. The dI component, which binds NAD ϩ and NADH, and the dIII component, which binds NADP ϩ and NADPH, are extrinsic proteins protruding from the membrane (on the matrix side in mitochondria and on the cytoplasmic side in bacteria), and dII spans the membrane. The enzyme is essentially a "dimer" of two dI-dIIdIII "monomers," although the polypeptide composition is variable among species. Crystal structures of Rhodospirillum rubrum dI (6, 7), bovine dIII (8), human dIII (9, 10), and R. rubrum dI 2 dIII 1 complex (11,12), and an NMR structure of R. rubrum dIII (13) have recently been published. Studies on the transient state kinetics of transhydrogenation reveal that the redox reaction between the two nucleotides is direct (14,15). Thus, the nicotinamide and dihydr...

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Transition Structures of Hydride Transfer Reactions of Protonated Pyridinium Ion with 1,4-Dihydropyridine and Protonated Nicotinamide with 1,4-Dihydronicotinamide

Cited by 63 publications

References 0 publications

Conformational Diversity in NAD(H) and Interacting Transhydrogenase Nicotinamide Nucleotide Binding Domains

Conformational Diversity in NAD(H) and Interacting Transhydrogenase Nicotinamide Nucleotide Binding Domains

Formamides Mimic Aldehydes and Inhibit Liver Alcohol Dehydrogenases and Ethanol Metabolism

Interactions between Transhydrogenase and Thio-nicotinamide Analogues of NAD(H) and NADP(H) Underline the Importance of Nucleotide Conformational Changes in Coupling to Proton Translocation

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