tailieunhanh - Báo cáo khóa học: New substrate analogues of human serotonin N-acetyltransferase produce in situ specific and potent inhibitors

Melatonin is synthesized by an enzymatic pathway, in which arylalkylamine (serotonin)N-acetyltransferase cata-lyzes the rate-limiting step. Aprevious study [Khalil, ., DeAngelis, J., Ishii,M.&Cole, . (1999). Sci. USA 96, 12418–12423] reported the discovery of bromoacetyltryptamine (BAT), a new type of inhibitor of this enzyme. This compound is the precursor of a potent bifunctional inhibitor (analogue of the transition state), capable of interfering with both the substrate and the cosubstrate binding sites. . | Eur. J. Biochem. 271 418-428 2004 FEBS 2003 doi New substrate analogues of human serotonin -acetyltransferase produce in situ specific and potent inhibitors Gilles Ferry1. Caroline Ubeaud1 Julien Mozo1 Christophe Pean2. Philinne Hennia2. Marianne Rodriauez1 BM F B F V B B B F B B B B w F W IV w B B BF B B B FF FF BB B B B B FF Bf B B F B BF fB BB B B B B B B FF FF BF B B BF B B B B B FF B B B FV B B FV B B B B BF B B FF fB B B fF w BF Catherine Seoul1 Anne Bonnaud1 Olivier Nosiean1 Jean-Pierre Galizzi1 Philinne Delaaranae3 Pierre Renard3 Jean-Paul Volland2 Said Yous4 Daniel Lesieur4 and Jean A. Boutin1 1 Pharmacologie Moleculaire et Cellulaire Institut de Recherches SERVIER Croissy-sur-Seine 2Physico-Chimie Analytique Institut de Recherches SERVIER Suresnes 3Institut de Recherches Internationales SERVIER Courbevoie 4Faculte de Pharmacie Lille France Melatonin is synthesized by an enzymatic pathway in which arylalkylamine serotonin N-acetyltransferase catalyzes the rate-limiting step. A previous ttudy Khialil . De Angelis J. Ishii M. Cole . 1999 Proc. Natl Acad. Sci. USA 96 12418-12423 reported the discovery of bromoacetyltryptamine BAT a new type of inhibitor of this enzyme. This compound is the precursor of a potent biflnctional inhibitor analogle of the transition state capable of interfering with both the substrate and the cosubstrate binding sites. This inhibitor is biosynthesized by the enzyme itself in the presence of free coenzyme A. In the present report we describe the potency of new N-halo-genoacetyl derivatives leading to a strong in situ inhibition of serotonin N-acetyltransferase. The new concept behind the mechanism of action of these precursors was studied by following the biosynthesis of the inhibitor from tritiated-BAT in a living cell. The fate of tritiated-phenylethylamine PEA a natural substrate of the enzyme in the presence or absence of 3H BAT was also followed leading to their incorporation into the .