Crystal structures of human glyoxalase I and its complex with TLSC702 reveal inhibitor binding mode and substrate preference

Abstract

Human glyoxalase I (hGLO I) is an enzyme for detoxification of methylglyoxal (MG) and has been considered an attractive target for the development of new anticancer drugs. In our previous report, the GLO I inhibitor TLSC702 induced apoptosis in tumor cells. Here, we determined the crystal structures of hGLO I and its complex with TLSC702. In the complex, the carboxyl O atom of TLSC702 is coordinated to Zn2+, and TLSC702 mainly shows van der Waals interaction with hydrophobic residues. In the inhibitor‐unbound structure, glycerol, which has similar functional groups to MG, was bound to Zn2+, indicating that GLO I can easily bind to MG. This study provides a structural basis to develop better anticancer drugs.

Structural and mutational studies suggest key residues to determine whether stomatin SPFH domains form dimers or trimers

“…Forward and reverse primers used in the amplification procedure were 5′-ATCTTCGAA TCT GCCGTTATCGTAGATTTGAGAACTCA-3′ and 5′-AACGGC AGA TTCGAAGATCATATGTATATCTCCTTC-3′, respectively, containing a mutation site (underlined). Using the amplified fragment, the Seamless Ligation Cloning Extract (SLiCE) reaction [ 23 ] was performed at 37 °C for 20 min using a similar protocol to that described previously [ 24 ]. The SLiCE method is a seamless DNA cloning tool that utilizes homologous recombination activities in Escherichia coli lysates to assemble DNA fragments with approximately 15–19-bp homology lengths into a plasmid.…”

Exosomal MALAT1 promotes the proliferation of esophageal squamous cell carcinoma through glyoxalase 1-dependent methylglyoxal removal

“…Using mRNA array screening, we found that glyoxalase I (GLO1) may be the most possible downstream effector of MALAT1. As reported, GLO1 is a ubiquitous enzyme involved in the detoxification of methylglyoxal (MGO) produced during tumor aerobic glycolysis [ 9 ], Methylglyoxal is an extremely cytotoxic metabolite that spontaneously glycates proteins and DNA, irreversibly forming toxic compounds called advanced glycation end products (AGEs) [ 10 ]. Glycation of DNA contributes to antiproliferative and apoptotic effects, and activates the DNA injury repair pathway to arrest the cell cycle, thus impairing tumor growth.…”

Unraveling Potential Glyoxalase-I Inhibitors Utilizing Structure-Based Drug Design Techniques

“…Due to the obstacles related to metabolic instability of GSH-based inhibitors, and to the violations of drug-like properties, some researchers have created non-GSHbased Glo-I inhibitors. 23,24 Natural flavonoids and anthocyanidins were investigated by Takasawa et al, as potential Glo-I enzyme inhibitors. 25 In order to identify crucial structural elements of flavonoids to serve as Glo-I inhibitors, computational and experimental approaches were performed by Al-Balas et al, where the structure-activity relationship (SAR) of a panel of 24 compounds belong to the flavonoid class of natural products, was explored.…”