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PMID:19015259

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Citation

Li, H and Jogl, G (2009) Structural and biochemical studies of TIGAR (TP53-induced glycolysis and apoptosis regulator). J. Biol. Chem. 284:1748-54

Abstract

Activation of the p53 tumor suppressor by cellular stress leads to variable responses ranging from growth inhibition to apoptosis. TIGAR is a novel p53-inducible gene that inhibits glycolysis by reducing cellular levels of fructose-2,6-bisphosphate, an activator of glycolysis and inhibitor of gluconeogenesis. Here we describe structural and biochemical studies of TIGAR from Danio rerio. The overall structure forms a histidine phosphatase fold with a phosphate molecule coordinated to the catalytic histidine residue and a second phosphate molecule in a position not observed in other phosphatases. The recombinant human and zebra fish enzymes hydrolyze fructose-2,6-bisphosphate as well as fructose-1,6-bisphosphate but not fructose 6-phosphate in vitro. The TIGAR active site is open and positively charged, consistent with its enzymatic function as bisphosphatase. The closest related structures are the bacterial broad specificity phosphatase PhoE and the fructose-2,6-bisphosphatase domain of the bifunctional 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. The structural comparison shows that TIGAR combines an accessible active site as observed in PhoE with a charged substrate-binding pocket as seen in the fructose-2,6-bisphosphatase domain of the bifunctional enzyme.

Links

PubMed PMC2615519 Online version:10.1074/jbc.M807821200

Keywords

Animals; Apoptosis Regulatory Proteins/chemistry; Apoptosis Regulatory Proteins/genetics; Apoptosis Regulatory Proteins/metabolism; Catalytic Domain/physiology; Escherichia coli Proteins/chemistry; Escherichia coli Proteins/genetics; Escherichia coli Proteins/metabolism; Fructosediphosphates/chemistry; Fructosediphosphates/metabolism; Hydrolysis; Intracellular Signaling Peptides and Proteins/chemistry; Intracellular Signaling Peptides and Proteins/genetics; Intracellular Signaling Peptides and Proteins/metabolism; Phosphofructokinase-2/chemistry; Phosphofructokinase-2/genetics; Phosphofructokinase-2/metabolism; Porins/chemistry; Porins/genetics; Porins/metabolism; Protein Folding; Protein Structure, Tertiary/physiology; Recombinant Proteins/chemistry; Recombinant Proteins/genetics; Recombinant Proteins/metabolism; Structural Homology, Protein; Substrate Specificity/physiology; Zebrafish/genetics; Zebrafish/metabolism; Zebrafish Proteins/chemistry; Zebrafish Proteins/genetics; Zebrafish Proteins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

SCHPO:YFFL

involved_in

GO:0045820: negative regulation of glycolytic process

ECO:0000305: curator inference used in manual assertion

GO:0004331

P

Seeded From UniProt

complete

SCHPO:YFFL

involved_in

GO:1905857: positive regulation of pentose-phosphate shunt

ECO:0000305: curator inference used in manual assertion

GO:0004331

P

Seeded From UniProt

complete

DANRE:TIGRB

enables

GO:0004083: bisphosphoglycerate 2-phosphatase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

DANRE:TIGRB

enables

GO:0004331: fructose-2,6-bisphosphate 2-phosphatase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

DANRE:TIGRB

involved_in

GO:0030388: fructose 1,6-bisphosphate metabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

DANRE:TIGRB

involved_in

GO:0006003: fructose 2,6-bisphosphate metabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

DANRE:TIGRB

enables

GO:0003824: catalytic activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:TIGAR

enables

GO:0004083: bisphosphoglycerate 2-phosphatase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:TIGAR

enables

GO:0004331: fructose-2,6-bisphosphate 2-phosphatase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:TIGAR

involved_in

GO:0030388: fructose 1,6-bisphosphate metabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TIGAR

involved_in

GO:0006003: fructose 2,6-bisphosphate metabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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