Monoamine oxidases are two isozymic flavoenzymes which are the important targets for drugs used in the treatment of depression, Parkinson and Alzheimer's diseases. The catalytic reaction taking place between the cofactor FAD and amine substrate is still not completely understood. Herein we employed quantum chemical methods on the recently proposed direct hydride transfer mechanism including full active site residues of MAO isoforms in the calculations. Activation free energy barriers of direct hydride transfer mechanism for MAO-A and MAO-B were calculated by ONIOM (our own n-layered integrated molecular orbital + molecular mechanics) method with QM/QM (quantum mechanics:quantum mechanics) approach employing several density functional theory functionals, B3LYP, WB97XD, CAM-B3LYP and M06-2X, for the high layer. The formation of very recently proposed αC-flavin N5 adduct inside the enzyme has been investigated. ONIOM (M06-2X/6-31+G(d,p):PM6) results revealed that such an adduct may form only in MAO-B suggesting slightly different hydride transfer mechanisms for MAO-A and MAO-B.
The proposed polar nucleophilic mechanism of MAO was investigated using quantum chemical calculations employing the semi-empirical PM3 method. In order to mimic the reaction at the enzyme's active site, the reactions between the flavin and the p-substituted benzylamine substrate analogs were modeled. Activation energies and rate constants of all the reactions were calculated and compared with the published experimental data. The results showed that electron-withdrawing groups at the para position of benzylamine increase the reaction rate. A good correlation between the log of the calculated rate constants and the electronic parameter (sigma) of the substituent was obtained. These results agree with the previous kinetic experiments on the effect of p-substituents on the reduction of MAO-A by benzylamine analogs. In addition, the calculated rate constants showed a correlation with the rate of reduction of the flavin in MAO-A. In order to verify the results obtained from the PM3 method single-point B3LYP/6-31G*//PM3 calculations were performed. These results demonstrated a strong reduction in the activation energy for the reaction of benzylamine derivatives having electron-withdrawing substituents, which is in agreement with the PM3 calculations and the previous experimental QSAR study. PM3 and B3LYP/6-31G* energy surfaces were obtained for the overall reaction of benzylamine with flavin. Results suggest that PM3 is a reasonable method for studying this kind of reaction. These theoretical findings support the proposed polar nucleophilic mechanism for MAO-A.
Computational studies using the ONIOM methods have been performed to probe the catalytic roles of tyrosine residues 398 and 435 which constitute the "aromatic cage" in the active site of MAO-B. The results presented here provide additional new insights into the interactions that take place on activation of the amine substrate by the aromatic cage residues in MAO-B catalysis and have relevance to the MAO-A catalytic mechanism.
Although a considerable amount of mechanistic data has accumulated in literature, the detailed mechanism for amine oxidation by monoamine oxidase is still controversial. The single electron transfer mechanism (SET) has been widely discussed, but not completely understood yet. In the present study, the modified SET mechanism, proposed by Silverman et al., was explored by quantum chemical calculations. The ONIOM method was applied with UDFT/B3LYP/6-31 + G(d,p) for the higher layer and with UHF/6-31G(d) for the lower layer. Isoalloxazin heterocyclic ring and benzylamine were employed in the calculations to represent flavin and the substrate, respectively. The substituents CH(3), OH, OCH(3), H, F, Cl, Br, CF(3) and NO(2) were incorporated at the para position of benzylamine to explore structure-activity relationships. The structures of the reactant complex, transition state and product complex were fully optimized. Activation energies and rate constants of all the reactions were calculated. The results obtained from the linear regression analysis showed that electron-donating groups at the para position of benzylamine increase the reaction rate. A linear but inverse correlation between the log of the calculated rate constants (log k) and the electronic parameter of the substituent was observed (R = 0.93). In accordance with this result, a relatively weak inverse correlation between the calculated log k and the experimental log k was obtained (R = 0.78). The results are contrary to the previous kinetic experiments and the computational study on the effect of p-substituents in the flavin reduction of MAO A by p-substituted benzylamine analogs. Therefore, they present negative evidence for the modeled biradical mechanism.
The pyrrole derivatives having carbonyl groups at the C-2 position were converted to N-propargyl pyrroles. The reaction of those compounds with hydrazine monohydrate resulted in the formation of 5H-pyrrolo[2,1-d][1,2,5]triazepine derivatives. The synthesis of these compounds was accomplished in three steps starting from pyrrole. On the other hand, attempted cyclization of a pyrrole ester substituted with a propargyl group at the nitrogen atom gave, unexpectedly, the six-membered cyclization product, 2-amino-3-methylpyrrolo[1,2-a]pyrazin-1(2H)-one as the major product. The expected cyclization product with a seven-membered ring, 4-methyl-2,3-dihydro-1H-pyrrolo[2,1-d][1,2,5]triazepin-1-one was formed as the minor product and was converted quantitatively to the major product. The formation mechanism of the products was investigated, and the results obtained were also supported by theoretical calculations.
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