Mechanism for the inhibition of transglutaminase 2 by cystamine. Academic Article uri icon

Overview

abstract

  • Cystamine is neuroprotective in a number of models of neurodegeneration. The therapeutic benefit of cystamine has been attributed, in part, to its inhibition of transglutaminase activity. Cystamine [beta-mercaptoethanolamine (MEA) disulfide] is reduced within cells to MEA which is largely responsible for the in vivo effects of its disulfide precursor. In the current study, the amine group of MEA was shown to act as a transglutaminase (TG) substrate resulting in the formation of N(beta)-(gamma-l-glutamyl)-MEA bonds. The formation of such bonds would compete with the generation of other TG-catalyzed reactions that may contribute to neurodegeneration such as polyamination, protein cross-linking, deamination and the covalent attachment of ceramide to proteins. The demonstration that cystamine-derived MEA can form N(beta)-(gamma-l-glutamyl)-MEA bonds offers a unique tool for identifying the TG substrates that occur in diseased brains in vivo. Structure-function studies also indicated that the mercapto group of MEA significantly influences the substrate behavior of this compound. These structure-function studies also identified the following hierarchy of physico-chemical characteristics: hydrophobicity > S as the group VIII atom > distance separating the N and group VIII atom, as the major determinants contributing to the substrate behavior for low-molecular weight amine substrates of TG 2.

publication date

  • March 15, 2005

Research

keywords

  • Cystamine
  • GTP-Binding Proteins
  • Transglutaminases

Identity

Scopus Document Identifier

  • 14644415488

Digital Object Identifier (DOI)

  • 10.1016/j.bcp.2004.12.011

PubMed ID

  • 15748707

Additional Document Info

volume

  • 69

issue

  • 6