3-氧代-β-磺内酰胺对弹性蛋白酶抑制作用中的酰化与磺酰化

Acylation versus sulfonylation in the inhibition of elastase by 3-oxo-beta-sultams.

作者信息

Tsang Wing Y, Ahmed Naveed, Harding Lindsay P, Hemming Karl, Laws Andrew P, Page Michael I

机构信息

Department of Chemical and Biological Sciences, The University of Huddersfield, Huddersfield, HD1 3DH, UK.

出版信息

J Am Chem Soc. 2005 Jun 29;127(25):8946-7. doi: 10.1021/ja050787z.

DOI:10.1021/ja050787z

PMID:15969560

Abstract

beta-Sultams are the sulfonyl analogues of beta-lactams, and 3-oxo-beta-sultams are both beta-lactams and beta-sultams and, therefore, susceptible to nucleophilic attack at either the acyl or the sulfonyl center. They are novel inactivators of serine enzymes. The second-order rate constant for the inactivation of elastase at pH 6 by N-benzyl-4,4-dimethyl-3-oxo-beta-sultam is 768 M-1 s-1, which is 103-fold greater than that with N-benzoyl beta-sultam. However, in contrast to N-acyl beta-sultams, which sulfonylate the active site serine residue to form a sulfonate ester, 3-oxo-beta-sultams inhibit the enzyme by acylation followed by slow deacylation to regenerate the active enzyme.

摘要

β-磺内酰胺是β-内酰胺的磺酰类似物，3-氧代-β-磺内酰胺既是β-内酰胺又是β-磺内酰胺，因此，在酰基或磺酰中心都易受到亲核攻击。它们是丝氨酸酶的新型失活剂。N-苄基-4,4-二甲基-3-氧代-β-磺内酰胺在pH 6时使弹性蛋白酶失活的二级速率常数为768 M-1 s-1，比N-苯甲酰基β-磺内酰胺的二级速率常数大103倍。然而，与将活性位点丝氨酸残基磺酰化以形成磺酸酯的N-酰基β-磺内酰胺不同，3-氧代-β-磺内酰胺通过酰化作用抑制酶，随后缓慢脱酰化以再生活性酶。