3D structure of new cancer-associated enzyme IDd--marker of early cancer/target?

[Lani]

Brown Researchers Work Out Structure of TIGAR, a Possible Cancer Flag [Brown University]
PROVIDENCE, R.I. [Brown University] — Two Brown University researchers have determined the three-dimensional structure of an enzyme whose presence in the body could help doctors detect cancer earlier or develop more targeted treatments.
Hua Li and Gerwald Jogl detail their progress with the enzyme known as TIGAR in a paper to be published Jan. 16, 2009, in The Journal of Biological Chemistry.
"It will help us to understand where else we should be looking for good [anti-cancer] targets," said Jogl, assistant professor of biology in the Department of Molecular Biology, Cell Biology and Biochemistry at Brown. Jogl is the study's principal investigator and corresponding author. Li is a fifth-year Ph.D. student based in Jogl's lab and is the lead author.
Jogl and Li wanted to determine the structure of TIGAR. After more than a year of research, they discovered that it is has a more substantive active site than they had expected. To map the structure, the pair used a method called X-ray crystallography.
The process involved using intensive X-ray light produced at the National Synchroton Light Source in Brookhaven, N.Y., to analyze crystals grown from samples of the TIGAR enzyme.
A separate study by researchers from St. Jude's Children's Research Hospital first identified the existence of TIGAR. Those results were published in CELL in 2006.
TIGAR, which helps regulate energy production in the cell, is activated after cell damage. Because of this, the presence of the enzyme can indicate potential problems that may lead to cancer. But TIGAR itself is positive. Once activated, TIGAR slows all processes in the cell, allowing time to repair cell damage. This process is also intended to prevent further damage that could lead to cancer.
Jogl and Li believe their finding may suggest that TIGAR has additional functions in the cell.
ABSTRACT: Structural and Biochemical Studies of TIGAR (TP53-induced Glycolysis and Apoptosis Regulator) [Journal of Biological Chemistry]
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.