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| - | [[Image:1p1r.gif|left|200px]] | + | {{Seed}} |
| | + | [[Image:1p1r.png|left|200px]] |
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| | {{STRUCTURE_1p1r| PDB=1p1r | SCENE= }} | | {{STRUCTURE_1p1r| PDB=1p1r | SCENE= }} |
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| - | '''Horse liver alcohol dehydrogenase complexed with NADH and R-N-1-methylhexylformamide'''
| + | ===Horse liver alcohol dehydrogenase complexed with NADH and R-N-1-methylhexylformamide=== |
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| - | ==Overview==
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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 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.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_12855684}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 12855684 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_12855684}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Michaelis complex analogue]] | | [[Category: Michaelis complex analogue]] |
| | [[Category: Puckered reduced nicotinamide ring]] | | [[Category: Puckered reduced nicotinamide ring]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 04:34:26 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Jul 27 16:50:48 2008'' |
Revision as of 13:50, 27 July 2008
Template:STRUCTURE 1p1r
Horse liver alcohol dehydrogenase complexed with NADH and R-N-1-methylhexylformamide
Template:ABSTRACT PUBMED 12855684
About this Structure
1P1R is a Single protein structure of sequence from Equus caballus. 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
Page seeded by OCA on Sun Jul 27 16:50:48 2008
