Mitochondrial phosphoglycerate mutase 5 uses alternate catalytic activity as a protein serine/threonine phosphatase to activate ASK1
Kohsuke TakedaYoshiko KomuroTeruyuki HayakawaHaruka OguchiYosuke IshidaShiori MurakamiTakuya NoguchiHideyuki KinoshitaYusuke SekineShun-ichiro IemuraTohru NatsumeHidenori Ichijo
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Abstract:
Phosphoglycerate mutase (PGAM) is an enzyme of intermediary metabolism that converts 3-phosphoglycerate to 2-phosphoglycerate in glycolysis. Here, we discovered PGAM5 that is anchored in the mitochondrial membrane lacks PGAM activity and instead associates with the MAP kinase kinase kinase ASK1 and acts as a specific protein Ser/Thr phosphatase that activates ASK1 by dephosphorylation of inhibitory sites. Mutation of an active site His-105 in PGAM5 abolished phosphatase activity with ASK1 and phospho-Thr peptides as substrates. The Drosophila and Caenorhabditis elegans orthologs of PGAM5 also exhibit specific Ser/Thr phosphatase activity and activate the corresponding Drosophila and C. elegans ASK1 kinases. PGAM5 is unrelated to the other known Ser/Thr phosphatases of the PPP, MPP, and FCP families, and our results suggest that this member of the PGAM family has crossed over from small molecules to protein substrates and been adapted to serve as a specialized activator of ASK1.Keywords:
Phosphoglycerate mutase
Phosphoglycerate kinase
ASK1
Yeast strains carrying recessive mutations representing four different loci that cause defects in pyruvate kinase, pyruvate decarboxylase, 3-phosphoglycerate kinase, and 3-phosphoglycerate mutase were isolated and partially characterized. Cells carrying these mutations were unable to use glucose as a carbon source as measured in turbidimetric growth experiments. Tetrad analysis indicated that these mutations were not linked to each other; one of the mutations, that affecting phosphoglycerate kinase, was located on chromosome III.
Phosphoglycerate kinase
Phosphoglycerate mutase
Pyruvate decarboxylase
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Phosphoglycerate mutases (PGAMs) participate in both the glycolytic and the gluconeogenic pathways in reversible isomerization of 3‐phosphoglycerate and 2‐phosphoglycerate. PGAMs are members of two distinct protein families: enzymes that are dependent on or independent of the 2,3‐bisphosphoglycerate cofactor. We determined the X‐ray structure of the monomeric Trypanosoma brucei independent PGAM ( Tb iPGAM) in its apoenzyme form, and confirmed this observation by small angle X‐ray scattering data. Comparing the Tb iPGAM structure with the Leishmania mexicana independent PGAM structure, previously reported with a phosphoglycerate molecule bound to the active site, revealed the domain movement resulting from active site occupation. The structure reported here shows the interaction between Asp319 and the metal bound to the active site, and its contribution to the domain movement. Substitution of the metal‐binding residue Asp319 by Ala resulted in complete loss of independent PGAM activity, and showed for the first time its involvement in the enzyme’s function. As Tb iPGAM is an attractive molecular target for drug development, the apoenzyme conformation described here provides opportunities for its use in structure‐based drug design approaches. Database Structural data for the Trypanosoma brucei 2,3‐bisphosphoglycerate‐independent phosphoglycerate mutase (iPGAM) has been deposited with the Research Collaboratory for Structural Bioinformatics (RCSB) Protein Data Bank under code 3NVL . Structured digital abstract TbiPGAM and TbiPGAM bind by x‐raycrystallography ( View interaction )
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Phosphoglycerate kinase
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2-Phosphotartronate has been synthesized by permanganate oxidation of glycerol 2-phosphate and has been tested as an inhibitor of five glycolytic enzymes that bind phosphoglycerate or phosphoglycollate. Competitive inhibition of rabbit muscle phosphoglycerate mutase, enolase and pyruvate kinase was observed. Triose phosphate isomerase and 3-phosphoglycerate kinase were not inhibited.
Phosphoglycerate mutase
Phosphoglycerate kinase
Triosephosphate isomerase
DHAP
Dihydroxyacetone phosphate
Phosphotransferases
Glycerol kinase
Enolase
Glucose-6-phosphate isomerase
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Phosphoglycerate kinase
Phosphoglycerate mutase
Red Cell
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Phosphoglycerate kinase
Phosphoglycerate mutase
Phosphofructokinase 2
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The glycolytic enzyme phosphoglycerate mutase exists in two evolutionarily unrelated forms. Vertebrates have only the 2,3‐bisphosphoglycerate‐dependent enzyme (dPGM), whilst higher plants have only the cofactor‐independent enzyme (iPGM). Certain eubacteria possess genes encoding both enzymes, and their respective metabolic roles and activities are unclear. We have over‐expressed, purified and characterised the two PGMs of Escherichia coli . Both are expressed at high levels, but dPGM has a 10‐fold higher specific activity than iPGM. Differential inhibition by vanadate was observed. The presence of an integral manganese ion in iPGM was confirmed by EPR spectroscopy.
Phosphoglycerate mutase
Phosphoglycerate kinase
Vanadate
Mutase
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Phosphoglycerate kinase
Phosphoglycerate mutase
Glucose-6-phosphate isomerase
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The phosphonomethyl analogue of 3-phosphoglycerate (2-hydroxy-4-phosphonobutanoate) is a potent competitive inhibitor of cofactor-dependent phosphoglycerate mutase from yeast and of cofactor-independent phosphoglycerate mutase from wheat germ. For the yeast enzyme Ki is 1.3 mM (Km for substrate is 0.71 mM); for the wheatgerm enzyme Ki is 18 mM (Km for substrate is 0.86 mM). This analogue should be a useful tool for n.m.r. spectroscopic studies on the mechanism of action of the two mutases. The arsonomethyl analogue of 3-phosphoglycerate (4-arsono-2-hydroxybutanoate) was a relatively poor inhibitor.
Phosphoglycerate mutase
Phosphoglycerate kinase
Phosphofructokinase 2
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Phosphoglycerate kinase
Phosphoglycerate mutase
Phosphotransferases
Phosphoglucomutase
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Phosphoglycerate mutase
Phosphoglycerate kinase
Mechanism of Action
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