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

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.

Six Decades of Dopamine Hypothesis: Is Aryl Hydrocarbon Receptor the New D2?

“…This links to wider bodies of data showing increases in pro-inflammatory cytokines and dysregulated HPA axis, leading to increased indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO), driving the raised levels of kynurenine and especially kynurenic acid evident in schizophrenia [331,332]. Both kynurenine and kynurenic acid activate AhR, whilst kynurenic acid may also antagonize the α7nAChR and N-methyl-daspartate (NMDA) receptor [332].…”

The Vital Role of Melatonin and Its Metabolites in the Neuroprotection and Retardation of Brain Aging

“…After oral administration melatonin undergoes extensive firstpass hepatic metabolism that is regulated by cytochrome P450 oxidases [191]. Exogenous, similar to endogenous melatonin, is metabolized mainly in the human liver but also in the brain, skin, and lungs through various CYP1 isozymes, mostly CYP1A2 [62,192]. CYP1A2 shows higher activity in men that could cause gender differences after melatonin supplementation [193].…”

The Role of the Kynurenine/AhR Pathway in Diseases Related to Metabolism and Cancer

“…122 This is likely to be of some importance in cancer, given that NAS is a brain-derived neurotrophic factor (BDNF) mimic via its activation of the BDNF receptor, tyrosine receptor kinase B (TrkB). 123 TrkB activation significantly increases the survival and proliferation of cancer stem-like cells, indicating that AhR/CYP1A2/CYP1B1 can increase NAS, 124 which if released by cells in the tumor microenvironment will increase the proliferation and survival of metastasis-inducing cancer stem-like cells. 125 Data indicates that tumor IDO leads to the release of Kyn that activates the AhR in other tumor microenvironment cells, including CD 8+ T cells 126 where AhR contributes to CD 8+ T cell “exhaustion.” 127 Consequently, the AhR is a significant contributor to alterations in intercellular signaling among the cells of the tumor microenvironment.…”