Crystal structures of human glyoxalase I and its complex with TLSC702 reveal inhibitor binding mode and substrate preference. Issue 11 (8th April 2022)

• Record Type: Journal Article
• Authors: Usami, Midori; Ando, Koki; Shibuya, Asuka; Takasawa, Ryoko; Yokoyama, Hideshi
• Is Part Of: FEBS letters. Volume 596:Issue 11(2022)
• Page Start: 1458
• Page End: 1467
• Publication Date: 2022-04-08
• Subjects: crystal packing -- crystal structure -- glycerol -- glyoxalase I -- methylglyoxal -- TLSC702; Biochemistry -- Periodicals; Biophysics -- Periodicals; Molecular biology -- Periodicals; Biochimie -- Périodiques; Biochemistry; Biophysics; Molecular biology; Periodicals; 572.05
• DOI: 10.1002/1873-3468.14344
• Languages: English
• ISSNs: 0014-5793

Abstract

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 Zn 2+, 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 Zn 2+, indicating that GLO I can easily bind to MG. This study provides a structural basis to develop better anticancer drugs. Abstract : Human glyoxalase I (hGLO I) is a zinc metalloenzyme for detoxification of methylglyoxal (MG), and it is an attractive target for the development of new anticancer drugs. Crystal structures of hGLO I provided insights into the binding mode of its inhibitor TLSC702 and showed that glycerol, which has similar functional groups to MG, can bind to zinc.