Abstract
The inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase from yeast was compared for both F-244 (1) and (RS)-β-butyrolactone (5). F-244 exhibits irreversible inhibition with an IC50 of 8 nM, similar to that reported for the rat liver enzyme, while the binding constant (1/K(I)) and inactivation rate constant (k(inact)) are similar to values reported for the human cytoplasmic enzyme. (RS)-β-Butyrolactone (5) also irreversibly inhibits the enzyme, but with much lower efficieny (IC50 2 mM). The values for K(I) (9 mM) and k(inact) (0.0078 s-1) for 5 were determined. The results show that k(inact) for 5 and 1 differ by a factor of only 2.5, while K(I) for 5 is higher by a factor of 1.8 x 105. Hence, the β-lactone ring is shown to be the sole essential structural feature in 1 for irreversible inactivation of HMG-CoA synthase; however, the remaining functionality enhances the binding of 1 to the enzyme relative to 5.
Original language | English |
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Pages (from-to) | 24-27 |
Number of pages | 4 |
Journal | Canadian Journal of Chemistry |
Volume | 74 |
Issue number | 1 |
DOIs | |
Publication status | Published - 1996 |
Keywords
- F-244
- HMG-CoA synthase
- butyrolactone
- inhibitor
- irreversible