The human xenobiotic‐metabolizing enzyme arylamine N‐acetyltransferase 1 (NAT1) is irreversibly inhibited by inorganic (Hg2+) and organic mercury (CH3Hg+): Mechanism and kinetics

Ragunathan, Nilusha; Busi, Florent; Pluvinage, B.; Sanfins, Elodie; Dupret, Jean‐Marie; Rodrigues‐Lima, Fernando; Dairou, Julien

doi:10.1016/j.febslet.2010.06.022

Cited by 13 publications

(10 citation statements)

References 22 publications

(39 reference statements)

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“…Although the cysteine-285 residue does not seem essential for the enzyme activity (Sorenson et al 1995), binding of MeHg to the thiol group could alter the active site of enzyme and in turn reduce its catalytic activity. This mechanism has been implicated in the inhibition of different enzymes by MeHg, such as thioredoxin (Carvalho et al 2008) and arylamine N -acetyl transferase-1 (Ragunathan et al 2010). Interestingly, we observed that blood selenium levels appeared to oppose the effect of blood mercury levels on plasma PON1 activity.…”

Section: Discussionmentioning

confidence: 99%

Relation between Methylmercury Exposure and Plasma Paraoxonase Activity in Inuit Adults from Nunavik

Ayotte

Carrier

Ouellet

et al. 2011

Environ Health Perspect

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Background: Methylmercury (MeHg) exposure has been linked to an increased risk of coronary heart disease (CHD). Paraoxonase 1 (PON1), an enzyme located in the high-density–lipoprotein (HDL) fraction of blood lipids, may protect against CHD by metabolizing toxic oxidized lipids associated with low-density liproprotein and HDL. MeHg has been shown to inhibit PON1 activity in vitro, but this effect has not been studied in human populations.Objectives: This study was conducted to determine whether blood mercury levels are linked to decreased plasma PON1 activities in Inuit people who are highly exposed to MeHg through their seafood-based diet.Methods: We measured plasma PON1 activity using a fluorogenic substrate and blood concentrations of mercury and selenium by inductively coupled plasma mass spectrometry in 896 Inuit adults. Sociodemographic, anthropometric, clinical, dietary, and lifestyle variables as well as PON1 gene variants (rs705379, rs662, rs854560) were considered as possible confounders or modifiers of the mercury–PON1 relation in multivariate analyses.Results: In a multiple regression model adjusted for age, HDL cholesterol levels, omega-3 fatty acid content of erythrocyte membranes, and PON1 variants, blood mercury concentrations were inversely associated with PON1 activities [β-coefficient = –0.063; 95% confidence interval (CI), –0.091 to –0.035; p < 0.001], whereas blood selenium concentrations were positively associated with PON1 activities (β-coefficient = 0.067; 95% CI, 0.045–0.088; p < 0.001). We found no interaction between blood mercury levels and PON1 genotypes.Conclusions: Our results suggest that MeHg exposure exerts an inhibitory effect on PON1 activity, which seems to be offset by selenium intake.

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Section: Discussionmentioning

confidence: 99%

Relation between Methylmercury Exposure and Plasma Paraoxonase Activity in Inuit Adults from Nunavik

Ayotte

Carrier

Ouellet

et al. 2011

Environ Health Perspect

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“…NATs are inhibited by iodoacetamide, which alkylates the SH group of Cys (36). In addition, inorganic (Hg 2ϩ ) and organic (CH 3 Hg ϩ ) mercury react irreversibly with the active-site Cys of NAT (37). In our study, the inhibition by amino acid-selective reagents (Table 2) and the kinetic parameters (see Fig.…”

Section: Discussionmentioning

confidence: 61%

Molecular Characterization of a Novel N -Acetyltransferase from Chryseobacterium sp

Takenaka

Yoshida

Tanaka

et al. 2014

Appl Environ Microbiol

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N-Acetyltransferase from Chryseobacterium sp. strain 5-3B is an acetyl coenzyme A (acetyl-CoA)-dependent enzyme that catalyzes the enantioselective transfer of an acetyl group from acetyl-CoA to the amino group of L-2-phenylglycine to produce (2S)-2-acetylamino-2-phenylacetic acid. We purified the enzyme from strain 5-3B and deduced the N-terminal amino acid sequence. The gene, designated natA, was cloned with two other hypothetical protein genes; the three genes probably form a 2.5-kb operon. The deduced amino acid sequence of NatA showed high levels of identity to sequences of putative N-acetyltransferases of Chryseobacterium spp. but not to other known arylamine and arylalkylamine N-acetyltransferases. Phylogenetic analysis indicated that NatA forms a distinct lineage from known N-acetyltransferases. We heterologously expressed recombinant NatA (rNatA) in Escherichia coli and purified it. rNatA showed high activity for L-2-phenylglycine and its chloro-and hydroxyl-derivatives. The K m and V max values for L-2-phenylglycine were 0.145 ؎ 0.026 mM and 43.6 ؎ 2.39 mol · min ؊1 · mg protein ؊1 , respectively. The enzyme showed low activity for 5-aminosalicylic acid and 5-hydroxytryptamine, which are reported as good substrates of a known arylamine N-acetyltransferase and an arylalkylamine N-acetyltransferase. rNatA had a comparatively broad acyl donor specificity, transferring acyl groups to L-2-phenylglycine and producing the corresponding 2-acetylamino-2-phenylacetic acids (relative activity with acetyl donors acetyl-CoA, propanoyl-CoA, butanoyl-CoA, pentanoyl-CoA, and hexanoyl-CoA, 100:108:122:10:<1). Optically active D-amino acids are widely used in the pharmaceutical industry as intermediates for the synthesis of semisynthetic antibiotics, pesticides, and biologically active peptides. Among them, the demand has been increasing for D-2-phenylglycine and its hydroxyl-derivative, D-4-hydroxy-2-phenylglycine, for the synthesis of drugs such as aspoxicillin and cefpiramide (1, 2). Various procedures for the bio-production of D-2-phenylglycines have been studied, such as production from DL-p-hydroxyphenylhydantoin by hydantoinase and carbamylase (3), from its keto analogue by D-amino acid aminotransferase (4), and from DL-2-phenylglycine using isoelectrically trapped penicillin G acylase (5) and bioconversion via the L-glutamate metabolic pathway (6). However, these procedures need to be improved to obtain large amounts and high purity of 2-phenylglycines (7). Also the organic synthesis of D-2-phenylglycines via hydrocyanation of Nbenzyloxycarbonyl aldimine and hydrolysis of the reaction product, the carbamic acid derivative, has been reported (8), but this precise synthesis using a bimetallic salt catalytic agent needs to be scaled up in the manufacturing process.Arylamine N-acetyltransferase (NAT; EC 2.3.1.5) and arylalkylamine N-acetyltransferase (AANAT; EC 2.3.1.87) catalyze the transfer of an acetyl group from acetyl coenzyme A (acetyl-CoA) to the amino groups of hydrazine, arylamine drugs, carcinogens, and ar...

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“…Human A549 cells exposed to either inorganic or organic mercury showed a dosedependent inhibition of NAT1 activity, with IC 50 values of 3 and 20 M, respectively (Ragunathan et al, 2010a). Murine Clara cells exposed to cadmium had a decreased capacity to acetylate the carcinogenic arylamine substrates (Ragunathan et al, 2010b).…”

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confidence: 97%

“…These heavy metals have high affinities for reactive thiol groups and are capable of inactivating thiol-containing enzymes (Jacoby et al, 1999;Bridges and Zalups, 2005). Both inorganic (Hg 2ϩ ) and organic (CH 3 Hg ϩ ) mercury inactivated purified recombinant human NAT1 at biologically relevant concentrations, with IC 50 values of 0.25 and 1.4 M, respectively (Ragunathan et al, 2010a). Cadmium also inactivated the enzyme (IC 50 , 0.055 M); total inhibition was observed at concentrations as low as 0.3 M (Ragunathan et al, 2010b).…”

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confidence: 99%

ArylamineN-Acetyltransferase 1: A Novel Drug Target in Cancer Development

2011

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The human xenobiotic‐metabolizing enzyme arylamine N‐acetyltransferase 1 (NAT1) is irreversibly inhibited by inorganic (Hg²⁺) and organic mercury (CH₃Hg⁺): Mechanism and kinetics

Cited by 13 publications

References 22 publications

Relation between Methylmercury Exposure and Plasma Paraoxonase Activity in Inuit Adults from Nunavik

Relation between Methylmercury Exposure and Plasma Paraoxonase Activity in Inuit Adults from Nunavik

Molecular Characterization of a Novel N -Acetyltransferase from Chryseobacterium sp

ArylamineN-Acetyltransferase 1: A Novel Drug Target in Cancer Development

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