A rationally designed aldolase foldamer.
A rationally designed aldolase foldamer.
复制标题
合理设计的醛缩酶折叠器。
DOI：
10.1002/anie.200804996
复制
发表时间：
2009
影响因子：
16.6
通讯作者：
Hilvert, Donald
中科院分区：
文献类型：
--
作者：
Mueller, Manuel M.;Windsor, Matthew A.;Pomerantz, William C.;Gellman, Samuel H.;Hilvert, Donald
目前创造类酶催化剂的策略包括从理性的[1]和计算设计[2]到大分子文库的进化搜索[3]序列特异性聚合物是这些努力的特别有吸引力的起点，因为它们能够采用三维结构来预先组织官能团进行催化。虽然天然酶是由α-氨基酸构成的，但许多其他主结构可以产生明确的二级和三级结构。这种非天然的低聚物，通常被称为“折叠物”，有可能显示出类似于蛋白质的特性。[4 - 8] β-肽在这种情况下很有趣，因为它们采用各种稳定的二级结构，包括螺旋、片和匝，[4,9]和四分之一的螺旋束组装已经产生。[10,11]它们可预测的结构已被用于抑制微生物生长，[12]破坏蛋白质-蛋白质相互作用，[13]和其他应用。[4,5]本研究表明，具有离散侧链官能团阵列的β-肽也可以作为有效的催化剂。作为一个模型反应，我们检测了β-羟基酮1的反醛醇裂解生成苯甲醛和丙酮酸。该反应受胺的催化作用（图1）。催化循环是由未质子化胺对底物羰基的亲核攻击引起的。由此产生的铝离子激活了CC键断裂的底物，这伴随着羟基的去质子化而释放苯甲醛。烯胺的重异构化和随后的水解产生丙酮酸并再生催化剂。天然I型醛缩酶[14]利用了这一机制，富含赖氨酸的两亲性α-螺旋肽、[15]催化抗体、[16]以及最近通过计算设计的酶也模拟了这一机制。[2a]
Current strategies for creating enzyme-like catalysts range from rational [1] and computational design [2] to evolutionary searches of large molecular libraries.[3] Sequence-specific polymers are particularly attractive starting points for these efforts because of their ability to adopt threedimensional structures that preorganize functional groups for catalysis. Although natural enzymes are constructed from α-amino acids, many other backbone structures can give rise to well-defined secondary and tertiary structures. Such non-natural oligomers, often referred to as “foldamers”, have the potential to display properties akin to those of proteins.[4–8] β-Peptides are interesting in this context because they adopt a variety of stable secondary structures, including helices, sheets and turns,[4, 9] and quarternary helix-bundle assemblies have been generated.[10, 11] Their predictable structures have been exploited to inhibit microbial growth,[12] disrupt protein-protein interactions,[13] and for other applications.[4, 5] Here we show that β-peptides presenting arrays of discrete side chain functional groups can also act as effective catalysts.As a model reaction, we examined the retro-aldol cleavage of β-hydroxyketone 1 to give benzaldehyde and pyruvate. This reaction is subject to amine catalysis (Figure 1). The catalytic cycle is initiated by nucleophilic attack of an unprotonated amine on the carbonyl group of the substrate. The resulting iminium ion activates the substrate for CC bond scission, which occurs with concomitant deprotonation of the hydroxyl group to release benzaldehyde. Tautomerization of the enamine and subsequent hydrolysis produces pyruvate and regenerates the catalyst. This mechanism is exploited by natural type I aldolases,[14] and has been mimicked by lysine-rich amphiphilic α-helical peptides,[15] catalytic antibodies,[16] and most recently by a computationally designed enzyme.[2a]
登录
查看更多内容
影响因子：
15
作者：
Lee BC;Chu TK;Dill KA;Zuckermann RN
通讯作者：
Zuckermann RN
影响因子：
56.9
作者：
Heine, A;DeSantis, G;Wilson, IA
通讯作者：
Wilson, IA
影响因子：
56.9
作者：
WAGNER, J;LERNER, RA;BARBAS, CF
通讯作者：
BARBAS, CF
影响因子：
15
作者：
Cheng, RP;DeGrado, WF
通讯作者：
DeGrado, WF
影响因子：
15
作者：
Daugherty, DL;Gellman, SH
通讯作者：
Gellman, SH