8fbz | pdb_00008fbz
Crystal Structure of apo human Glutathione Synthetase Y270E
Structural highlights
DiseaseGSHB_HUMAN Defects in GSS are the cause of glutathione synthetase deficiency (GSS deficiency) [MIM:266130; also known as 5-oxoprolinuria or pyroglutamic aciduria. It is a severe form characterized by an increased rate of hemolysis and defective function of the central nervous system. Defects in GSS are the cause of glutathione synthetase deficiency of erythrocytes (GLUSYNDE)[MIM:231900. Glutathione synthetase deficiency of erythrocytes is a mild form causing hemolytic anemia. FunctionPublication Abstract from PubMedProtein tyrosine phosphatases (PTPs) play major roles in cancer and are emerging as therapeutic targets. Recent reports suggest low-molecular weight PTP (LMPTP)-encoded by the ACP1 gene-is overexpressed in prostate tumors. We found ACP1 up-regulated in human prostate tumors and ACP1 expression inversely correlated with overall survival. Using CRISPR-Cas9-generated LMPTP knockout C4-2B and MyC-CaP cells, we identified LMPTP as a critical promoter of prostate cancer (PCa) growth and bone metastasis. Through metabolomics, we found that LMPTP promotes PCa cell glutathione synthesis by dephosphorylating glutathione synthetase on inhibitory Tyr(270). PCa cells lacking LMPTP showed reduced glutathione, enhanced activation of eukaryotic initiation factor 2-mediated stress response, and enhanced reactive oxygen species after exposure to taxane drugs. LMPTP inhibition slowed primary and bone metastatic prostate tumor growth in mice. These findings reveal a role for LMPTP as a critical promoter of PCa growth and metastasis and validate LMPTP inhibition as a therapeutic strategy for treating PCa through sensitization to oxidative stress. Targeting prostate tumor low-molecular weight tyrosine phosphatase for oxidation-sensitizing therapy.,Stanford SM, Nguyen TP, Chang J, Zhao Z, Hackman GL, Santelli E, Sanders CM, Katiki M, Dondossola E, Brauer BL, Diaz MA, Zhan Y, Ramsey SH, Watson PA, Sankaran B, Paindelli C, Parietti V, Mikos AG, Lodi A, Bagrodia A, Elliott A, McKay RR, Murali R, Tiziani S, Kettenbach AN, Bottini N Sci Adv. 2024 Feb 2;10(5):eadg7887. doi: 10.1126/sciadv.adg7887. Epub 2024 Jan , 31. PMID:38295166[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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