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Rajakumara, E.; Saniya, D.; Bajaj, P.; Rajeshwari, R.; Giri, J.; Davari, M. D.; Hijacking chemical reactions of P450 enzymes for altered chemical reactions and asymmetric synthesis Int. J. Mol. Sci. 24 214 (2023) DOI: 10.3390/ijms24010214
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Cytochrome P450s are heme-containing enzymes capable of the oxidative transformation of a wide range of organic substrates. A protein scaffold that coordinates the heme iron, and the catalytic pocket residues, together, determine the reaction selectivity and regio- and stereo-selectivity of the P450 enzymes. Different substrates also affect the properties of P450s by binding to its catalytic pocket. Modulating the redox potential of the heme by substituting iron-coordinating residues changes the chemical reaction, the type of cofactor requirement, and the stereoselectivity of P450s. Around hundreds of P450s are experimentally characterized, therefore, a mechanistic understanding of the factors affecting their catalysis is increasingly vital in the age of synthetic biology and biotechnology. Engineering P450s can enable them to catalyze a variety of chemical reactions viz. oxygenation, peroxygenation, cyclopropanation, epoxidation, nitration, etc., to synthesize high-value chiral organic molecules with exceptionally high stereo- and regioselectivity and catalytic efficiency. This review will focus on recent studies of the mechanistic understandings of the modulation of heme redox potential in the engineered P450 variants, and the effect of small decoy molecules, dual function small molecules, and substrate mimetics on the type of chemical reaction and the catalytic cycle of the P450 enzymes.

Publications

Abhishek, S.; Deeksha, W.; Nethravathi, K. R.; Davari, M. D.; Rajakumara, E.; Allosteric crosstalk in modular proteins: Function fine-tuning and drug design Comp Struct Biotechnol J 21 5003-5015 (2023) DOI: 10.1016/j.csbj.2023.10.013
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Modular proteins are regulatory proteins that carry out more than one function. These proteins upregulate or downregulate a biochemical cascade to establish homeostasis in cells. To switch the function or alter the efficiency (based on cellular needs), these proteins require different facilitators that bind to a site different from the catalytic (active/orthosteric) site, aka ‘allosteric site’, and fine-tune their function. These facilitators (or effectors) are allosteric modulators. In this Review, we have discussed the allostery, characterized them based on their mechanisms, and discussed how allostery plays an important role in the activity modulation and function finetuning of proteins. Recently there is an emergence in the discovery of allosteric drugs. We have also emphasized the role, significance, and future of allostery in therapeutic applications.

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