Novel bisubstrate analog inhibitors of serotonin N-acetyltransferase: The importance of being neutral

Weiping Zheng, Philip A. Cole

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)398-411
Number of pages14
JournalBioorganic Chemistry
Volume31
Issue number5
DOIs
StatePublished - Oct 2003

Keywords

  • Catalysis
  • Inhibitors
  • Serotonin N-acetyltransferase
  • pK

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Drug Discovery
  • Organic Chemistry

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