The Engagement of Cytochrome P450 Enzymes in Tryptophan Metabolism

Abstract

Tryptophan is metabolized along three main metabolic pathways, namely the kynurenine, serotonin and indole pathways. The majority of tryptophan is transformed via the kynurenine pathway, catalyzed by tryptophan-2,3-dioxygenase or indoleamine-2,3-dioxygenase, leading to neuroprotective kynurenic acid or neurotoxic quinolinic acid. Serotonin synthesized by tryptophan hydroxylase, and aromatic L-amino acid decarboxylase enters the metabolic cycle: serotonin → N-acetylserotonin → melatonin → 5-methoxytryptamine→serotonin. Recent studies indicate that serotonin can also be synthesized by cytochrome P450 (CYP), via the CYP2D6-mediated 5-methoxytryptamine O-demethylation, while melatonin is catabolized by CYP1A2, CYP1A1 and CYP1B1 via aromatic 6-hydroxylation and by CYP2C19 and CYP1A2 via O-demethylation. In gut microbes, tryptophan is metabolized to indole and indole derivatives. Some of those metabolites act as activators or inhibitors of the aryl hydrocarbon receptor, thus regulating the expression of CYP1 family enzymes, xenobiotic metabolism and tumorigenesis. The indole formed in this way is further oxidized to indoxyl and indigoid pigments by CYP2A6, CYP2C19 and CYP2E1. The products of gut-microbial tryptophan metabolism can also inhibit the steroid-hormone-synthesizing CYP11A1. In plants, CYP79B2 and CYP79B3 were found to catalyze N-hydroxylation of tryptophan to form indole-3-acetaldoxime while CYP83B1 was reported to form indole-3-acetaldoxime N-oxide in the biosynthetic pathway of indole glucosinolates, considered to be defense compounds and intermediates in the biosynthesis of phytohormones. Thus, cytochrome P450 is engaged in the metabolism of tryptophan and its indole derivatives in humans, animals, plants and microbes, producing biologically active metabolites which exert positive or negative actions on living organisms. Some tryptophan-derived metabolites may influence cytochrome P450 expression, affecting cellular homeostasis and xenobiotic metabolism.

Lactobacillus gallinarum-derived metabolites boost anti-PD1 efficacy in colorectal cancer by inhibiting regulatory T cells through modulating IDO1/Kyn/AHR axis

“…The indole pathway in host and bacteria is known to be a highly dynamic process, which is characterised by rapid biotransformation and biodegradation of various indole metabolites in vivo. While ICA is reported to be a direct downstream metabolite of IAld, 21 and the conversion from IAld to ICA only involves a single oxidation step, we therefore posited that the conversion could be driven by the cytochrome P450 enzymes in the liver, 31 which have been reported to engage in biotransformation of indole metabolites in vivo. 32 Meanwhile, taking accounting into the key role of gut microbiota in tryptophan and indole metabolism, other gut commensal bacteria may also be potential candidates responsible for the IAld conversion.…”

“… 32 Meanwhile, taking accounting into the key role of gut microbiota in tryptophan and indole metabolism, other gut commensal bacteria may also be potential candidates responsible for the IAld conversion. 31 To this end, we strongly believe that such IAld-to-ICA conversion was physiologically plausible, given the simplicity of conversion step, as well as the documented presence of host/bacterial catalysts.…”

Melatonin, BAG-1 and cortisol circadian interactions in tumor pathogenesis and patterned immune responses

“…Pro-inflammatory cytokine and stress/cortisol-induction of indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) lead to tryptophan being converted to kynurenine and kynurenine pathway products, such as kynurenic acid and quinolinic acid, which depletes tryptophan availability concurrent to altering wider physiology. IDO and TDO conversion of tryptophan to kynurenine activates the aryl hydrocarbon receptor (AhR), which “backward” converts melatonin to NAS via O -demethylation driven by AhR-induced cytochrome P450 enzyme 1A2 (CYP1A2), and CYP1B1 [ 27 ] as well as by hepatic CYP2A19 and the many factors and alleles that regulate hepatic CYP2C19 expression and function [ 28 ]. The O -demethylation of melatonin to NAS is of some importance in the tumor microenvironment as tumor cell exposure to melatonin invariably leads to tumor apoptosis [ 29 ], whilst NAS exposure may enhance the survival and proliferations of cancer stem-like cells via the capacity of NAS to mimic brain-derived neurotrophic factor (BDNF) by activating the BDNF receptor, tyrosine receptor kinase B (TrkB) [ 30 ].…”

“…This is further complicated by factors acting to increase the NAS/melatonin ratio, such as the AhR-induced CYP1A2 and CYP1B1 ( Figure 1 ) [ 27 , 28 ], which O -demethylate melatonin to NAS. NAS, by activating TrkB-FL and TrkB-T1 on the plasma membrane and/or mitochondrial membrane will have distinct effects in different immune cells, as well as indirect effects on immune and wider cells via the regulation of hypothalamic hormones/fluxes over the circadian rhythm.…”

Genome-wide identification of the CYP82 gene family in cucumber and functional characterization of CsCYP82D102 in regulating resistance to powdery mildew

“…CYP450s, named for its characteristic spectral property of an absorption peak at 450 nm when binding with CO, are characterized by a preserved heme-binding region with the sequence FxxGxRxCxG ( Bolwell, Bozak & Zimmerlin, 1994 ; Distefano et al, 2021 ). P450s are involved in both basic metabolism and secondary metabolism of plants and play an essential role in enhancing plant resistance to stress and pests ( Aubert et al, 2015 ; Haduch et al, 2023 ; Minerdi, Savoi & Sabbatini, 2023 ; Pan et al, 2018 ). According to the criteria of homology and phylogeny, plant P450 genes are clustered into 10 clans, including seven single families (CYP51, CYP74, CYP97, CYP710, CYP711, CYP727, CYP746) and four multiple-families (CYP71, CYP72, CYP85, and CYP86) ( Nelson et al, 2004 ).…”