1p1r
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(New page: 200px<br /><applet load="1p1r" size="450" color="white" frame="true" align="right" spinBox="true" caption="1p1r, resolution 1.57Å" /> '''Horse liver alcohol ...)
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Revision as of 21:16, 20 November 2007
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Horse liver alcohol dehydrogenase complexed with NADH and R-N-1-methylhexylformamide
Overview
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 A 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.
About this Structure
1P1R is a Single protein structure of sequence from Equus caballus with ZN, NAJ, NMH and MPD as ligands. Active as Alcohol dehydrogenase, with EC number 1.1.1.1 Full crystallographic information is available from OCA.
Reference
Formamides mimic aldehydes and inhibit liver alcohol dehydrogenases and ethanol metabolism., Venkataramaiah TH, Plapp BV, J Biol Chem. 2003 Sep 19;278(38):36699-706. Epub 2003 Jul 10. PMID:12855684
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