engleski

Human 3-hydroxyanthranilate 3, 4-dioxygenase (3HAO) dynamics and reaction, a multilevel computational study

3- hydroxyanthranilate 3, 4-dioxygenase (3HAO) is non-heme iron dependent enzyme. It catalyzes the cleavage of the benzene ring of 3-hydroxyanthranilic acid (3-Ohaa), an intermediate in the kynurenine pathway and because of that represents a potential target in treating numerous disorders related to the concentration of quinolinic acid (QUIN), the kynurenine pathway product, in tissues. Stability and behaviour of the enzyme in nearly physiological conditions was studied by applying the empirical molecular modelling methods. The results enabled us to determine influence of the several, for the enzyme activity relevant, point mutations on the protein structure, particularly on the active site architecture and the metal ion environment, as well as on the substrate binding. Besides, the water population of the active site, and the protein flexibility as well as the amino acid residues interaction networks relevant for the enzyme activity were determined for both, the native and the mutated complexes. Finally, using the hybrid quantum-mechanics/molecular-mechanics (QM/MM) calculations the reaction mechanism was elucidated and the oxygen molecule cleavage was determined to be the rate determining step.

non hem iron; molecular dynamics; force field; semiempirical calculations; quantum mechanical calculations; human 3-Hydroxyanthranilic-acid dioxygenase; reaction mechanism

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