Human Aldehyde Dehydrogenase Catalytic Activity and Structural Interactions with Coenzyme Analogs
| Autor: | Alexander D. MacKerell, Gonzalo Izaguirre, Regina Pietruszko, Samuel S. Cho |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
Adult
Purine Stereochemistry Glutamine Aldehyde dehydrogenase Isozyme Catalysis Cofactor Substrate Specificity Structure-Activity Relationship chemistry.chemical_compound Structural Biology Catalytic Domain Pyridine Humans Computer Simulation Molecular Biology biology Substrate (chemistry) General Medicine Aldehyde Dehydrogenase NAD Isoenzymes Kinetics Liver chemistry Biochemistry biology.protein Quantum Theory Thermodynamics NAD+ kinase Selectivity Algorithms |
| Zdroj: | Scopus-Elsevier |
| ISSN: | 1538-0254 0739-1102 |
| DOI: | 10.1080/07391102.2001.10506752 |
| Popis: | K(m) and V(max) values for 10 coenzyme analogs never previously studied with any aldehyde dehydrogenase and NADP(+) were compared with those for NAD(+) for three human aldehyde dehydrogenases (EC 1.2.1.3); the cytoplasmic E1 (the product of the aldh1 gene), the mitochondrial E2 (the product of the aldh2 gene) and the cytoplasmic E3 (the product of the aldh9 gene) isozymes. Structural information on changes in coenzyme-protein interactions were obtained via molecular dynamics (MD) studies with the E2 isozyme and quantum mechanical (QM) calculations were used to study changes in charge distribution of the pyridine ring and relative free energies of solvation of the purine ring in the analogs. E1 showed the broadest substrate specificity and was the only isozyme subject to substrate inhibition, both of which are suggested to be due to the two coenzyme conformations observed previously in the sheep crystal structure. NADP(+) selectivity is indicated to be influenced by Glu195 in E1 and E2. Substitutions in the purine ring affected K(m) but not V(max), with the changes in K(m) being dominated by the hydrophobicity of the purine ring as indicted by the QM calculations. Substitutions in the pyridine ring sometimes rendered the coenzymes inactive, with no consistent pattern observed for the three coenzymes. Structural analysis of the coenzyme analog-E2 MD simulations revealed different structural perturbations of the surrounding active site, though interactions with Asn169 and Glu399 were preserved in all cases. |
| Databáze: | OpenAIRE |
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