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| - | [[Image:1b16.gif|left|200px]] | + | {{Seed}} |
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| | {{STRUCTURE_1b16| PDB=1b16 | SCENE= }} | | {{STRUCTURE_1b16| PDB=1b16 | SCENE= }} |
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| - | '''ALCOHOL DEHYDROGENASE FROM DROSOPHILA LEBANONENSIS TERNARY COMPLEX WITH NAD-3-PENTANONE'''
| + | ===ALCOHOL DEHYDROGENASE FROM DROSOPHILA LEBANONENSIS TERNARY COMPLEX WITH NAD-3-PENTANONE=== |
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| - | ==Overview==
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| - | Drosophila alcohol dehydrogenase (DADH) is an NAD+-dependent enzyme that catalyzes the oxidation of alcohols to aldehydes/ketones. DADH is the member of the short-chain dehydrogenases/reductases family (SDR) for which the largest amount of biochemical data has been gathered during the last three decades. The crystal structures of one binary form (NAD+) and three ternary complexes with NAD+.acetone, NAD+.3-pentanone and NAD+.cyclohexanone were solved at 2.4, 2.2, 1. 4 and 1.6 A resolution, respectively. From the molecular interactions observed, the reaction mechanism could be inferred. The structure of DADH undergoes a conformational change in order to bind the coenzyme. Furthermore, upon binding of the ketone, a region that was disordered in the apo form (186-191) gets stabilized and closes the active site cavity by creating either a small helix (NAD+. acetone, NAD+.3-pentanone) or an ordered loop (NAD+.cyclohexanone). The active site pocket comprises a hydrophobic bifurcated cavity which explains why the enzyme is more efficient in oxidizing secondary aliphatic alcohols (preferably R form) than primary ones. Difference Fourier maps showed that the ketone inhibitor molecule has undergone a covalent reaction with the coenzyme in all three ternary complexes. Due to the presence of the positively charged ring of the coenzyme (NAD+) and the residue Lys155, the amino acid Tyr151 is in its deprotonated (tyrosinate) state at physiological pH. Tyr151 can subtract a proton from the enolic form of the ketone and catalyze a nucleophilic attack of the Calphaatom to the C4 position of the coenzyme creating an NAD-ketone adduct. The binding of these NAD-ketone adducts to DADH accounts for the inactivation of the enzyme. The catalytic reaction proceeds in a similar way, involving the same amino acids as in the formation of the NAD-ketone adduct. The p Kavalue of 9-9.5 obtained by kinetic measurements on apo DADH can be assigned to a protonated Tyr151 which is converted to an unprotonated tyrosinate (p Ka7.6) by the influence of the positively charged nicotinamide ring in the binary enzyme-NAD+form. pH independence during the release of NADH from the binary complex enzyme-NADH can be explained by either a lack of electrostatic interaction between the coenzyme and Tyr151 or an apparent p Kavalue for this residue higher than 10.0.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_10366509}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 10366509 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_10366509}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Short-chain dehydrogenases/reductase]] | | [[Category: Short-chain dehydrogenases/reductase]] |
| | [[Category: Ternary complex]] | | [[Category: Ternary complex]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 10:56:45 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jun 30 18:01:35 2008'' |
Revision as of 15:01, 30 June 2008
Template:STRUCTURE 1b16
ALCOHOL DEHYDROGENASE FROM DROSOPHILA LEBANONENSIS TERNARY COMPLEX WITH NAD-3-PENTANONE
Template:ABSTRACT PUBMED 10366509
About this Structure
1B16 is a Single protein structure of sequence from Scaptodrosophila lebanonensis. Full crystallographic information is available from OCA.
Reference
The catalytic reaction and inhibition mechanism of Drosophila alcohol dehydrogenase: observation of an enzyme-bound NAD-ketone adduct at 1.4 A resolution by X-ray crystallography., Benach J, Atrian S, Gonzalez-Duarte R, Ladenstein R, J Mol Biol. 1999 Jun 4;289(2):335-55. PMID:10366509
Page seeded by OCA on Mon Jun 30 18:01:35 2008
