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Structural and biochemical studies of TIGAR (TP53-induced glycolysis and apoptosis regulator)

Hua Li1, Gerwald Jogl

  • 1Department of Molecular Biology, Cellular Biology and Biochemistry, Brown University, Providence, Rhode Island 02912, USA.

The Journal of Biological Chemistry
|November 19, 2008
PubMed

Insights

TIGAR, a p53-inducible gene, inhibits glycolysis by degrading fructose-2,6-bisphosphate. Structural and biochemical studies reveal its unique histidine phosphatase fold and bisphosphatase activity, offering insights into cellular metabolism regulation.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • The p53 tumor suppressor regulates cellular responses to stress, influencing growth inhibition and apoptosis.
  • TIGAR (TP53-induced glycolysis regulator) is a p53-inducible gene that modulates cellular metabolism.
  • TIGAR functions by reducing fructose-2,6-bisphosphate, a key regulator of glycolysis and gluconeogenesis.

Purpose of the Study:

  • To elucidate the structural and biochemical properties of TIGAR from Danio rerio (zebrafish).
  • To understand the enzymatic mechanism and substrate specificity of TIGAR.
  • To compare TIGAR's structure to related phosphatases for functional insights.

Main Methods:

  • X-ray crystallography for structural determination of TIGAR.
  • Biochemical assays to assess enzymatic activity and substrate hydrolysis.
  • Bioinformatic analysis and structural comparisons with homologous proteins.

Main Results:

  • TIGAR exhibits a histidine phosphatase fold with a unique phosphate binding site.
  • Recombinant TIGAR enzymes (human and zebrafish) efficiently hydrolyze fructose-2,6-bisphosphate and fructose-1,6-bisphosphate.
  • The TIGAR active site is open and positively charged, facilitating bisphosphatase activity.

Conclusions:

  • TIGAR possesses a distinct structural and functional profile as a bisphosphatase.
  • Its structure combines features of bacterial phosphatases and bifunctional enzymes, suggesting a specialized role in metabolism.
  • Understanding TIGAR's structure-function relationship provides insights into p53-mediated metabolic control.

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