NEWS OF THE WEEK
CLICK CHEMISTRY: Approach could help
researchers find antiobesity drug leads
A
NEW TYPE OF ASSAY based on click chemistry
substrate for the fatty acid that GOAT attaches when it activates ghrelin. They then use click chemistry to attach an azide-tagged version of horseradish peroxidase (HRP) to the alkyne-derivatized ghrelin. When GOAT is active, HRP, in the presence of a reagent called Amplex Red, generates an amplified signal denoting the enzyme’s activity by catalyzing production of a fluorescent product, resorufin. When GOAT is inactive because it has been turned off by an inhibitor, no resorufin is produced. The technique could be useful for assaying not only GOAT activity but also that of other enzymes that make posttranslational modifications to peptides and proteins, such as palmitoylation enzymes and histone acetylases and deacetylases. Such enzymes have been widely
will make it possible to carry out high-throughput screens to find inhibitors of the gut hormone ghrelin, a target for obesity and diabetes medications. Ghrelin promotes hunger, helps regulate energy use, and impairs glucose control, and researchers have been actively seeking agents that lower ghrelin levels as obeGETTING GOAT Click chemistry attaches a fluorescence-producing enzyme to GOAT-activated sity or diabetes treatments. ghrelin. GOAT inhibitors stop the reaction sequence in its first step and turn off fluorescence. Some have focused on findN HO OH O ing inhibitors for ghrelinG G G N ( )5 ( )5 S S S O-acyltransferase (GOAT), OH O O N N O O S S S which activates ghrelin by HRP Acyl transfer F F Click chemistry F esterifying an inactive form GOAT O Catalytic L L L with a fatty acid group. signal Amplex Red, nonfluorescent amplification But measuring GOAT Biotin activity has been hard, O HO O impeding the search for GOAT inhibitors. Current Streptavidin-coated N well plate procedures, such as radiolaG, S, F, and L = amino acids; HRP = horseradish peroxidase Resorufin, fluorescent beling tests, are difficult and time-consuming, and they can’t be used in high-throughput studies to screen for studied for their role in cancer and other diseases. enzyme inhibitors. If a functional group “involved in posttranslational Now, research associate Amanda L. Garner and modification can carry an alkyne, and the enzyme dochemistry professor Kim D. Janda of Scripps Research ing the posttranslational modification accepts that Institute, in La Jolla, Calif., have fixed that problem by group as a substrate,” then the new technique could devising a simple assay called cat-ELCCA (catalytic be used to measure that enzyme’s activity, says bioasenzyme-linked click-chemistry assay) that’s highly say specialist Eric V. Anslyn of the University of Texas, sensitive for GOAT and amenable to high-throughput Austin. “What’s unique here,” compared with existing screening (Angew. Chem. Int. Ed., DOI: 10.1002/anie. assays, “is that click chemistry brings along an enzyme 201003387). They substitute an alkyne-containing that catalytically amplifies a signal.” —STU BORMAN
ACS President Joseph S. Francisco is one of four scientists whom President Barack Obama says he intends to appoint as members of his Committee on the National Medal of Science. “I am deeply honored and delighted to have been appointed to serve” on this committee, Francisco says. Francisco “The National Medal of Science is awarded to distinguished scien-
PETER CUTTS PHOTOGRAPHY
APPOINTMENT Francisco to be named National Medal of Science Committee member tists and engineers for lifetime contributions to research and development. It is our nation’s expression of thanks to the men and women who have devoted decades to scientific discovery and achievement.” In this post Francisco will join Carlos Castillo-Chavez, a professor of mathematical biology and executive director of the Mathematical & Theoretical Biology Institute at Arizona State University; Inez
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Fung, a professor of atmospheric science at the University of California, Berkeley, and director of the Berkeley Institute of the Environment; and Margaret Murnane, a professor in the department of physics and of electrical and computer engineering at the University of Colorado, Boulder. “I am confident that these impressive men and women will make valued additions to this Administration,” Obama said on Sept. 17. “I look forward to working with them in the months and years ahead.”—SUSAN AINSWORTH
ADAPTED FROM ANGEW. CHEM. INT. ED. © 2010
ASSAY FOR KEY GHRELIN ENZYME
