Normal cell division involves a structure called the mitotic spindle, which pulls apart the chromosomes before the cell splits. The spindle is primarily made out of a substance called tubulin. Some anti-cancer drugs attack tubulin, but they have serious side effects, such as nerve damage and depletion of bone marrow and white blood cells.
The UT Southwestern researchers found that while diazonamide A blocked cell division, it seemed not to bind directly to tubulin. Instead, Dr. Xiaodong Wang, professor of biochemistry, and Dr. Gelin Wang, instructor of biochemistry, found that the toxin interacted with an enzyme called OAT, which was known to be involved in cellular metabolism but had no previously known role in cell division.
Interestingly, diazonamide did not block OAT's enzyme activity, the researchers said. Rather, it uncovered a second function for the protein in cell division.
"The finding that OAT is the cellular target of diazonamide is surprising for two reasons: First, there is no previous report that a mitochondrial enzyme like OAT can play a direct role in mitosis; second, OAT seems dispensable for normal cell division occurring in mice and men but is required for the division of cancer cells. This may explain the cancer specificity of diazonamide," said Dr. Wang, who is also a Howard Hughes Medical Institute investigator.
Dr. Noelle Williams, assistant professor of biochemistry and internal medicine, led the second phase of the research, which tested the effect of a variant of diazonamide A, called AB-5, in mice with tumors.