Research in the Cutler lab is focused on two complementary interests– the identification of new factors that regulate plant cell expansion and the dissection of natural variation using small molecules. Both of these goals have been pursued in parallel using LATCA, a collection of small molecule cell expansion inhibitors that the lab identified in several chemical genetic screens conducted over the past few years.

To harness the power of natural variation in chemical genomics, the lab's screens incorporated parallel assays on multiple ecotypes, or wild type strains. This work demonstrated that there is pervasive variation between Arabidopsis isolates in their sensitivity to small molecules. This variation can be used to identify natural drug-resistance and drug-hypersensitivity alleles, which can facilitate both mechanism of action studies and provide insight into the molecular mechanisms of pharmacogenetic variation.
By characterizing a new cell expansion inhibitor called hypostatin and naturally occurring hypostatin resistance alleles, the lab uncovered evidence for an unusual mechanism of pro-drug activation through glucosylation; we have named this process glycoactivation. This activation pathway uses enzymes that are homologous to human drug metabolism enzymes (UGTs) and the lab's work showed that natural variation in the same enzyme family can cause pharmacogenetic variation across biological kingdoms.

The lab’s efforts have recently focused on understanding the mechanism of action of pyrabactin (an ACS "Molecule of the Week"). Pyrabactin is a new growth inhibitor that we discovered in our chemical genetic screens. We have shown that it is an agonist of the abscisic acid (ABA) signal transduction pathway. ABA is a stress hormone and growth inhibitor that plays important roles in many aspects of plant physiology. A combination of genetic, transcriptomic and physiological evidence has demonstrated that pyrabactin activates the ABA pathway in a manner very similar to ABA. As such, pyrabactin is the first ABA agonist that is not an ABA analog and may ultimately lead to the development of a new family of synthetic plant growth regulators. In addition, pyrabactin shows intriguing selectivity for the seed ABA signaling pathway and has relatively modest effects on the vegetative pathway. Our characterization of pyrabactin has provided new insights into the mechanisms of ABA signal transduction, an in particular led to the identfication of a new family of ABA receptors called the PYR/PYL proteins.
Our work on pyrabactin was published online in ScienceExpress April 30. Check out the Tierney Lab post about how this paper exposed some of my, err, unusual proclivities. A discussion with my colleague, friend, ethicist and big brain, Coleen Macnamara, helped my hone my argument and enable a second round at Tierney lab.
More recently, our receptor work has led to a series of papers that provide detailed insight into the structural mechanism of ABA perception and PP2C inhibition. Of additional note, the recent work on ABA perception was selected as a 2009 "Breakthrough of the Year" by Science magazine. Our current efforts in ABA signaling are focused on 3 interrelated areas: (1) Understanding the structural mechanism of pyrabactin action and selectivity, (2) Designing, synthesizing and characterizing new synthetic ABA agonists and (3) Characterizing new endogenous plant agonists of the the PYR/PYL receptors.

The Cutler lab has also been developing new small molecule screening libraries designed specifically for chemical genetic initiatives as part of an IIGB funded project. These projects exploit click chemistry and a clickable library of ~4000 terminal acetlyene compounds assembled by the Cutler lab to capitalize on the ease and power of the "biologist-friendly" click chemistry reactions. One goal of this project is to generate new chemical probes that facilitate target identification, a current bottleneck in chemical genomic initiatives.