Molecular insights into the role of a distal F240A mutation that alters CYP1A1 activity towards persistent organic pollutants
Jazyk angličtina Země Nizozemsko Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
28780123
DOI
10.1016/j.bbagen.2017.08.002
PII: S0304-4165(17)30247-7
Knihovny.cz E-zdroje
- Klíčová slova
- Biotransformation, Distal mutation, MM-PBSA, Protein engineering, Rational enzyme design, Tunnel,
- MeSH
- adukty DNA účinky léků MeSH
- biotransformace účinky léků MeSH
- cytochrom P-450 CYP1A1 chemie genetika MeSH
- katalytická doména účinky léků MeSH
- katalýza * MeSH
- krysa rodu Rattus MeSH
- látky znečišťující životní prostředí chemie toxicita MeSH
- lidé MeSH
- metabolická inaktivace účinky léků genetika MeSH
- mutace MeSH
- polychlorované bifenyly chemie toxicita MeSH
- polychlorované dibenzodioxiny chemie toxicita MeSH
- substrátová specifita MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- 3,4,3',4'-tetrachlorobiphenyl MeSH Prohlížeč
- adukty DNA MeSH
- cytochrom P-450 CYP1A1 MeSH
- látky znečišťující životní prostředí MeSH
- polychlorované bifenyly MeSH
- polychlorované dibenzodioxiny MeSH
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',4,4'-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 2.5nm 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.
Graduate School of Agricultural Science Kobe University Kobe Hyogo 657 8501 Japan
Hyogo Prefectural Institute of Environmental Sciences Kobe Hyogo 654 0037 Japan
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