Substrate specificity and inhibition studies of human serotonin N-acetyltransferase.

Ferry, Gilles; Loynel, Armelle; Kucharczyk, Nathalie; Bertin, Sophie; Rodriguez, Marianne; Delagrange, Philippe; Galizzi, Jean‐Pierre; Jacoby, Edgar; Volland, Jean‐Paul; Lesieur, D.; Renard, Pierre; Canet, Emmanuel; Fauchère, Jean‐Luc; Boutin, Jean A.

doi:10.1016/s0021-9258(19)55928-2

Cited by 5 publications

(8 citation statements)

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“…The replacement of the piperidine with a thiomorpholine (17) or a morpholine (18) also caused no change in affinity but seems to improve the potency on the cellular model. To continue exploring the structure-activity relationships of the piperidine moiety, a number of polar groups were incorporated (19)(20)(21)(22)(23)(24)(25)(26). In general, these compounds retained affinity compared to the piperidine derivatives 7, but the most important result was their cellular potency improvement.…”

Section: Resultsmentioning

confidence: 99%

“…Expression and Production of hAANAT. Expression, production, and purification of hAANAT have been described by Ferry et al 43 In brief, the human arylalkylamine N-acetyltransferase cDNA coding five region (kindly provided by D. C. Klein and S. L. Coon, National Institutes of Health, Bethesda, MD) was inserted into the bacterial expression vector pGEX-4T (Pharmacia, Les Ulis, France), leading to the expression of a protein fused to glutathione-S-transferase. An Escherichia coli strain [BL21(DE3)pLysS] was transformed with the resulting plasmid.…”

Section: Experimental Sectionsmentioning

confidence: 99%

“…Ferry et al reported the discovery of tetrapeptides coming from the deconvolution of combinatorial libraries …”

Section: Introductionmentioning

confidence: 99%

“…Ferry et al reported the discovery of tetrapeptides coming from the deconvolution of combinatorial libraries. 21 Bisubstrate Analogs. It is suggested that AANAT catalyzes the transfer of an acetyl group from acetylcoenzyme A (acetyl-CoA) to serotonin, with the involvement of an intermediate ternary complex, to produce N-acetylserotonin.…”

Section: Introductionmentioning

confidence: 99%

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Receptor- and Ligand-Based Study on Novel 2,2′-Bithienyl Derivatives as Non-Peptidic AANAT Inhibitors

Lepailleur

Lemaître

Xiao

et al. 2010

J. Chem. Inf. Model.

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Arylalkylamine N-acetyl transferase (serotonin N-acetyl transferase, AANAT) is a critical enzyme in the light-mediated regulation of melatonin production and circadian rythm. With the objective of discovering new chemical entities with inhibitory potencies against AANAT, a medium-throughput screening campaign was performed on a chemolibrary. We found a class of molecules based on a 2,2'-bithienyl scaffold, and compound 1 emerged as a first hit. Herein, we describe our progress from hit discovery and to optimization of this new class of compounds. To complete the study, computational approaches were carried out: a docking study which provided insights into the plausible binding modes of these new AANAT inhibitors and a three-dimensional quantitative structure-activity relationship study that applied comparative molecular field analysis (CoMFA) methodology. Several CoMFA models were developed (variable alignments and options), and the best predictive one yields good statistical results (q(2) = 0.744, r(2) = 0.891, and s = 0.273). The resulting CoMFA contour maps were used to illustrate the pharmacomodulations relevant to the biological activities in this series of analogs and to design new active inhibitors. This novel series of 2,2'-bithienyl derivatives gives new insights into the design of AANAT inhibitors.

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Section: Resultsmentioning

confidence: 99%

Section: Experimental Sectionsmentioning

confidence: 99%

“…Ferry et al reported the discovery of tetrapeptides coming from the deconvolution of combinatorial libraries …”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Receptor- and Ligand-Based Study on Novel 2,2′-Bithienyl Derivatives as Non-Peptidic AANAT Inhibitors

Lepailleur

Lemaître

Xiao

et al. 2010

J. Chem. Inf. Model.

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“…Plates were monitored on a 28°C thermostated CellKey CDS reader . Some assays were performed in our laboratory (in italic characters): AANAT activity measurements were performed as described in Ferry et al [33] and for chk1, as described in [34]. Furthermore, MT binding assays -GTPcS included -were performed as described in [35].…”

Section: Cellular Dichroism Spectroscopymentioning

confidence: 99%

Molecular and cellular pharmacological properties of 5‐methoxycarbonylamino‐N‐acetyltryptamine (MCA‐NAT): a nonspecific MT3 ligand

Vincent

Cohen

Delagrange

et al. 2010

Journal of Pineal Research

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5-Methoxycarbonylamino-N-acetyltryptamine (MCA-NAT) has been initially described as a ligand at non MT(1), non MT(2) melatonin binding site (MT3) selective versus MT(1) and MT(2), two membrane melatonin receptors. MCA-NAT activity has been reported by others in different models, in vivo, particularly in the intra-ocular pressure (IOP) models in rabbits and monkeys. Its activity was systematically linked to either MT3 or to a new, yet unknown, melatonin receptor. In this article, the melatonin receptor pharmacology of MCA-NAT is described. MCA-NAT has micromolar range affinities at the melatonin receptors MT(1) and MT(2), while in functional studies, MCA-NAT proved to be a powerful MT(1)/MT(2) partial agonist in the sub-micromolar range. These data strongly suggest that MCA-NAT actions might be mediated by these receptors in vivo. Finally, as described by others, we show that MCA-NAT is unable to elicit any type of receptor-like functional responses from Chinese hamster ovary cells over-expressing quinone reductase 2, the MT3.

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Mechanistic and Structural Analysis of a Drosophila melanogaster Enzyme, Arylalkylamine N-Acetyltransferase Like 7, an Enzyme That Catalyzes the Formation of N-Acetylarylalkylamides and N-Acetylhistamine

et al. 2015

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Arylalkylamine N-acetyltransferase like 7 (AANATL7) catalyzes the formation of N-acetylarylalkylamides and N-acetylhistamine from acetyl-CoA and the corresponding amine substrate. AANATL7 is a member of the GNAT superfamily of >10000 GCN5-related N-acetyltransferases, many members being linked to important roles in both human metabolism and disease. Drosophila melanogaster utilizes the N-acetylation of biogenic amines for the inactivation of neurotransmitters, the biosynthesis of melatonin, and the sclerotization of the cuticle. We have expressed and purified D. melanogaster AANATL7 in Escherichia coli and used the purified enzyme to define the substrate specificity for acyl-CoA and amine substrates. Information about the substrate specificity provides insight into the potential contribution made by AANATL7 to fatty acid amide biosynthesis because D. melanogaster has emerged as an important model system contributing to our understanding of fatty acid amide metabolism. Characterization of the kinetic mechanism of AANATL7 identified an ordered sequential mechanism, with acetyl-CoA binding first followed by histamine to generate an AANATL7·acetyl-CoA·histamine ternary complex prior to catalysis. Successive pH–activity profiling and site-directed mutagenesis experiments identified two ionizable groups: one with a pKa of 7.1 that is assigned to Glu-26 as a general base and a second pKa of 9.5 that is assigned to the protonation of the thiolate of the coenzyme A product. Using the data generated herein, we propose a chemical mechanism for AANATL7 and define functions for other important amino acid residues involved in substrate binding and regulation of catalysis.

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Substrate specificity and inhibition studies of human serotonin N-acetyltransferase.

Cited by 5 publications

References 0 publications

Receptor- and Ligand-Based Study on Novel 2,2′-Bithienyl Derivatives as Non-Peptidic AANAT Inhibitors

Receptor- and Ligand-Based Study on Novel 2,2′-Bithienyl Derivatives as Non-Peptidic AANAT Inhibitors

Molecular and cellular pharmacological properties of 5‐methoxycarbonylamino‐N‐acetyltryptamine (MCA‐NAT): a nonspecific MT3 ligand

Mechanistic and Structural Analysis of a Drosophila melanogaster Enzyme, Arylalkylamine N-Acetyltransferase Like 7, an Enzyme That Catalyzes the Formation of N-Acetylarylalkylamides and N-Acetylhistamine

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