Abstract
Background: Quantitative analysis of enzyme reactivity is a basic requirement for the development of precise diagnostic methods and drug discovery processes, and reduces the number of animal tests. Designed engineering proteins are preferred for developing effective synthesis methods for industrial uses. The specific affinity for an enzyme reaction can be analyzed in silico, but it is difficult to develop a general rule for the selectivity of the enzyme reaction because of a lack of sufficient data. The oxidation reactivity of pig and sheep D-amino acid oxidase (DAO) was quantitatively analyzed in silico.
Methods: The unknown stereo structure of sheep DAO was constructed based on its sequence datum and the stereo structure of pig DAO. Stereo structures of new DAO and amino acid complex as well as an amino acid and inhibitor complex were optimized using the MM2 program. The reactivity was analyzed by further calculation of the atomic partial charge (apc) using MOPAC-PM5. Results: Conformation analysis of DAO and an inhibitor complex was achieved but not described the reactivity as the calculated energy level and the difference in enzyme-ligand interactions. The stereo structures indicated that the electron transfer (oxidation reaction) center of DAO is α -carbon. The calculated atomic partial charge of the targeted atoms using the PM5 program was found to be related to the relative oxidation reactivity (r2 = 0.84, n = 7). The inhibition of kojic acid was also quantitatively analyzed. The atomic partial charge was related to the inhibition ratio (r2 = 0.95, n = 4). Conclusion: Qantitative in silico analysis of the enzyme reaction of DAO was achieved with high precision. Inhibition of kojic acid was also quantitatively analyzed. However, the selective inhibition of pmercuric benzoic acid (HgBA) for glycine was not quantitatively described. Inhibition of pig DAO was clear, but that of sheep DAO was uncertain. The small size of glycine may enable its entrance into the reaction chamber of the sheep DAO structure whereas HgBA did not tightly contact the flavin ring of coenzyme FAD.Keywords: Quantitative analysis of enzyme reaction, in silico, D-amino acid oxidase, inhibitor, 3D structure of protein, molecular mechanics, MOPAC-PM5.
Graphical Abstract
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