Mayville P, Ji G, Beavis R, Yang H, Goger M, Novick R P, Muir T W
Laboratory of Synthetic Protein Chemistry, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1218-23. doi: 10.1073/pnas.96.4.1218.
The synthesis of virulence factors and other extracellular proteins responsible for pathogenicity in Staphylococcus aureus is under the control of the agr locus. A secreted agr-encoded peptide, AgrD, processed from the AgrD gene product, is known to be an effector of self-strain activation and cross-strain inhibition of the agr response. Biochemical analysis of AgrD peptides isolated from culture supernatants has suggested that they contain an unusual thiol ester-linked cyclic structure. In the present work, chemical synthesis is used to confirm that the mature AgrD peptides contain a thiolactone structure and that this feature is absolutely necessary for full biological activity. The AgrD synthetic thiolactone peptides exhibited biological activity in vivo in a mouse protection test. Structure-activity studies have allowed key aspects of the peptide structure involved in the differential activation and inhibition functions to be identified. Accordingly, we propose a model for activation and inhibition of the agr response in which the former, but not the latter, involves specific acylation of the agr transmembrane receptor, AgrC.
金黄色葡萄球菌中负责致病性的毒力因子和其他细胞外蛋白的合成受agr基因座的控制。已知一种从AgrD基因产物加工而来的分泌型agr编码肽AgrD是agr反应的自我菌株激活和跨菌株抑制的效应物。对从培养上清液中分离出的AgrD肽进行的生化分析表明，它们含有一种不寻常的硫酯连接的环状结构。在本研究中，通过化学合成来确认成熟的AgrD肽含有硫内酯结构，并且该特征对于充分的生物学活性是绝对必要的。AgrD合成硫内酯肽在小鼠保护试验中在体内表现出生物学活性。结构-活性研究已能够鉴定出参与差异激活和抑制功能的肽结构的关键方面。因此，我们提出了一个agr反应激活和抑制的模型，其中前者（而非后者）涉及agr跨膜受体AgrC的特异性酰化。
