Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo náměstí 2, 16610 Praha 6, Czech Republic.
Inorg Chem. 2021 Dec 20;60(24):18620-18624. doi: 10.1021/acs.inorgchem.1c03030. Epub 2021 Dec 3.
The natural tripeptide glutathione (GSH) is a ubiquitous compound harboring various biological tasks, among them interacting with essential and toxic metal ions. Yet, although weakly binding the poisonous metal lead (Pb), GSH poorly detoxifies it. β-Mercaptoaspartic acid is a new-to-nature novel amino acid that was found to enhance the Pb-detoxification capability of a synthetic cyclic tetrapeptide. Aiming to explore the advantages of noncanonical amino acids (ncAAs) of this nature, we studied the detoxification capabilities of GSH and three analogue peptides, each of which contains at least one ncAA that harbors both free carboxylate and thiolate groups. A thorough investigation that includes detoxification and mechanistic evaluations, metal-binding affinity, metal selectivity, and computational studies shows that these ncAAs are highly beneficial in additively enhancing Pb binding and reveals the importance of both high affinity and metal selectivity in synergistically reducing Pb toxicity in cells. Hence, such ncAAs join the chemical toolbox against Pb poisoning and pollution, enabling peptides to strongly and selectively bind the toxic metal ion.
天然三肽谷胱甘肽 (GSH) 是一种普遍存在的化合物，具有多种生物学功能，包括与必需和有毒金属离子相互作用。然而，尽管 GSH 与有毒的金属铅 (Pb) 结合较弱，但它对其解毒能力很差。β-巯基天冬氨酸是一种新发现的天然氨基酸，它被发现可以增强合成环状四肽的 Pb 解毒能力。为了探索这种非典型氨基酸 (ncAA) 的优势，我们研究了 GSH 及其三种类似肽的解毒能力，每种类似肽都至少含有一个同时含有游离羧酸盐和硫醇盐基团的 ncAA。包括解毒和机制评估、金属结合亲和力、金属选择性和计算研究在内的全面研究表明，这些 ncAA 在附加增强 Pb 结合方面非常有益，并揭示了高亲和力和金属选择性在协同降低细胞中 Pb 毒性方面的重要性。因此，这些 ncAA 加入了针对 Pb 中毒和污染的化学工具箱，使肽能够强烈且选择性地结合有毒金属离子。
