TY  - JOUR
A1  - Jeanclos, Elisabeth
A1  - Schlötzer, Jan
A1  - Hadamek, Kerstin
A1  - Yuan-Chen, Natalia
A1  - Alwahsh, Mohammad
A1  - Hollmann, Robert
A1  - Fratz, Stefanie
A1  - Yesilyurt-Gerhards, Dilan
A1  - Frankenbach, Tina
A1  - Engelmann, Daria
A1  - Keller, Angelika
A1  - Kaestner, Alexandra
A1  - Schmitz, Werner
A1  - Neuenschwander, Martin
A1  - Hergenröder, Roland
A1  - Sotriffer, Christoph
A1  - von Kries, Jens Peter
A1  - Schindelin, Hermann
A1  - Gohla, Antje
T1  - Glycolytic flux control by drugging phosphoglycolate phosphatase
JF  - Nature Communications
N2  - 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.
KW  - phosphoglycolate phosphatase
KW  - glycolytic flux control
KW  - intrinsic metabolism
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300928
VL  - 13
IS  - 1
ER  - 
TY  - JOUR
A1  - Segerer, Gabriela
A1  - Hadamek, Kerstin
A1  - Zundler, Matthias
A1  - Fekete, Agnes
A1  - Seifried, Annegrit
A1  - Mueller, Martin J.
A1  - Koentgen, Frank
A1  - Gessler, Manfred
A1  - Jeanclos, Elisabeth
A1  - Gohla, Antje
T1  - An essential developmental function for murine phosphoglycolate phosphatase in safeguarding cell proliferation
JF  - Scientific Reports
N2  - Mammalian phosphoglycolate phosphatase (PGP) is thought to target phosphoglycolate, a 2-deoxyribose fragment derived from the repair of oxidative DNA lesions. However, the physiological role of this activity and the biological function of the DNA damage product phosphoglycolate is unknown. We now show that knockin replacement of murine Pgp with its phosphatase-inactive Pgp\(^{D34N}\) mutant is embryonically lethal due to intrauterine growth arrest and developmental delay in midgestation. PGP inactivation attenuated triosephosphate isomerase activity, increased triglyceride levels at the expense of the cellular phosphatidylcholine content, and inhibited cell proliferation. These effects were prevented under hypoxic conditions or by blocking phosphoglycolate release from damaged DNA. Thus, PGP is essential to sustain cell proliferation in the presence of oxygen. Collectively, our findings reveal a previously unknown mechanism coupling a DNA damage repair product to the control of intermediary metabolism and cell proliferation.
KW  - cell proliferation
KW  - DNA metabolism
KW  - lipidomics
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-181094
VL  - 6
ER  - 
TY  - INPR
A1  - Brenner, Marian
A1  - Zink, Christoph
A1  - Witzinger, Linda
A1  - Keller, Angelika
A1  - Hadamek, Kerstin
A1  - Bothe, Sebastian
A1  - Neuenschwander, Martin
A1  - Villmann, Carmen
A1  - von Kries, Jens Peter
A1  - Schindelin, Hermann
A1  - Jeanclos, Elisabeth
A1  - Gohla, Antje
T1  - 7,8-Dihydroxyflavone is a direct inhibitor of pyridoxal phosphatase
T2  - eLife
N2  - Vitamin B6 deficiency has been linked to cognitive impairment in human brain disorders for decades. Still, the molecular mechanisms linking vitamin B6 to these pathologies remain poorly understood, and whether vitamin B6 supplementation improves cognition is unclear as well. Pyridoxal phosphatase (PDXP), an enzyme that controls levels of pyridoxal 5’-phosphate (PLP), the co-enzymatically active form of vitamin B6, may represent an alternative therapeutic entry point into vitamin B6-associated pathologies. However, pharmacological PDXP inhibitors to test this concept are lacking. We now identify a PDXP and age-dependent decline of PLP levels in the murine hippocampus that provides a rationale for the development of PDXP inhibitors. Using a combination of small molecule screening, protein crystallography and biolayer interferometry, we discover and analyze 7,8-dihydroxyflavone (7,8-DHF) as a direct and potent PDXP inhibitor. 7,8-DHF binds and reversibly inhibits PDXP with low micromolar affinity and sub-micromolar potency. In mouse hippocampal neurons, 7,8-DHF increases PLP in a PDXP-dependent manner. These findings validate PDXP as a druggable target. Of note, 7,8-DHF is a well-studied molecule in brain disorder models, although its mechanism of action is actively debated. Our discovery of 7,8-DHF as a PDXP inhibitor offers novel mechanistic insights into the controversy surrounding 7,8-DHF-mediated effects in the brain.
KW  - 7,8-dihydroxyflavone (7,8-DHF)
KW  - pyridoxal phosphatase (PDXP)
KW  - vitamin B6
KW  - PDXP inhibitors
Y1  - 2024
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-350446
ER  -