Coupling the Power of Chemical Synthesis with Metabolic Engineering: College of Pharmacy Monthly Publication HighlightMar 08, 2013
A publication in the Journal of American Chemical Society has been selected as the UK College of Pharmacy’s Monthly Publication Highlight for March. The selected publication elucidated a biosynthetic pathway for gilvocarcin V, which has shown promise in cancer therapy.
The publication is entitled, “Roles of the Synergistic Reductive O-Methyltransferase GilM and of O-Methyltransferase GilMT in the Gilvocarcin Biosynthetic Pathway,” with Dr. Nidhi Tibrewal, a recent PhD graduate of the UK College of Pharmacy serving as lead author. The research was carried out in the laboratory of faculty member Dr. Jurgen Rohr. Joining Drs. Tibrewal and Rohr as co-authors on the publication are Drs. Steven Van Lanen, Ehesan Ul Sharif, George O’Doherty, and Ms Theresa Downey.
“This publication investigates the activity of key enzymes of the gilvocarcin V biosynthesis, and paves the way to develop this class of unique anticancer agents into clinical chemotherapeutics. The gilvocarcins are complex natural products with excellent antitumor activity and remarkably low in vivo toxicity” said Dr. Rohr. “They bind to histone H3, which is a rare activity among cancer drugs. These natural products would be good candidates to be developed into chemotherapeutic agents, if they weren’t suffering from solubility issues. The work on GilM and GilMT now revealed a relatively simple intermediate of the biosynthetic pathway. Synthesizing derivatives of this intermediate that can be further converted into the complex final structures by the downstream enzymes of the biosynthetic pathway now opens up the possibility of making new analogues with improved solubility properties for subsequent development.”
“This project showcases the innovative research coupling the power of chemical synthesis with metabolic engineering taking place in Dr. Rohr’s laboratory,” said Linda Dwoskin, Associate Dean for Research for the UK College of Pharmacy. “Nidhi Tibrewal and the entire research team have elucidated an exciting biosynthetic pathway that could lead to breakthroughs in cancer therapy.”
Two enzymes of the gilvocarcin biosynthetic pathway, GilMT and GilM were investigated in in vitro studies using purified, recombinant enzymes along with synthetically prepared intermediates. The studies revealed GilMT as a typical S-adenosylmethionine (SAM) dependent O-methyltransferase, but GilM was identified as a pivotal enzyme in the pathway that exhibits dual functionality in that it catalyzes a reduction of a quinone intermediate to a hydroquinone, which goes hand-in-hand with a stabilizing O-methylation and a hemiacetal formation. GilM mediates its reductive catalysis through the aid of GilR that provides FADH(2) for the GilM reaction, through which FAD is regenerated for the next catalytic cycle. This unusual synergy eventually completes the biosynthesis of the polyketide-derived defuco-gilvocarcin chromophore.
Original article: Tibrewal N, Downey TE, Van Lanen SG, Ul Sharif E, O'Doherty GA, Rohr J.
Roles of the synergistic reductive O-methyltransferase GilM and of O-methyltransferase GilMT in the gilvocarcin biosynthetic pathway, J Am Chem Soc, 2012 Aug 1;134(30):12402-5.