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Comparative Study of Binding Pockets in Human CYP1A2, CYP3A4, CYP3A5, and CYP3A7 with Aflatoxin B1, a
1Department of Biochemistry and Biophysics, University of Kalyani, Kalyani, West Bengal, PIN 741235, India.
Background:
Aflatoxin B1 is a harmful hepatocarcinogen which is metabolized in our body by Cytochrome P450 enzymes, namely CYP1A2, CYP3A4, CYP3A5, and CYP3A7, into toxic (exo-8, 9-epoxide) and nontoxic (AFQ1, endo-epoxide) products. We have found from the literature that due to cooperativity, the rate of metabolic reactions increases in CYP1A2 and CYP3A4 involving more than one site of proteins to form two products at a given time, whereas the interaction of CYP3A5 and CYP3A7 is still unknown. Our work aims to study these four enzymes with AFB1 based on binding site pocket characterization and to find the probable resultant products at each binding site.
Methods:
We used computational approaches like homology modeling, molecular docking to form mono and double ligated systems, molecular dynamic simulations to analyze the potential energies (vdW & electrostatic), PCA, RMSF, and residue-wise interactions at the active as well as allosteric sites of these four enzymes.
Results:
We found that CYP1A2, CYP3A4, and CYP3A5 were more hydrophobic at the first site and may induce epoxidation reaction to form toxic products, whereas the second site would be expected to be more polar and comprising charged interactions, thus enhancing non-toxic hydroxylated products. However, in CYP3A7, the first site favors hydroxylation, whereas the second site is involved in higher hydrophobic interactions.
Conclusion:
Thus, in the fetus where AFB1 is metabolized only by CYP3A7, a lower concentration of toxic metabolites will be expected, while in adults exhibiting CYP1A2, CYP3A4 and CYP3A5 may increase the concentration of the toxic metabolites due to the combined effect of these enzymes, consequently increasing liver toxicity. We believe that AFB1 binding characteristics will be helpful for medicinal chemists in the process of designing a new drug.
Insights
Aflatoxin B1 metabolism by Cytochrome P450 enzymes (CYP1A2, CYP3A4, CYP3A5, CYP3A7) differs between adults and fetuses. Adult enzymes produce more toxic epoxides, increasing liver toxicity risk, while fetal CYP3A7 produces fewer toxic products.
Area of Science:
- Biochemistry
- Pharmacology
- Computational Chemistry
Background:
- Aflatoxin B1 (AFB1) is a potent hepatocarcinogen metabolized by Cytochrome P450 enzymes (CYP1A2, CYP3A4, CYP3A5, CYP3A7).
- Metabolism yields toxic epoxides and non-toxic hydroxylated products.
- Enzyme cooperativity in CYP1A2 and CYP3A4 enhances metabolic rates, while CYP3A5 and CYP3A7 interactions remain unclear.
Purpose of the Study:
- To characterize binding sites of CYP1A2, CYP3A4, CYP3A5, and CYP3A7 in relation to AFB1.
- To predict metabolic products formed at different enzyme binding sites.
Main Methods:
- Homology modeling and molecular docking were employed.
- Mono- and double-ligated systems were constructed.
- Molecular dynamics simulations analyzed van der Waals, electrostatic potentials, PCA, RMSF, and residue interactions.
Main Results:
- CYP1A2, CYP3A4, and CYP3A5 exhibit hydrophobic first sites favoring toxic epoxidation, and polar second sites favoring non-toxic hydroxylation.
- CYP3A7 shows a hydroxylation-favoring first site and a hydrophobic second site.
Conclusions:
- Fetal metabolism by CYP3A7 yields lower toxic AFB1 metabolites.
- Adult metabolism involving CYP1A2, CYP3A4, and CYP3A5 increases toxic metabolite concentrations, elevating liver toxicity risk.
- Understanding AFB1 binding characteristics can aid in designing novel therapeutic agents.
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