Natural Product's Target Identified

Chemical Biology

The primary cellular target of bistramide A is actin, a protein that makes cells mechanically strong and enables them to move, according to a new study.

Bistramide A is a potent suppressor of cell proliferation. Its activity was attributed previously to inhibition of protein kinase C d. The new study establishes that bistramide As activity is instead due to its high and specific affinity for actin (Nature Chem. Biol., published Nov. 13, dx.doi.org/10.1038/nchem bio748).

Sergey A. Kozmin and Alexander V. Statsuk at the University of Chicago carried out the research with Ernest Hamel of NIHs National Cancer Institute and Paul A. Wenders group at Stanford University.

Key to the work is Kozmins recent synthesis of bistramide A (J. Am. Chem. Soc. 2004, 126, 9546), which enabled the binding studies.

Bistramide A disrupts the equilibrium between monomeric and polymeric actin and causes the latter to depolymerize, Kozmin explains. Polymeric actin makes up the cytoskeleton, the structure that is responsible for cell shape, strength, and locomotion and that plays a key role in cell division. Small organic molecules targeting actin with high affinity and specificity are invaluable for studies of these cellular processes, the authors write.

Identifying the targets of bioactive compounds is fundamental to understanding cellular pathways, Wender explains. Recognizing that actin mediates the effect of bistramide A now allows researchers to explore how the natural product may be used to probe processes such as cell motility. How cells move around is both remarkably exciting at the fundamental level and rich with consequences in therapy, he adds.