{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T02:17:44Z","timestamp":1791685064961,"version":"4.3.4"},"reference-count":36,"publisher":"National Academy of Sciences","issue":"22","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[1999,10,26]]},"abstract":"<jats:p>\n                    Serotonin\n                    <jats:italic>N<\/jats:italic>\n                    -acetyltransferase is the enzyme responsible for the diurnal rhythm of melatonin production in the pineal gland of animals and humans. Inhibitors of this enzyme active in cell culture have not been reported previously. The compound\n                    <jats:italic>N<\/jats:italic>\n                    -bromoacetyltryptamine was shown to be a potent inhibitor of this enzyme\n                    <jats:italic>in vitro<\/jats:italic>\n                    and in a pineal cell culture assay (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2248 500 nM). The mechanism of inhibition is suggested to involve a serotonin\n                    <jats:italic>N<\/jats:italic>\n                    -acetyltransferase-catalyzed alkylation reaction between\n                    <jats:italic>N<\/jats:italic>\n                    -bromoacetyltryptamine and reduced CoA, resulting in the production of a tight-binding bisubstrate analog inhibitor. This alkyltransferase activity is apparently catalyzed at a functionally distinct site compared with the acetyltransferase activity active site on serotonin\n                    <jats:italic>N<\/jats:italic>\n                    -acetyltransferase. Such active site plasticity is suggested to result from a subtle conformational alteration in the protein. This plasticity allows for an unusual form of mechanism-based inhibition with multiple turnovers, resulting in \u201cmolecular fratricide.\u201d\n                    <jats:italic>N<\/jats:italic>\n                    -bromoacetyltryptamine should serve as a useful tool for dissecting the role of melatonin in circadian rhythm as well as a potential lead compound for therapeutic use in mood and sleep disorders.\n                  <\/jats:p>","DOI":"10.1073\/pnas.96.22.12418","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:41:48Z","timestamp":1027680108000},"page":"12418-12423","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":49,"title":["Mechanism-based inhibition of the melatonin rhythm enzyme: Pharmacologic exploitation of active site functional plasticity"],"prefix":"10.1073","volume":"96","author":[{"given":"Ehab M.","family":"Khalil","sequence":"first","affiliation":[{"name":"Laboratory of Bioorganic Chemistry, The Rockefeller University, New York, NY 10021"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline","family":"De Angelis","sequence":"additional","affiliation":[{"name":"Laboratory of Bioorganic Chemistry, The Rockefeller University, New York, NY 10021"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Ishii","sequence":"additional","affiliation":[{"name":"Laboratory of Bioorganic Chemistry, The Rockefeller University, New York, NY 10021"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip A.","family":"Cole","sequence":"additional","affiliation":[{"name":"Laboratory of Bioorganic Chemistry, The Rockefeller University, New York, NY 10021"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[1999,10,26]]},"reference":[{"key":"e_1_3_3_1_2","volume-title":"Melatonin and the Mammalian Pineal Gland","author":"Arendt J","year":"1995","unstructured":"J Arendt Melatonin and the Mammalian Pineal Gland (Chapman & Hall, New York, 1995)."},{"key":"e_1_3_3_2_2","volume-title":"The Melatonin Miracle. 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