Exploring exocytosis using chemical genomics
Proc Natl Acad Sci U S A. 2015,113 (1):14-16
Baral A, Bhalerao RP
Genome-sequencing data coupled with the availability of genetic manipulation tools in diverse model organisms has rapidly advanced our understanding of the role of individual molecular players in biological processes (1). Classical genetic approaches (using knockout mutants), although highly successful, are often hindered by the functional redundancy due to occurrence of multiple genes with similar functions. Additionally, loss-of-function mutants, which either lead to lethality or severe defects, hinder a proper understanding of the primary role of individual genes in biological processes. Such obstacles prompted the development of small chemical inhibitors to dissect biological pathways in an approach popularly known as chemical genomics (2). Use of chemical genomics overcomes several of the limitations posed by the classical genetic approaches. For example, simultaneous chemical targeting of several closely related genes in a family overcomes the obstacle of functional redundancy. The possibility to modulate the dosage and reversibility of chemical treatments also enables one to elucidate the primary function of indispensable players without causing long-term and severe developmental defects. Moreover, use of small molecules allows the possibility to perform local or tissue-specific applications, thus making it feasible to study specific developmental processes. Furthermore, the use of small-molecule inhibitors coupled with target identification has considerable promise in the area of drug discovery. The group of Natasha Raikhel has been one of the pioneers in the use of chemical genomics in plants and have demonstrated its use in identifying several novel compounds that can be used in analysis of endomembrane trafficking (3). In PNAS, Zhang et al. (4) describe a novel molecule Endosidin 2 (ES2) as a specific inhibitor for EXO70, a key player in exocytosis in both plants and animals.
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