Quantum chemical studies for oxidation of morpholine by Cytochrome P450

Shaikh, Abdul Rajjak; Sahnoun, Riadh; Brocławik, Ewa; Koyama, Michihisa; Tsuboi, Hideyuki; Hatakeyama, Nozomu; Endou, Akira; Takaba, Hiromitsu; Kubo, Momoji; Carpio, Carlos A. Del; Miyamoto, Akira

doi:10.1016/j.jinorgbio.2008.08.013

Cited by 13 publications

(10 citation statements)

References 48 publications

(73 reference statements)

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“…A few studies were carried out in order to understand the morpholine biodegradation process and its regulation (Shaikh et al, 2009). Swain et al (1991) proposed a hypothetical pathway for the biodegradation of morpholine by Mycobacterium chelonae that could proceed via 2-(2-aminoethoxy) acetate and glycolate and/or ethanolamine.…”

Section: Discussionmentioning

confidence: 99%

Degradation of morpholine by Mycobacterium sp. isolated from contaminated wastewater collected from Egypt

Aly¹

2011

Afr. J. Biotechnol.

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The biodegradation of morpholine has attracted much interest because morpholine causes environmental pollution. Ten species belonging to nine genera were tested for their abilities to degrade morpholine in mineral salts medium containing morpholine (1 g/l). Mycobacterium sp. isolated from polluted water sample collected from Abu Za"baal lakes, effectively utilized morpholine as carbon, nitrogen and energy source. The tested Mycobacterium was able to grow in high concentrations of morpholine but the rapidly increase in pH of the growth medium and accumulation of ammonia inhibited bacterial growth and complete mineralization of morpholine. The molar conversion ratio of morpholine to ammonia was 1:0.89. Growing of the selected bacterium in liquid medium with 1 g/l morpholine at 37°C and pH 6.5, enhanced morpholine degradation. Addition of metyrapone to the growth medium inhibited morpholine degradation. Immobilization of Mycobacterium cells in sodium alginate increased morpholine degradation compared with free cells. At high concentrations of morpholine (4 to 6 g/l), there was a decrease in both cell viability and respiration of Mycobacterium but no genotoxicity was found.

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Section: Discussionmentioning

confidence: 99%

Degradation of morpholine by Mycobacterium sp. isolated from contaminated wastewater collected from Egypt

Aly¹

2011

Afr. J. Biotechnol.

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“…The majority of studies showed that the species Mycobacterium and Pseudomonas are the two potential bacterial isolates that utilize morpholine as their sole source of carbon and nitrogen, thereby undergoing degradation [4][5][6][7]. A few studies have been carried out to understand the biodegradation of morpholine and its regulation [8][9][10]. Later a hypothetical pathway was proposed for the complete mineralization of morpholine that could proceed via 2-(2-aminoethoxy)acetate to produce its diglycolate salt and/or ethanolamine [5,11,12].…”

Section: Sustainable Remediation Of Morpholine and Its Degradation Pa...mentioning

confidence: 99%

Unraveling the Novel Bacterial Assisted Biodegradation Pathway of Morpholine

Kumar¹,

Kapila²,

Vulichi³

2022

Hung. J. Ind. Chem.

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Most xenobiotics are biodegradable, persistent or recalcitrant in nature. Morpholine, a typical xenobiotic, was initially regarded as recalcitrant, however, later proved to be biodegradable by bacterial species like Mycobacterium and Pseudomonas in particular. However, establishing the metabolic pathways involved for the successful biodegradation of morpholine is challenging because of its extreme level of water solubility that affects various analytical procedures. In addition, to date, no suitable analytical methods have been reported to directly estimate the activity of morpholine and its degradable products or intermediates. Nevertheless, methods, especially optical density, gas chromatography and mass spectrophotometric analysis, could indirectly estimate the degradation product(s) of morpholine formed as a result of its biotransformation. In this present study, the degradation pathway of morpholine was scertained by selected bacterial isolates by measuring their capacity to degrade morpholine. Based on this analysis of culture filtrates, it was determined that the novel isolate is the genus Halobacillus blutaparonensis which utilizes the diglycolic acid route from the metabolic degradation pathway of morpholine to induce one of two branches of the morpholine biodegradation pathway in the presence of morpholine while the other branch is inhibited. Whatever the branches with regard to the degradation pathway of morpholine exhibited by bacteria are, ammonia is the final end product of degradation which might be biochemically utilized by the isolate.

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“…Nicotine undergoes initial metabolism by hydroxylation on the pyrrolidine ring catalyzed by P450, followed by metabolism by AOX to form the inactive metabolite cotinine (Brandänge and Lindblom, 1979). It was demonstrated that morpholine hydroxylation by P450s occurs at the a-carbon next to nitrogen through a hydrogen atom abstraction and rebound mechanism facilitated by the presence of nitrogen in a morpholine heterocycle (Shaikh et al, 2009). In the case of MMB, however, bioactivation of the morpholine ring at the a-carbon next to nitrogen with nitrogen directly attached to phenyl via P450 followed by AOX appears to be a unique occurrence.…”

Section: Pharmacokinetics and Disposition Of Momelotinibmentioning

confidence: 99%

Pharmacokinetics and Disposition of Momelotinib Revealed a Disproportionate Human Metabolite—Resolution for Clinical Development

et al. 2018

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Momelotinib (MMB), a small-molecule inhibitor of Janus kinase (JAK)1/2 and of activin A receptor type 1 (ACVR1), is in clinical development for the treatment of myeloproliferative neoplasms. The pharmacokinetics and disposition of [C]MMB were characterized in a single-dose, human mass-balance study. Metabolism and the pharmacologic activity of key metabolites were elucidated in multiple in vitro and in vivo experiments. MMB was rapidly absorbed following oral dosing with approximately 97% of the radioactivity recovered, primarily in feces with urine as a secondary route. Mean blood-to-plasma [C] area under the plasma concentration-time curve ratio was 0.72, suggesting low association of MMB and metabolites with blood cells. [C]MMB-derived radioactivity was detectable in blood for ≤48 hours, suggesting no irreversible binding of MMB or its metabolites. The major circulating human metabolite, M21 (a morpholino lactam), is a potent inhibitor of JAK1/2 and ACVR1 in vitro. Estimation of pharmacological activity index suggests M21 contributes significantly to the pharmacological activity of MMB for the inhibition of both JAK1/2 and ACVR1. M21 was observed in disproportionately higher amounts in human plasma than in rat or dog, the rodent and nonrodent species used for the general nonclinical safety assessment of this molecule. This discrepancy was resolved with additional nonclinical studies wherein the circulating metabolites and drug-drug interactions were further characterized. The human metabolism of MMB was mediated primarily by multiple cytochrome P450 enzymes, whereas M21 formation involved initial P450 oxidation of the morpholine ring followed by metabolism via aldehyde oxidase.

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Quantum chemical studies for oxidation of morpholine by Cytochrome P450

Cited by 13 publications

References 48 publications

Degradation of morpholine by Mycobacterium sp. isolated from contaminated wastewater collected from Egypt

Degradation of morpholine by Mycobacterium sp. isolated from contaminated wastewater collected from Egypt

Unraveling the Novel Bacterial Assisted Biodegradation Pathway of Morpholine

Pharmacokinetics and Disposition of Momelotinib Revealed a Disproportionate Human Metabolite—Resolution for Clinical Development

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