Groll Michael, Balskus Emily P, Jacobsen Eric N
Center for Integrated Protein Science at the Department Chemie, Lehrstuhl für Biochemie, Technische Universität München, Lichtenbergstrasse 4, D-85747 Garching, Germany.
J Am Chem Soc. 2008 Nov 12;130(45):14981-3. doi: 10.1021/ja806059t. Epub 2008 Oct 17.
Spiro beta-lactone-based proteasome inhibitors were discovered in the context of an asymmetric catalytic total synthesis of the natural product (+)-lactacystin (1). Lactone 4 was found to be a potent inhibitor of the 26S proteasome, while its C-6 epimer (5) displayed weak activity. Crystallographic studies of the two analogues covalently bound to the 20S proteasome permitted characterization of the important stabilizing interactions between each inhibitor and the proteasome's key catalytic N-terminal threonine residue. This structural data support the hypothesis that the discrepancy in potency between 4 and 5 may be due to differences in the hydrolytic stabilities of the resulting acyl enzyme complexes.
基于螺环β-内酯的蛋白酶体抑制剂是在天然产物(+)-乳胞素(1)的不对称催化全合成过程中发现的。发现内酯4是26S蛋白酶体的有效抑制剂，而其C-6差向异构体(5)活性较弱。对与20S蛋白酶体共价结合的两种类似物的晶体学研究，使得能够表征每种抑制剂与蛋白酶体关键催化N端苏氨酸残基之间重要的稳定相互作用。这一结构数据支持了这样的假设，即4和5之间效力的差异可能是由于所得酰基酶复合物水解稳定性的差异。
