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Author, Editor(s)

Author(s):

Lisurek, Michael
Simgen, Birgit
Antes, Iris
Bernhardt, Rita

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Not MPG Author(s):

Lisurek, Michael
Simgen, Birgit
Bernhardt, Rita

BibTeX cite key*:

Antes2008b

Title

Title*:

Theoretical and Experimental Evaluation of a CYP106A2 Low Homology Model and Production of Mutants with Changed Activity and Selectivity of Hydroxylation

Journal

Journal Title*:

ChemBioChem

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Language:

English

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Vol, No, pp, Date

Volume*:

9

Number:

9

Publishing Date:

May 2008

Pages*:

1439-1449

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DOI:

10.1002/cbic.200700670

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(LaTeX) Abstract:

Steroids are important pharmaceutically active compounds. In contrast to the liver drug-metabolising cytochrome P450s, which metabolise a variety of substrates, steroid hydroxylases generally display a rather narrow substrate specificity. It is therefore a challenging goal to change their regio- and stereoselectivity. CYP106A2 is one of only a few bacterial steroid hydroxylases and hydroxylates 3-oxo-\Delta^4-steroids mainly in 15\beta-position. In order to gain insights into the structure and function of this enzyme, whose crystal structure is unknown, a homology model has been created. The substrate progesterone was then docked into the active site to predict which residues might affect substrate binding. The model was substantiated by using a combination of theoretical and experimental investigations. First, numerous computational structure evaluation tools assessed the plausibility of its protein geometry and its quality. Second, the model explains many key properties of common cytochrome P450s. Third, two sets of mutants have been heterologously expressed, and the influence of the mutations on the catalytic activity towards deoxycorticosterone and progesterone has been studied experimentally: the first set comprises six mutations located in the structurally variable regions of this enzyme that are very difficult to predict by cytochrome P450 modelling (K27R, I86T, E90V, I71T, D185G and I215T). For these positions, no participation in the active-site formation was predicted, or could be experimentally demonstrated. The second set comprises five mutants in substrate recognition site 6 (S394I, A395L, T396R, G397P and Q398S). For these residues, participation in active-site formation and an influence on substrate binding was predicted by docking. These mutants are based on an alignment with human CYP11B1, and in fact most of these mutants altered the active-site structure and the hydroxylation activity of CYP106A2 dramatically.

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MPG Unit:

Max-Planck-Institut für Informatik



MPG Subunit:

Computational Biology and Applied Algorithmics

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experts only

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MPII WWW Server, MPII FTP Server, MPG publications list, university publications list, working group publication list, Fachbeirat, VG Wort


BibTeX Entry:

@ARTICLE{Antes2008b,
AUTHOR = {Lisurek, Michael and Simgen, Birgit and Antes, Iris and Bernhardt, Rita},
TITLE = {Theoretical and Experimental Evaluation of a {CYP106A2} Low Homology Model and Production of Mutants with Changed Activity and Selectivity of Hydroxylation},
JOURNAL = {ChemBioChem},
YEAR = {2008},
NUMBER = {9},
VOLUME = {9},
PAGES = {1439--1449},
MONTH = {May},
DOI = {10.1002/cbic.200700670},
}


Entry last modified by Elena Zotenko, 03/09/2009
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Editor(s)
Elena Zotenko
Created
03/09/2009 06:32:31 PM
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Editor
Elena Zotenko



Edit Date
03/09/2009 06:32:31 PM