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Review of Ligand Specificity Factors for CYP1A Subfamily Enzymes from Molecular Modeling Studies Reported to-Date.

ABSTRACT: The cytochrome P450 (CYP) family 1A enzymes, CYP1A1 and CYP1A2, are two of the most important enzymes implicated in the metabolism of endogenous and exogenous compounds through oxidation. These enzymes are also known to metabolize environmental procarcinogens into carcinogenic species, leading to the advent of several types of cancer. The development of selective inhibitors for these P450 enzymes, mitigating procarcinogenic oxidative effects, has been the focus of many studies in recent years. CYP1A1 is mainly found in extrahepatic tissues while CYP1A2 is the major CYP enzyme in human liver. Many molecules have been found to be metabolized by both of these enzymes, with varying rates and/or positions of oxidation. A complete understanding of the factors that govern the specificity and potency for the two CYP 1A enzymes is critical to the development of effective inhibitors. Computational molecular modeling tools have been used by several research groups to decipher the specificity and potency factors of the CYP1A1 and CYP1A2 substrates. In this review, we perform a thorough analysis of the computational studies that are ligand-based and protein-ligand complex-based to catalog the various factors that govern the specificity/potency toward these two enzymes.

SUBMITTER: Sridhar J

PROVIDER: S-EPMC6152251 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Review of Ligand Specificity Factors for CYP1A Subfamily Enzymes from Molecular Modeling Studies Reported to-Date.

Sridhar Jayalakshmi J Goyal Navneet N Liu Jiawang J Foroozesh Maryam M

Molecules (Basel, Switzerland) 20170708 7

The cytochrome P450 (CYP) family 1A enzymes, CYP1A1 and CYP1A2, are two of the most important enzymes implicated in the metabolism of endogenous and exogenous compounds through oxidation. These enzymes are also known to metabolize environmental procarcinogens into carcinogenic species, leading to the advent of several types of cancer. The development of selective inhibitors for these P450 enzymes, mitigating procarcinogenic oxidative effects, has been the focus of many studies in recent years. C ...[more]

PMID: 28698457

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Project description:Feruloyl esterases (FAEs) have an important role in the enzymatic conversion of lignocellulosic biomass by decoupling plant cell wall polysaccharides and lignin. Moreover, FAEs release anti-oxidative hydroxycinnamic acids (HCAs) from biomass. As a plethora of FAE candidates were found in fungal genomes, FAE classification related to substrate specificity is an indispensability for selection of most suitable candidates. Hence, linking distinct substrate specificities to a FAE classification, such as the recently classified FAE subfamilies (SF), is a promising approach to improve the application of these enzymes for a variety of industrial applications. In total, 14 FAEs that are classified members of SF1, 5, 6, 7, 9, and 13 were tested in this research. All FAEs were investigated for their activity toward a variety of substrates: synthetic model substrates, plant cell wall-derived substrates, including lignin, and natural substrates. Released HCAs were determined using reverse phase-ultra high performance liquid chromatography coupled to UV detection and mass spectrometry. Based on this study, FAEs of SF5 and SF7 showed the highest release of FA, pCA, and diFAs over the range of substrates, while FAEs of SF6 were comparable but less pronounced for diFAs release. These results suggest that SF5 and SF7 FAEs are promising enzymes for biorefinery applications, like the production of biofuels, where a complete degradation of the plant cell wall is desired. In contrast, SF6 FAEs might be of interest for industrial applications that require a high release of only FA and pCA, which are needed as precursors for the production of biochemicals. In contrast, FAEs of SF1, 9 and 13 showed an overall low release of HCAs from plant cell wall-derived and natural substrates. The obtained results substantiate the previous SF classification as a useful tool to predict the substrate specificity of FAEs, which eases the selection of FAE candidates for industrial applications.

Dataset Information

Review of Ligand Specificity Factors for CYP1A Subfamily Enzymes from Molecular Modeling Studies Reported to-Date.

Publications

Review of Ligand Specificity Factors for CYP1A Subfamily Enzymes from Molecular Modeling Studies Reported to-Date.

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