The Nonenzymatic Reactivity of the Acyl-Linked Metabolites of Mefenamic Acid toward Amino and Thiol Functional Group Bionucleophiles

Horng, Howard; Benet, Leslie Z.

doi:10.1124/dmd.113.053223

Cited by 14 publications

(12 citation statements)

References 37 publications

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“…More commonly, drug toxicity is often caused by electrophilic drug metabolites nonenzymatically reacting with cellular proteins, and minimizing this problem is one of the foremost challenges during the development and optimization of small-molecule pharmaceuticals (Evans et al, 2004; Horng and Benet, 2013). Interestingly, the reactivity and toxicity of many drug metabolites is dependent on their bioactivation to acyl-CoA thioesters (Sallustio et al, 2000).…”

Section: Role Of Carbon Stress In Diseasementioning

confidence: 99%

Nonenzymatic Protein Acylation as a Carbon Stress Regulated by Sirtuin Deacylases

2014

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Cellular proteins are decorated with a wide range of acetyl and other acyl modifications. Many studies have demonstrated regulation of site-specific acetylation by acetyltransferases and deacetylases. Acylation is emerging as a new type of lysine modification, but less is known about its overall regulatory role. Furthermore, the mechanisms of lysine acylation, its overlap with protein acetylation, and how it influences cellular function are major unanswered questions in the field. In this review, we discuss the known roles of acetyltransferases and deacetylases, and the sirtuins as a conserved family of NAD+-dependent protein deacylases that are important for response to cellular stress and homeostasis. We also consider the evidence for an emerging idea of non-enzymatic protein acylation. Finally, we put forward the hypothesis that protein acylation is a form of protein “carbon stress”, that the deacylases evolved to remove as a part of a global protein quality control network.

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Section: Role Of Carbon Stress In Diseasementioning

confidence: 99%

Nonenzymatic Protein Acylation as a Carbon Stress Regulated by Sirtuin Deacylases

2014

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“…It is known from human metabolism that MEF can form activated ester derivatives, namely MEF-adenylate (AMP) and MEF-coenzyme A (CoA). Such activated esters are nonenzymatically reactive with biological nucleophiles including amino acids 53 . However we found no evidence for conjugation to any other amino acid.…”

Section: Glutamate Conjugation Of Mefenamic Acidmentioning

confidence: 99%

Exploring micropollutant biotransformation in three freshwater phytoplankton species

Stravs

Pomati

Hollender

2017

Environ. Sci.: Processes Impacts

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Phytoplankton constitute an important component of surface water ecosystems; however little is known about their contribution to biotransformation of organic micropollutants. To elucidate biotransformation processes, batch experiments with two cyanobacterial species (Microcystis aeruginosa and Synechococcus sp.) and one green algal species (Chlamydomonas reinhardtii) were conducted. Twenty-four micropollutants were studied, including 15 fungicides and 9 pharmaceuticals. Online solid phase extraction (SPE) coupled with liquid chromatography (LC)-high resolution tandem mass spectrometry (HRMS/MS) was used together with suspect and nontarget screening to identify transformation products (TPs). 14 TPs were identified for 9 micropollutants, formed by cytochrome P450-mediated oxidation, conjugation and methylation reactions. The observed transformation pathways included reactions likely mediated by promiscuous enzymes, such as glutamate conjugation to mefenamic acid and pterin conjugation of sulfamethoxazole. For 15 compounds, including all azole fungicides tested, no TPs were identified. Environmentally relevant concentrations of chemical stressors had no influence on the transformation types and rates.

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“…As described for AM2201, AM694, 5F-PB-22, XLR-11, and MAM2201 [5,11,19,21,35], oxidative defluorination is common for 5-fluoropentyl-containing synthetic cannabinoids and, as expected, occurred for 5F-AB-PINACA, generating metabolites shared with AB-PINACA. MS/MS spectra and fragmentation patterns are depicted in Fig.…”

Section: Metabolites Generated By Oxidative Defluorinationmentioning

confidence: 99%

“…(33). Acyl glucuronides are reactive and can irreversibly bind to proteins and nucleic acids, potentially leading to in vivo toxicity (34,35). Ketone formation (A16) occurred at the pentyl chain (m/ z 145, m/z 229), but the exact location is unclear.…”

Section: Metabolites Generated By Carboxamide Hydrolysismentioning

confidence: 99%

Pentylindole/Pentylindazole Synthetic Cannabinoids and Their 5-Fluoro Analogs Produce Different Primary Metabolites: Metabolite Profiling for AB-PINACA and 5F-AB-PINACA

Wohlfarth

Castaneto

Zhu

et al. 2015

AAPS J

144

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Abstract. Whereas non-fluoropentylindole/indazole synthetic cannabinoids appear to be metabolized preferably at the pentyl chain though without clear preference for one specific position, their 5-fluoro analogs' major metabolites usually are 5-hydroxypentyl and pentanoic acid metabolites. We determined metabolic stability and metabolites of N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-pentyl-1H-indazole-3-carboxamide (AB-PINACA) and 5-fluoro-AB-PINACA (5F-AB-PINACA), two new synthetic cannabinoids, and investigated if results were similar. In silico prediction was performed with MetaSite (Molecular Discovery). For metabolic stability, 1 μmol/L of each compound was incubated with human liver microsomes for up to 1 h, and for metabolite profiling, 10 μmol/L was incubated with pooled human hepatocytes for up to 3 h. Also, authentic urine specimens from AB-PINACA cases were hydrolyzed and extracted. All samples were analyzed by liquid chromatography high-resolution mass spectrometry on a TripleTOF 5600+ (AB SCIEX) with gradient elution (0.1% formic acid in water and acetonitrile). High-resolution full-scan mass spectrometry (MS) and information-dependent acquisition MS/MS data were analyzed with MetabolitePilot (AB SCIEX) using different data processing algorithms. Both drugs had intermediate clearance. We identified 23 AB-PINACA metabolites, generated by carboxamide hydrolysis, hydroxylation, ketone formation, carboxylation, epoxide formation with subsequent hydrolysis, or reaction combinations. We identified 18 5F-AB-PINACA metabolites, generated by the same biotransformations and oxidative defluorination producing 5-hydroxypentyl and pentanoic acid metabolites shared with AB-PINACA. Authentic urine specimens documented presence of these metabolites. AB-PINACA and 5F-AB-PINACA produced suggested metabolite patterns. AB-PINACA was predominantly hydrolyzed to AB-PINACA carboxylic acid, carbonyl-AB-PINACA, and hydroxypentyl AB-PINACA, likely in 4-position. The most intense 5F-AB-PINACA metabolites were AB-PINACA pentanoic acid and 5-hydroxypentyl-AB-PINACA.

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The Nonenzymatic Reactivity of the Acyl-Linked Metabolites of Mefenamic Acid toward Amino and Thiol Functional Group Bionucleophiles

Cited by 14 publications

References 37 publications

Nonenzymatic Protein Acylation as a Carbon Stress Regulated by Sirtuin Deacylases

Nonenzymatic Protein Acylation as a Carbon Stress Regulated by Sirtuin Deacylases

Exploring micropollutant biotransformation in three freshwater phytoplankton species

Pentylindole/Pentylindazole Synthetic Cannabinoids and Their 5-Fluoro Analogs Produce Different Primary Metabolites: Metabolite Profiling for AB-PINACA and 5F-AB-PINACA

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