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Dear Colleagues,

Enzymes are efficient molecular catalysts in nature that work under ambient pressures and temperatures and catalyse a large variety of chemical reactions by using environmentally benign systems. There is much to learn from nature on how to convert chemicals into useful products. In particular, enzymes react very fast and often, these fleeting intermediates are difficult to trap and characterize. Over the past few years, major breakthroughs in understanding enzymatic catalysis have been obtained and highlights of novel research problems and solutions are the topic of this Special Issue. This Special Issue will welcome review, opinion, and research articles that focus on, but are not limited to, the above topics.

Prof. Dr. Samuel De Visser
Guest Editor

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Keywords

enzyme
catalysis
catalysts
enzyme reaction

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Open AccessArticle

Melatonin Activation by Cytochrome P450 Isozymes: How Does CYP1A2 Compare to CYP1A1?

Thirakorn Mokkawes

and

Sam P. de Visser

Int. J. Mol. Sci. 2023, 24(4), 3651; https://doi.org/10.3390/ijms24043651 - 11 Feb 2023

Cited by 2 | Viewed by 1228

Abstract

Cytochrome P450 enzymes are versatile enzymes found in most biosystems that catalyze mono-oxygenation reactions as a means of biosynthesis and biodegradation steps. In the liver, they metabolize xenobiotics, but there are a range of isozymes with differences in three-dimensional structure and protein chain. Consequently, the various P450 isozymes react with substrates differently and give varying product distributions. To understand how melatonin is activated by the P450s in the liver, we did a thorough molecular dynamics and quantum mechanics study on cytochrome P450 1A2 activation of melatonin forming 6-hydroxymelatonin and N-acetylserotonin products through aromatic hydroxylation and O-demethylation pathways, respectively. We started from crystal structure coordinates and docked substrate into the model, and obtained ten strong binding conformations with the substrate in the active site. Subsequently, for each of the ten substrate orientations, long (up to 1 μs) molecular dynamics simulations were run. We then analyzed the orientations of the substrate with respect to the heme for all snapshots. Interestingly, the shortest distance does not correspond to the group that is expected to be activated. However, the substrate positioning gives insight into the protein residues it interacts with. Thereafter, quantum chemical cluster models were created and the substrate hydroxylation pathways calculated with density functional theory. These relative barrier heights confirm the experimental product distributions and highlight why certain products are obtained. We make a detailed comparison with previous results on CYP1A1 and identify their reactivity differences with melatonin. Full article

(This article belongs to the Special Issue New Molecular Research and Perspective: Enzyme and Its Catalysis)

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