Sawazaki Taka, Murai Fuma, Yamamoto Kai, Sasaki Daisuke, Sohma Youhei
Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Wakayama Medical University, Wakayama, Japan.
Nat Commun. 2025 Apr 2;16(1):3164. doi: 10.1038/s41467-025-58536-5.
Enzyme catalysis is essential for molecular transformations. Here, we make use of amyloid, a fibrillar aggregate formed by stacking peptides with β-sheet, which offers unique selectivity in enzymatic reactions. Azo-stilbene derivative (ASB), the amyloid-recognition motif, is incorporated into the substrate, which allows the amyloid consisting of Bz-Phe-Phe-Ala-Ala-Leu-Leu-NH (BL7) to shield the substrates from the approaching enzyme. X-ray crystallographic analysis and structure-shielding effect relationship studies of BL7 reveal that the benzene rings present in the N-terminal benzoyl group and Phe1 side chain are particularly important for the shielding effect on the substrate. The finding results in a selective transformation system in which the reactive site close to ASB is protected by amyloid, while a site far from ASB is converted by the enzymes (trypsin, protein arginine deiminase [PAD], and Staphylococcus aureus V-8 Protease [Glu-C]). Further, the amyloid-shielded enzyme catalysis is compatible with an intact peptide, as the side chain of Tyr can be converted to the amyloid-recognizing motif. The enzymatic reactions combining amyloid provide unique selectivity for molecular transformation which may be used in diverse fields, including in synthetic chemistry.
酶催化对于分子转化至关重要。在此，我们利用淀粉样蛋白，一种由β-折叠肽堆叠形成的纤维状聚集体，其在酶促反应中具有独特的选择性。将淀粉样蛋白识别基序偶氮-二苯乙烯衍生物（ASB）引入底物中，这使得由Bz-Phe-Phe-Ala-Ala-Leu-Leu-NH（BL7）组成的淀粉样蛋白能够保护底物免受接近的酶的作用。BL7的X射线晶体学分析和结构屏蔽效应关系研究表明，N端苯甲酰基和Phe1侧链中存在的苯环对底物的屏蔽效应尤为重要。这一发现产生了一种选择性转化系统，其中靠近ASB的反应位点被淀粉样蛋白保护，而远离ASB的位点则被酶（胰蛋白酶、蛋白质精氨酸脱亚氨酶[PAD]和金黄色葡萄球菌V-8蛋白酶[Glu-C]）转化。此外，淀粉样蛋白屏蔽的酶催化与完整肽兼容，因为酪氨酸的侧链可以转化为淀粉样蛋白识别基序。结合淀粉样蛋白的酶促反应为分子转化提供了独特的选择性，可用于包括合成化学在内的各种领域。
