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Scientists at The Scripps Research Institute Determine Structures of Human Enzymes Important in Cell Survival; Implications for New Class of Anti-Cancer Drugs

September 15, 1996, La Jolla, CA. -- Scientists at The Scripps Research Institute (TSRI) have determined a series of structures for a human enzyme that is critical to cell survival and is related to two current major anti-cancer drug targets. This research establishes precisely how a key DNA building block is recognized. Scientists are hopeful that these atomic structures could ultimately lead to a new class of anti-cancer drugs.

TSRI molecular biologists Cliff Mol, Ph.D., and John Tainer, Ph.D., in collaboration with researchers in Australia and Canada, have determined a series of atomic structures for human dUTPase that increases understanding of the fundamental chemistry responsible for maintaining the chemical integrity of DNA. The essential human protein dUTPase is an enzyme that catalyzes the breakdown of uracil nucleotide triphosphates to provide material for the biosynthesis of the DNA building block dTTP. dUTPase also acts to keep the RNA base uracil out of DNA. These two functions of dUTPase are required to avoid cycles of uracil misincorporation and removal that generate multiple DNA strand breaks and eventual cell death. This cycle, which is termed thymine-less cell death, is the target of several current anti-cancer drugs, including methotrexate, but none of these act directly on dUTPase. According to Mol, the researchers hope to design dUTPase inhibitors that can be used as part of a cocktail of anti-cancer drugs that could allow for improved cancer treatments at lower drug doses and thus fewer side effects.

Mol and Tainer have determined the shape and structure of human dUTPase at the level of atomic detail and in complexes with its substrate dUTP and other uracil analogues. These atomic structures of dUTPase-nucleotide interactions reveal how the binding region of the enzyme can totally enclose the bound uracil. Understanding how dUTPase recognizes its substrate and reacts with it provides a basis for the design of inhibitors as future anti-cancer drugs.

Enzymes, such as dUTPase, are long polymers of amino acids that fold into complicated molecular machines capable of transforming one chemical species into another. To establish how these enzymes can catalyze reactions that are critical to life provides fundamental understanding that has many practical applications. The technique of protein crystallography was used to determine the structure of dUTPase.

The work was supported by a grant from the National Institutes of Health, an Australian Commonwealth AIDS Research Postgraduate Fellowship, and by a Special Fellowship from the Leukemia Society of America.

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