TAILIEUCHUNG - Báo cáo Y học: The effect of amino-acid substitutions I112P, D147E and K152N in CYP11B2 on the catalytic activities of the enzyme

By replacing specific amino acids at positions 112, 147 and 152 of the human aldosterone synthase (CYP11B2) with the corresponding residues from human, mouse or rat 11b-hydroxylase (CYP11B1), we have been able to investigate whether these residues belong to structural determinants of individual enzymatic activities. When incubated with 11-deoxycorticosterone (DOC), the 11b-hydroxylation activity of the mutants was most effectively increased by combining D147E and I112P (sixfold increase). | Eur. J. Biochem. 269 1118-1127 2002 FEBS 2002 The effect of amino-acid substitutions I112P D147E and K152N in CYP11B2 on the catalytic activities of the enzyme Stephanie Bechtel1 Natalya Belkina2 and Rita Bernhardt1 1 Universitat des Saarlandes SaarbrUcken Germany 2Insitute of Biomedical Chemistry RAMS Moscow Russia By replacing specific amino acids at positions 112 147 and 152 of the human aldosterone synthase CYP11B2 with the corresponding residues from human mouse or rat 11 b-hydroxylase CYP11B1 we have been able to investigate whether these residues belong to structural determinants of individual enzymatic activities. When incubated with 11-deoxycorticosterone DOC the 11 b-hydroxylation activity of the mutants was most effectively increased by combining D147E and I112P sixfold increase . The two substitutions displayed an additive effect. The same tendency can be observed when using 11-deoxycortisol as a substrate although the effect is less pronounced. The second step of the CYP11B2-dependent DOC conversion the 18-hydroxyla-tion activity was not as strongly increased as the 11 b-hydroxylation potential. Activity was unaffected by D147E whereas the single mutant I112P displayed the most pronounced activation 70 enhancement thus causing different increasing effects on the first two enzymatic reaction steps. A slightly enhanced aldosterone synthesis from DOC could be measured due to increased levels of the intermediates. However the 18-oxidation activity of all the mutants except for I112S and D147E was slightly reduced. The strongly enhanced 18-hydroxycorticosterone and aldosterone formation observed in the mutants provides important information on a possible role of such amino-acid replacements in the development of essential hypertension. Furthermore the results indicate the possibility of a differential as well as independent modification of CYP11B2 reaction steps. The combination of functional data and computer modelling of CYP11B2 suggests an indirect .

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