title: Novel bisubstrate analog inhibitors of serotonin N-acetyltransferase: the importance of being neutral.
abstract: Linker modified novel bisubstrate analog inhibitors 4-7 for serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase, AANAT) have been designed and synthesized. Examination of these inhibitors with AANAT in vitro suggested that: (i) linker hydrogen bonding makes only modest contributions to the affinity of bisubstrate analog inhibitors studied; (ii) greater than or equal to four methylene groups between the indole and the coenzyme A (CoASH) moieties are required for a bisubstrate analog inhibitor to achieve strong AANAT inhibition; (iii) the AANAT active site appears not to accommodate positively charged linkers as well as neutral ones; and (iv) substrate amine pKa depression may constitute one strategy for AANAT substrate recognition and catalysis. The results reported here have enhanced our understanding of AANAT substrate recognition/catalysis, and are important for novel inhibitor design. Since AANAT belongs to the GCN5-related N-acetyltransferase (GNAT) superfamily, our experimental strategies should find applications for other acetyltransferases.
authors.affiliation: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.
authors.forename: Weiping
authors.initials: W
authors.lastname: Zheng
authors.forename: Philip A
authors.initials: PA
authors.lastname: Cole
mesh_terms: D001191:Arylamine N-Acetyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003065:Coenzyme A / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015394:Molecular Structure
chemical_list: D004791:Enzyme Inhibitors; D001191:Arylamine N-Acetyltransferase; D003065:Coenzyme A