Computational characterization for catalytic activities of human CD38's wild type, E226 and E146 mutants
| Autor: | Van U. Dang, Boi V. Luu, My H. Nguyen |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Stereochemistry
Glutamic Acid Health Informatics Nicotinamide adenine dinucleotide Ligands Cyclase General Biochemistry Genetics and Molecular Biology Catalysis chemistry.chemical_compound Catalytic Domain Humans Databases Protein biology Nicotinamide Chemistry Hydrogen bond Hydrolysis Wild type Active site Computational Biology Hydrogen Bonding NAD ADP-ribosyl Cyclase 1 Computer Science Applications Kinetics Mutation biology.protein NAD+ kinase Cyclase activity Algorithms Software |
| Zdroj: | Interdisciplinary sciences, computational life sciences. 2(2) |
| ISSN: | 1913-2751 |
| Popis: | A series of the complexes of human CD38's wild type, E226 and E146 mutants as well have been simulated. The biosoftwares well simulate the penetration of nicotinamide-adenine-dinucleotide (NAD) into the active site. The nicotinamide end of NAD penetrates deep into the active site consistent with cleavage of the nicotinamide-glycosidic bond which is the first step of catalysis creating a Michaelis complex regarded as the intermediate product of NAD cyclase and hydrolysis reaction. The breaking down hydrogen bond between 2'-3' OH ribosyl and the residues replaced Glu(226) makes NAD to be less constrained in active site and nicotinamide (NA) becomes more difficult to be cleaved and eliminates the mutant catalytic activities. The large majority of the substrate NAD is hydrolyzed to ADPR while the conversion of NAD to cADPR is not the dominant reaction catalyzed by wild-type human CD38. The more strongly kept ribosyl group by hydrogen bonds the more NADase and the less cyclase activity. Breaking hydrogen bonds of ribosyl 2'- and 3'-OH by mutation will loosen it to promote the cyclase. The cyclic adenosine diphosphate-ribose (cADPR) could also penetrate deeply into active site to make some hydrogen bonds with Glu(146) and Glu(226); however, its docking poses are affected by a residue located at the entrance of the catalytic pocket (Lys(129)). These results are in good agreement with the previous crystallographic analysis and the experiments quantified the catalytic activities of human CD38 and its mutants. |
| Databáze: | OpenAIRE |
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