Comparison of substrate specificity among human arylacetamide deacetylase and carboxylesterases

Fukami, Tatsuki; Kariya, Motoki; Kurokawa, Takaya; Iida, Azumi; Nakajima, Miki

doi:10.1016/j.ejps.2015.07.006

Cited by 72 publications

(55 citation statements)

References 30 publications

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“…The active site cavity of hCE1 is very large (≈1300 Å 3 in volume), mostly flexible and is lined mainly by hydrophobic residues, with the exception of the catalytic triad. The enzyme is therefore considered to be relatively promiscuous and capable of interacting with a variety of diverse ligands preferring those with small alcoholic group and a bulky acyl group, such as oseltamivir, clopidogrel and enalapril …”

Section: Resultsmentioning

confidence: 74%

Synthesis, Biological Evaluation, and Molecular Docking of Combretastatin and Colchicine Derivatives and their hCE1‐Activated Prodrugs as Antiviral Agents

et al. 2019

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Recent studies indicate that tubulin can be a host factor for vector‐borne flaviviruses like dengue (DENV) and Zika (ZIKV), and inhibitors of tubulin polymerization such as colchicine have been demonstrated to decrease virus replication. However, toxicity limits the application of these compounds. Herein we report prodrugs based on combretastatin and colchicine derivatives that contain an ester cleavage site for human carboxylesterase, a highly abundant enzyme in monocytes and hepatocytes targeted by DENV. Relative to their parent compounds, the cytotoxicity of these prodrugs was reduced by several orders of magnitude. All synthesized prodrugs containing a leucine ester were hydrolyzed by the esterase in vitro. In contrast to previous reports, the phenylglycine esters were not cleaved by human carboxylesterase. The antiviral activity of combretastatin, colchicine, and selected prodrugs against DENV and ZIKV in cell culture was observed at low micromolar and sub‐micromolar concentrations. In addition, docking studies were performed to understand the binding mode of the studied compounds to tubulin.

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Section: Resultsmentioning

confidence: 74%

Synthesis, Biological Evaluation, and Molecular Docking of Combretastatin and Colchicine Derivatives and their hCE1‐Activated Prodrugs as Antiviral Agents

et al. 2019

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“…First, it has not been previously associated with warfarin response. Second, the chemical properties of warfarin suggest that it is very unlikely, from a pharmacokinetics perspective, that CES2 is involved in warfarin metabolism (Shimizu et al, 2014; Fukami et al, 2015). Third, previous studies showed association of CES2 with diabetes in a rodent model (Li et al, 2016), and this disease was also associated with an increase in warfarin dose requirements in our multivariate regression model.…”

Section: Discussionmentioning

confidence: 99%

Warfarin Anticoagulation Therapy in Caribbean Hispanics of Puerto Rico: A Candidate Gene Association Study

Claudio‐Campos

Labastida²,

Ramos

et al. 2017

Front. Pharmacol.

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Existing algorithms account for ~50% of observed variance in warfarin dose requirements after including common polymorphisms. However, they do not perform as well in populations other than Caucasians, in part because some ethno-specific genetic variants are overlooked. The objective of the present study was to identify genetic polymorphisms that can explain variability in warfarin dose requirements among Caribbean Hispanics of Puerto Rico. Next-Generation Sequencing of candidate genes CYP2C9 and VKORC1 and genotyping by DMET® Plus Assay of cardiovascular patients were performed. We also aimed at characterizing the genomic structure and admixture pattern of this study cohort. Our study used the Extreme Discordant Phenotype approach to perform a case-control association analysis. The CYP2C9 variant rs2860905, which was found in all the major haplotypes occurring in the Puerto Rican population, showed stronger association with warfarin sensitivity (<4 mg/day) than common variants CYP2C9*2 and CYP2C9*3. Although, CYP2C9*2 and CYP2C9*3 are separately contained within two of the haplotypes, 10 subjects with the sensitive phenotype were carriers of only the CYP2C9 rs2860905 variant. Other polymorphisms in CES2 and ABCB1 were found to be associated with warfarin resistance. Incorporation of rs2860905 in a regression model (R2 = 0.63, MSE = 0.37) that also includes additional genetics (i.e., VKORC1-1639 G>A; CYP2C9 rs1856908; ABCB1 c.IVS9-44A>G/ rs10276036; CES2 c.269-965A>G/ rs4783745) and non-genetic factors (i.e., hypertension, diabetes and age) showed better prediction of warfarin dose requirements than CYP2C9*2 and CYP2C9*3 combined (partial R2 = 0.132 vs. 0.023 and 0.007, respectively, p < 0.001). The genetic background of Puerto Ricans in the study cohort showed a tri-hybrid admixture pattern, with a slightly higher than expected contribution of Native American ancestry (25%). The genomic diversity of Puerto Ricans is highlighted by the presence of four different major haplotype blocks in the CYP2C9 locus. Although, our findings need further replication, this study contributes to the field by identifying novel genetic variants that increase predictability of stable warfarin dosing among Caribbean Hispanics.

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“…To estimate the contribution of AADAC, CES1, and CES2 to prasugrel hydrolase activity in HIMs and HLMs, RAF values for each esterase in HIMs and HLMs were calculated (Table 2). We previously demonstrated that indiplon, fenofibrate, and procaine were specifically hydrolyzed by AADAC, CES1, and CES2, respectively (Shimizu et al, 2014a;Fukami et al, 2015). Therefore, we selected these compounds as the specific substrates of each esterase.…”

Section: Resultsmentioning

confidence: 99%

“…Indiplon, Phenacetin, Fenofibrate, and Procaine Hydrolase Activity. Indiplon, phenacetin, fenofibrate, and procaine hydrolase activities were measured according to previous studies (Watanabe et al, 2010;Shimizu et al, 2014a;Fukami et al, 2015). Their substrate concentrations were 1 mM, 5 mM, 25 mM, and 5 mM, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…To date, it has been shown that human AADAC catalyzes the hydrolysis of flutamide, phenacetin, rifamycins, and indiplon (Watanabe et al, 2009(Watanabe et al, , 2010Nakajima et al, 2011;Shimizu et al, 2014a). Recent studies have uncovered that human AADAC prefers compounds containing a quite small acyl moiety (e.g., Fukami et al, 2015). Based on the chemical structure of prasugrel (Fig.…”

Section: Introductionmentioning

confidence: 99%

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Arylacetamide Deacetylase is Responsible for Activation of Prasugrel in Human and Dog

Kurokawa

Fukami

Yoshida

et al. 2015

Drug Metabolism and Disposition

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Prasugrel, a thienopyridine anti-platelet agent, is pharmacologically activated by hydrolysis and hydroxylation. It is efficiently hydrolyzed in the intestine after oral administration, and the enzyme responsible for the hydrolysis in humans was demonstrated to be carboxylesterase (CES)2. Prasugrel hydrolase activity is detected in dog intestines, where CES enzymes are absent; therefore, this prompted us to investigate the involvement of an enzyme(s) other than CES. Human arylacetamide deacetylase (AADAC) is highly expressed in the small intestine, catalyzing the hydrolysis of several clinical drugs containing small acyl moieties. In the present study, we investigated whether AADAC catalyzes prasugrel hydrolysis. Recombinant human AADAC was shown to catalyze prasugrel hydrolysis with a CL int value of 50.0 6 1.2 ml/min/mg protein with a similar K m value to human intestinal and liver microsomes, whereas the CL int values of human CES1 and CES2 were 4.6 6 0.1 and 6.6 6 0.3 ml/min/mg protein, respectively. Inhibition studies using various chemical inhibitors and the relative activity factor approach suggested that the contribution of AADAC to prasugrel hydrolysis in human intestine is comparable to that of CES2. In dog intestine, the expression of AADAC, but not CES1 and CES2, was confirmed by measuring the marker hydrolase activities of each human esterase. The similar K m values and inhibition profiles between recombinant dog AADAC and small intestinal microsomes suggest that AADAC is a major enzyme responsible for prasugrel hydrolysis in dog intestine. Collectively, we found that AADAC largely contributes to prasugrel hydrolysis in both human and dog intestine.

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Comparison of substrate specificity among human arylacetamide deacetylase and carboxylesterases

Cited by 72 publications

References 30 publications

Synthesis, Biological Evaluation, and Molecular Docking of Combretastatin and Colchicine Derivatives and their hCE1‐Activated Prodrugs as Antiviral Agents

Synthesis, Biological Evaluation, and Molecular Docking of Combretastatin and Colchicine Derivatives and their hCE1‐Activated Prodrugs as Antiviral Agents

Warfarin Anticoagulation Therapy in Caribbean Hispanics of Puerto Rico: A Candidate Gene Association Study

Arylacetamide Deacetylase is Responsible for Activation of Prasugrel in Human and Dog

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