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 language | English (US) |
---|---|
Pages (from-to) | 398-411 |
Number of pages | 14 |
Journal | Bioorganic Chemistry |
Volume | 31 |
Issue number | 5 |
DOIs | |
State | Published - Oct 2003 |
Keywords
- Catalysis
- Inhibitors
- Serotonin N-acetyltransferase
- pK
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Drug Discovery
- Organic Chemistry