7po7

From Proteopedia

Phosphoglycolate phosphatase from Mus musculus

Structural highlights

7po7 is a 8 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.31Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PGP_MOUSE Glycerol-3-phosphate phosphatase hydrolyzing glycerol-3-phosphate into glycerol. Thereby, regulates the cellular levels of glycerol-3-phosphate a metabolic intermediate of glucose, lipid and energy metabolism (PubMed:26755581). Was also shown to have a 2-phosphoglycolate phosphatase activity and a tyrosine-protein phosphatase activity. However, their physiological relevance is unclear (PubMed:24338473, PubMed:26755581). In vitro, has also a phosphatase activity toward ADP, ATP, GDP and GTP (PubMed:24338473).^[1] ^[2]

Publication Abstract from PubMed

Targeting the intrinsic metabolism of immune or tumor cells is a therapeutic strategy in autoimmunity, chronic inflammation or cancer. Metabolite repair enzymes may represent an alternative target class for selective metabolic inhibition, but pharmacological tools to test this concept are needed. Here, we demonstrate that phosphoglycolate phosphatase (PGP), a prototypical metabolite repair enzyme in glycolysis, is a pharmacologically actionable target. Using a combination of small molecule screening, protein crystallography, molecular dynamics simulations and NMR metabolomics, we discover and analyze a compound (CP1) that inhibits PGP with high selectivity and submicromolar potency. CP1 locks the phosphatase in a catalytically inactive conformation, dampens glycolytic flux, and phenocopies effects of cellular PGP-deficiency. This study provides key insights into effective and precise PGP targeting, at the same time validating an allosteric approach to control glycolysis that could advance discoveries of innovative therapeutic candidates.

Glycolytic flux control by drugging phosphoglycolate phosphatase.,Jeanclos E, Schlotzer J, Hadamek K, Yuan-Chen N, Alwahsh M, Hollmann R, Fratz S, Yesilyurt-Gerhards D, Frankenbach T, Engelmann D, Keller A, Kaestner A, Schmitz W, Neuenschwander M, Hergenroder R, Sotriffer C, von Kries JP, Schindelin H, Gohla A Nat Commun. 2022 Nov 11;13(1):6845. doi: 10.1038/s41467-022-34228-2. PMID:36369173^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Seifried A, Knobloch G, Duraphe PS, Segerer G, Manhard J, Schindelin H, Schultz J, Gohla A. Evolutionary and Structural Analyses of the Mammalian Haloacid Dehalogenase-Type Phosphatases AUM and Chronophin Provide Insight into the Basis of their Different Substrate Specificities. J Biol Chem. 2013 Dec 13. PMID:24338473 doi:http://dx.doi.org/10.1074/jbc.M113.503359
↑ Mugabo Y, Zhao S, Seifried A, Gezzar S, Al-Mass A, Zhang D, Lamontagne J, Attane C, Poursharifi P, Iglesias J, Joly E, Peyot ML, Gohla A, Madiraju SR, Prentki M. Identification of a mammalian glycerol-3-phosphate phosphatase: Role in metabolism and signaling in pancreatic beta-cells and hepatocytes. Proc Natl Acad Sci U S A. 2016 Jan 26;113(4):E430-9. doi: , 10.1073/pnas.1514375113. Epub 2016 Jan 11. PMID:26755581 doi:http://dx.doi.org/10.1073/pnas.1514375113
↑ Jeanclos E, Schlötzer J, Hadamek K, Yuan-Chen N, Alwahsh M, Hollmann R, Fratz S, Yesilyurt-Gerhards D, Frankenbach T, Engelmann D, Keller A, Kaestner A, Schmitz W, Neuenschwander M, Hergenröder R, Sotriffer C, von Kries JP, Schindelin H, Gohla A. Glycolytic flux control by drugging phosphoglycolate phosphatase. Nat Commun. 2022 Nov 11;13(1):6845. PMID:36369173 doi:10.1038/s41467-022-34228-2