A general strategy for enriching various classes of metabolites directly from biological samples is described online in Nature Methods this week. The method allows researchers to profile small molecule metabolites that are difficult to detect with more conventional discovery-based methods.
The proteomics community has greatly benefited from chemical enrichment methods allowing the targeted isolation of proteins with similar functional or structural properties. The 'metabolome', or entire spectrum of small molecules found in an organism, is even greater than the proteome in terms of numbers and chemical complexity. Benjamin Cravatt and Erin Carlson reasoned that metabolomics researchers would therefore also benefit from targeted chemical enrichment strategies.
Cravatt and Carlson synthesized chemical probes to target specific functional groups on small molecules. The probes were attached to a solid bead for easy isolation of the captured small molecules. The captured metabolites were then released from the probe and analyzed by liquid chromatography-mass spectrometry. They demonstrated that the method was able to isolate and profile low mass and polar small molecules, which are usually missed with conventional analysis without enrichment.
Engineering diverse sets of drug-sensitive proteins
Nature Methods
A paper published online this week in Nature Methods describes a general approach to genetically engineer proteins that are regulated by small chemical drugs.
Previous approaches that combined the strengths of genetics and pharmacology targeted specific proteins; the protein of choice was genetically modified in such a way that it became susceptible to small-molecule drugs. However, a general method for the engineering of drug-sensitive proteins has been lacking.
Mordechai Liscovitch and colleagues now introduce such a general method, which they call ligand interaction scan. They serially insert a short amino acid motif, specific for binding to a small-molecule ligand, into a protein of choice. Then, by scanning the activity of these mutant proteins, they are able to identify proteins that are activated or inhibited by the drug. Any protein can be made drug-sensitive by this approach; the only requirements for the scan are a read-out for protein activity and a cell-permeable drug, if the technique is to be carried out in live cells.
This method will aid in the functional analysis of proteins or even in the generation of transgenic organisms that carry proteins that are sensitive to a small-molecule drug.
CONTACT
Mordechai Liscovitch (Weizmann Institute of Science, Rehovot, Israel)
Tel: +972 8 934 2773; E-mail: moti.liscovitch@weizmann.ac.il
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