Molecular insights into the role of a distal F240A mutation that alters CYP1A1 activity towards persistent organic pollutants

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15310%2F17%3A73584573" target="_blank" >RIV/61989592:15310/17:73584573 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.sciencedirect.com/science/article/pii/S0304416517302477" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0304416517302477</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.bbagen.2017.08.002" target="_blank" >10.1016/j.bbagen.2017.08.002</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Molecular insights into the role of a distal F240A mutation that alters CYP1A1 activity towards persistent organic pollutants

Popis výsledku v původním jazyce

Background: Cytochromes P450 are major drug-metabolizing enzymes involved in the biotransformation of diverse xenobiotics and endogenous chemicals. Persistent organic pollutants (POPs) are toxic hydrophobic compounds that cause serious environmental problems because of their poor degradability. This calls for rational design of enzymes capable of catalyzing their biotransformation. Cytochrome P450 1A1 isoforms catalyze the biotransformation of some POPs, and constitute good starting points for the design of biocatalysts with tailored substrate specificity. Methods: We rationalized the activities of wild type and mutant forms of rat cytochrome P450 1A1 towards 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD) and 3,3&apos;,4,4&apos;-tetrachlorobiphenyl (PCB77) using experiments and molecular dynamics simulations. Results: We showed that the enhanced activity of the CYP1A1 mutant towards TCDD was due to more efficient binding of the substrate in the active site even though the mutated site was over 2.5 nm away from the catalytic center. Moreover, this mutation reduced activity towards PCB77. General significance: Amino acids that affect substrate access channels can be viable targets for rational enzyme design even if they are located far from the catalytic site.

Název v anglickém jazyce

Molecular insights into the role of a distal F240A mutation that alters CYP1A1 activity towards persistent organic pollutants

Popis výsledku anglicky

Background: Cytochromes P450 are major drug-metabolizing enzymes involved in the biotransformation of diverse xenobiotics and endogenous chemicals. Persistent organic pollutants (POPs) are toxic hydrophobic compounds that cause serious environmental problems because of their poor degradability. This calls for rational design of enzymes capable of catalyzing their biotransformation. Cytochrome P450 1A1 isoforms catalyze the biotransformation of some POPs, and constitute good starting points for the design of biocatalysts with tailored substrate specificity. Methods: We rationalized the activities of wild type and mutant forms of rat cytochrome P450 1A1 towards 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD) and 3,3&apos;,4,4&apos;-tetrachlorobiphenyl (PCB77) using experiments and molecular dynamics simulations. Results: We showed that the enhanced activity of the CYP1A1 mutant towards TCDD was due to more efficient binding of the substrate in the active site even though the mutated site was over 2.5 nm away from the catalytic center. Moreover, this mutation reduced activity towards PCB77. General significance: Amino acids that affect substrate access channels can be viable targets for rational enzyme design even if they are located far from the catalytic site.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10403 - Physical chemistry

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2017

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Biochimica et Biophysica Acta - General Subjects

ISSN

0304-4165

e-ISSN

—

Svazek periodika

1861

Číslo periodika v rámci svazku

11

Stát vydavatele periodika

NL - Nizozemsko

Počet stran výsledku

9

Strana od-do

2852-2860

Kód UT WoS článku

000415768500034

EID výsledku v databázi Scopus

2-s2.0-85027445564