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  - Jeanclos, Elisabeth
A1  - Knobloch, Gunnar
A1  - Hoffmann, Axel
A1  - Fedorchenko, Oleg
A1  - Odersky, Andrea
A1  - Lamprecht, Anna‐Karina
A1  - Schindelin, Hermann
A1  - Gohla, Antje
T1  - Ca\(^{2+}\) functions as a molecular switch that controls the mutually exclusive complex formation of pyridoxal phosphatase with CIB1 or calmodulin
JF  - FEBS Letters
N2  - Pyridoxal 5′‐phosphate (PLP) is an essential cofactor for neurotransmitter metabolism. Pyridoxal phosphatase (PDXP) deficiency in mice increases PLP and γ‐aminobutyric acid levels in the brain, yet how PDXP is regulated is unclear. Here, we identify the Ca\(^{2+}\)‐ and integrin‐binding protein 1 (CIB1) as a PDXP interactor by yeast two‐hybrid screening and find a calmodulin (CaM)‐binding motif that overlaps with the PDXP‐CIB1 interaction site. Pulldown and crosslinking assays with purified proteins demonstrate that PDXP directly binds to CIB1 or CaM. CIB1 or CaM does not alter PDXP phosphatase activity. However, elevated Ca\(^{2+}\) concentrations promote CaM binding and, thereby, diminish CIB1 binding to PDXP, as both interactors bind in a mutually exclusive way. Hence, the PDXP‐CIB1 complex may functionally differ from the PDXP‐Ca\(^{2+}\)‐CaM complex.
KW  - calmodulin
KW  - chronophin
KW  - CIB1
KW  - haloacid dehalogenase
KW  - pyridoxal phosphatase
KW  - vitamin B6
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-217963
VL  - 594
IS  - 13
SP  - 2099
EP  - 2115
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  -