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Thiolation and Carboxylation of Glutathione Synergistically Enhance Its Lead-Detoxification Capabilities


Sauser, Luca; Mohammed, Tagwa A; Kalvoda, Tadeáš; Feng, Sheng-Jan; Spingler, Bernhard; Rulíšek, Lubomír; Shoshan, Michal S (2021). Thiolation and Carboxylation of Glutathione Synergistically Enhance Its Lead-Detoxification Capabilities. Inorganic Chemistry, 60(24):18620-18624.

Abstract

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 in vitro 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.

Abstract

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 in vitro 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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Scopus Subject Areas:Physical Sciences > Physical and Theoretical Chemistry
Physical Sciences > Inorganic Chemistry
Uncontrolled Keywords:Inorganic Chemistry, Physical and Theoretical Chemistry
Language:English
Date:20 December 2021
Deposited On:08 Feb 2022 15:15
Last Modified:26 Feb 2024 02:47
Publisher:American Chemical Society (ACS)
ISSN:0020-1669
OA Status:Green
Publisher DOI:https://doi.org/10.1021/acs.inorgchem.1c03030
Project Information:
  • : FunderSNSF
  • : Grant IDPZ00P2_179818
  • : Project TitleSelective Heavy Metal Detoxification by Short Peptides: A New Approach for Chelation Therapy
  • : FunderUZH Forschungskredit
  • : Grant IDFK-20-100
  • : Project Title
  • : FunderUZH Forschungskredit
  • : Grant IDFK-20-123
  • : Project Title
  • Content: Accepted Version