PHILADELPHIA - An enzyme that plays a pivotal role in controlling genes in yeast acts through a more versatile mechanism than was previously thought to be the case, according to a new study by researchers at The Wistar Institute.
Its mode of action is also distinct from that of other members of the vital enzyme family into which it falls, the scientists found. Because the human counterpart of the enzyme has been associated with certain forms of leukemia, this observation raises the possibility that drugs designed to specifically inhibit the enzyme might be useful in treating these cancers.
A report on the study appears in the November issue of Nature Structural Biology.
The enzyme studied, called Esa1, is one of a family of enzymes called HATs, which are responsible for relaxing, when appropriate, the tightly compacted DNA packaging that prevents genes from being accessed and activated most of the time. HATs do this by transferring an acetyl group from a coenzyme donor molecule to target proteins called histones that control the DNA packaging.
Other members of the enzyme family can accomplish this transfer only when all three components - the donor molecule, the enzyme, and the target - are in the same place. Esa1, on the other hand, is able to temporarily accept an acetyl group from the coenzyme donor before handing it off to the histone protein.
"This enzyme uses what we call a ping-pong mechanism," says Ronen Marmorstein, Ph.D., senior author on the study and an associate professor at The Wistar Institute. "First the acetyl molecule is transferred to the enzyme - ping - and then it goes from the enzyme to the histone protein - pong. It's a different and more flexible way of getting your business done."
The time during which the enzyme is carrying the acetyl group is quite brief, Marmorstein notes, but he and his team were able to trap the moment in a crystallized form of the enzyme that they were then able to analyze more closely.
Earlier studies by Marmorstein's group had shown that the molecular structure of the active region of the enzyme was nearly identical to the structures of the corresponding regions of other HATs. At that time, his team hypothesized that the mode of action of the enzymes might also be similar. The current study showed this not to be the case, however.
###The lead author on the Nature Structural Biology study is Yuan Yan, B.S. David W. Speicher, Ph.D., a professor at The Wistar Institute, is a collaborating author on the study, and Sandy Harper is a co-author.
Funding for the research was provided by the National Institutes of Health.
The Wistar Institute is an independent nonprofit biomedical research institution dedicated to discovering the causes and cures for major diseases, including cancer, cardiovascular disease, autoimmune disorders, and infectious diseases. Founded in 1892 as the first institution of its kind in the nation, The Wistar Institute today is a National Cancer Institute-designated Cancer Center - one of only eight focused on basic research. Discoveries at Wistar have led to the development of vaccines for such diseases as rabies and rubella, the identification of genes associated with breast, lung, and prostate cancer, and the development of monoclonal antibodies and other significant research technologies and tools.
Cite This Page: