RRC ID 43437
Author Kawatani M, Okumura H, Honda K, Kanoh N, Muroi M, Dohmae N, Takami M, Kitagawa M, Futamura Y, Imoto M, Osada H.
Title The identification of an osteoclastogenesis inhibitor through the inhibition of glyoxalase I.
Journal Proc Natl Acad Sci U S A
Abstract Osteoclasts, bone-resorptive multinucleated cells derived from hematopoietic stem cells, are associated with many bone-related diseases, such as osteoporosis. Osteoclast-targeting small-molecule inhibitors are valuable tools for studying osteoclast biology and for developing antiresorptive agents. Here, we have discovered that methyl-gerfelin (M-GFN), the methyl ester of the natural product gerfelin, suppresses osteoclastogenesis. By using M-GFN-immobilized beads, glyoxalase I (GLO1) was identified as an M-GFN-binding protein. GLO1 knockdown and treatment with an established GLO1 inhibitor in osteoclast progenitor cells interfered with osteoclast generation, suggesting that GLO1 activity is required for osteoclastogenesis. In cells, GLO1 plays a critical role in the detoxification of 2-oxoaldehydes, such as methylglyoxal. M-GFN inhibited the enzymatic activity of GLO1 in vitro and in situ. Furthermore, the cocrystal structure of the GLO1/M-GFN complex revealed the binding mode of M-GFN at the active site of GLO1. These results suggest that M-GFN targets GLO1, resulting in the inhibition of osteoclastogenesis.
Volume 105(33)
Pages 11691-6
Published 2008-8-19
DOI 10.1073/pnas.0712239105
PII 0712239105
PMID 18695250
PMC PMC2575282
MeSH Alcohol Oxidoreductases / metabolism Animals Biphenyl Compounds / chemistry Biphenyl Compounds / pharmacology* Cells, Cultured Crystallography, X-Ray Enzyme Inhibitors / pharmacology* Ethers / chemistry Ethers / pharmacology* Lactoylglutathione Lyase / antagonists & inhibitors* Lactoylglutathione Lyase / chemistry Lactoylglutathione Lyase / metabolism* Macrophages / cytology Macrophages / drug effects Macrophages / enzymology Male Methylation Mice Models, Molecular Molecular Structure Osteoclasts / cytology* Osteoclasts / drug effects Osteoclasts / enzymology* Osteogenesis / drug effects* Phagocytosis / drug effects Protein Binding
IF 9.412
Times Cited 92
WOS Category BIOCHEMISTRY & MOLECULAR BIOLOGY
Resource
Human and Animal Cells RAW 264(RCB0535)