Monoamine Oxidases and Flavin-Containing Monooxygenases

Cashman, John R.

doi:10.1016/b978-0-12-801238-3.64091-6

Cited by 5 publications

(4 citation statements)

References 378 publications

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“…As only a fraction of the substrates l -kynurenine and 1 are converted to their desired heterocyclic products 5 and 7 by the PcncAAAD aldehyde synthase activity or yeast endogenous enzymatic activities, we introduced an additional plasmid containing H. sapiens monoamine oxidase A ( Hs MAO-A) to enhance the conversion of 4 and 6 to 5 and 7 , respectively. Hs MAO-A has been extensively studied as this flavin-containing amine oxidoreductase is responsible for the mono-oxidation of dietary monoamines and neurotransmitters in vivo and is associated with numerous neurological disorders, including schizophrenia, depression, substance abuse, and attention deficit disorder. , The addition of Hs MAO-A to the yeast strain coexpressing Hs TDO2 and PcncAAAD further drives flux toward the decarboxylated heterocyclic scaffolds as yields of 5 and 7 are enhanced (Figure a–c). It is likely that yeast FAD-utilizing polyamine oxidase (FMS1) additionally catalyzes this monoamine mono-oxidation reaction endogenously, as expression of Hs TDO2 and PcncAAAD in the fms1 knockout strain displays the accumulation of monoamine 4 (Figure S8).…”

Section: Resultsmentioning

confidence: 99%

Engineering New Branches of the Kynurenine Pathway To Produce Oxo-(2-aminophenyl) and Quinoline Scaffolds in Yeast

2019

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The kynurenine pathway, named after its nonproteinogenic amino acid precursor l-kynurenine, is responsible for the de novo biosynthesis of nicotinamide adenine dinucleotide (NAD+) in eukaryotes. Oxo-(2-aminophenyl) and quinoline molecules downstream from l-kynurenine also serve as antagonists of several receptors of the central nervous system in mammals. In this study, we engineered new biosynthetic routes in yeast Saccharomyces cerevisiae to produce a suite of l-kynurenine-derived natural products. Overexpression of Homo sapiens l-tryptophan 2,3-dioxygenase (HsTDO2) in S. cerevisiae led to a marked increase in the production of l-kynurenine and downstream metabolites. Using this background, new branch points to the kynurenine pathway were added through the incorporation of a Psilocybe cubensis noncanonical L-aromatic amino acid decarboxylase (PcncAAAD) capable of catalyzing both decarboxylation and decarboxylation-dependent oxidative-deamination reactions of l-kynurenine and 3-hydroxy-l-kynurenine to yield their corresponding monoamines, aldehydes, and downstream nonenzymatically cyclized quinolines. The PcncAAAD-catalyzed decarboxylation products, kynuramine and 3-hydroxykynuramine, could further be converted to quinoline scaffolds through the addition of H. sapiens monoamine oxidase A (HsMAO-A). Finally, by incorporating upstream regiospecific l-tryptophan halogenases into the engineering scheme, we produced a number of halogenated oxo-(2-aminophenyl) and quinoline compounds. This work illustrates a synthetic biology approach to expand primary metabolic pathways in the production of novel natural-product-like scaffolds amenable for downstream functionalization.

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Section: Resultsmentioning

confidence: 99%

Engineering New Branches of the Kynurenine Pathway To Produce Oxo-(2-aminophenyl) and Quinoline Scaffolds in Yeast

2019

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“…A related compound to mexiletine (i.e., amphetamine) did not show a significant C‐H (C‐D) metabolic kinetic isotope effect 46 but FMO is a thermally unstable enzyme and functional activity is highly dependent on quality of its source and the nature of how metabolism is conducted. 45 Amphetamine hydroxylamine showed a modest inverse deuterium kinetic isotope effect on further oxygenation. 47 Accordingly, the true intrinsic isotope effect (i.e., the full effect originating from the single isotopically sensitive step in catalysis) for alpha‐deutero mexiletine or phenyl mexiletine is likely due to terminal C‐H (C‐D) bond cleavage.…”

Section: Discussionmentioning

confidence: 99%

“…Mexiletine N ‐oxidation could arise via CYP metabolism. Alternatively, N ‐oxygenation and oxidative deamination involving cleavage of the alpha‐amino C‐H bond could occur in principle via two routes: FMO‐dependent and/or monoamine oxidase (MAO)‐dependent pathways, 45 respectively. In the case of FMO, N ‐oxygenation occurs twice to afford a di‐ N ‐hydroxy species that leads to the loss of the elements of water to produce an oxime.…”

Section: Discussionmentioning

confidence: 99%

Human‐induced pluripotent stem cell‐derived cardiomyocytes: Cardiovascular properties and metabolism and pharmacokinetics of deuterated mexiletine analogs

Gómez-Galeno

Okolotowicz

Johnson

et al. 2021

Pharmacology Res & Perspec

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Prolongation of the cardiac action potential (AP) and early after depolarizations (EADs) are electrical anomalies of cardiomyocytes that can lead to lethal arrhythmias and are potential liabilities for existing drugs and drug candidates in development. For example, long QT syndrome‐3 (LQTS3) is caused by mutations in the Na v 1.5 sodium channel that debilitate channel inactivation and cause arrhythmias. We tested the hypothesis that a useful drug (i.e., mexiletine) with potential liabilities (i.e., potassium channel inhibition and adverse reactions) could be re‐engineered by dynamic medicinal chemistry to afford a new drug candidate with greater efficacy and less toxicity. Human cardiomyocytes were generated from LQTS3 patient‐derived induced pluripotent stem cells (hIPSCs) and normal hIPSCs to determine beneficial (on‐target) and detrimental effects (off‐target) of mexiletine and synthetic analogs, respectively. The approach combined “drug discovery” and "hit to lead” refinement and showed that iterations of medicinal chemistry and physiological testing afforded optimized compound 22 . Compared to mexiletine, compound 22 showed a 1.85‐fold greater AUC and no detectable CNS toxicity at 100 mg/kg. In vitro hepatic metabolism studies showed that 22 was metabolized via cytochrome P‐450, as previously shown, and by the flavin‐containing monooxygenase (FMO). Deuterated‐ 22 showed decreased metabolism and showed acceptable cardiovascular and physicochemical properties.

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“…The FMO3 gene contains nine exons, and exon 1 is noncoding [30]. Multiple motifs have been identified throughout the FMO3 protein, including FAD-binding motif (GXGXXG within the region 3-26), NAPDH-binding motif (GXGXXG within the region 186-213), and FMO signature (xGxxxHxxxF/Y) and identifying (FxGxxxHxxxF) motifs [31][32][33]. In the yeast FMO protein, Asn91 (Asn61 in human FMO3) was believed to be the only amino acid involved in enzymatic activity of its substrates [3,34] until recently when new active sites involved in enzymatic activity have been discovered [35].…”

Section: Discussionmentioning

confidence: 99%

Proteomics-Based Identification of Interaction Partners of the Xenobiotic Detoxification Enzyme FMO3 Reveals Involvement in Urea Cycle

Zhao

Stemmer

Petriello

2022

Toxics

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The hepatic xenobiotic metabolizing enzyme flavin-containing monooxygenase 3 (FMO3) has been implicated in the development of cardiometabolic disease primarily due to its enzymatic product trimethylamine-N oxide (TMAO), which has recently been shown to be associated with multiple chronic diseases, including kidney and coronary artery diseases. Although TMAO may have causative roles as a pro-inflammatory mediator, the possibility for roles in metabolic disease for FMO3, irrespective of TMAO formation, does exist. We hypothesized that FMO3 may interact with other proteins known to be involved in cardiometabolic diseases and that modulating the expression of FMO3 may impact on these interaction partners. Here, we combine a co-immunoprecipitation strategy coupled to unbiased proteomic workflow to report a novel protein:protein interaction network for FMO3. We identified 51 FMO3 protein interaction partners, and through gene ontology analysis, have identified urea cycle as an enriched pathway. Using mice deficient in FMO3 on two separate backgrounds, we validated and further investigated expressional and functional associations between FMO3 and the identified urea cycle genes. FMO3-deficient mice showed hepatic overexpression of carbamoylphosphate synthetase (CPS1), the rate-limiting gene of urea cycle, and increased hepatic urea levels, especially in mice of FVB (Friend leukemia virus B strain) background. Finally, overexpression of FMO3 in murine AML12 hepatocytes led to downregulation of CPS1. Although there is past literature linking TMAO to urea cycle, this is the first published work showing that FMO3 and CPS1 may directly interact, implicating a role for FMO3 in chronic kidney disease irrespective of TMAO formation.

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Monoamine Oxidases and Flavin-Containing Monooxygenases

Cited by 5 publications

References 378 publications

Engineering New Branches of the Kynurenine Pathway To Produce Oxo-(2-aminophenyl) and Quinoline Scaffolds in Yeast

Engineering New Branches of the Kynurenine Pathway To Produce Oxo-(2-aminophenyl) and Quinoline Scaffolds in Yeast

Human‐induced pluripotent stem cell‐derived cardiomyocytes: Cardiovascular properties and metabolism and pharmacokinetics of deuterated mexiletine analogs

Proteomics-Based Identification of Interaction Partners of the Xenobiotic Detoxification Enzyme FMO3 Reveals Involvement in Urea Cycle

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