Benjamin F. Cravatt
Board Member: 2007 -2010
FATTY ACID AMIDES IN CELLULAR AND ORGANISMAL BIOLOGY
Our laboratory is interested in understanding complex physiology and behavior at the level of chemistry and molecules. At the center of crosstalk between different physiological processes are endogenous compounds which serve as a molecular mode for intersystem communication. However, many of these molecular messages remain unknown, and even in the cases where the participating molecules have been defined, the mechanisms by which these compounds function are for the most part still a mystery. We are presently focusing our efforts on a family of chemical messengers termed the fatty acid amides, which have been shown to affect many physiological functions, including sleep, thermoregulation, pain sensitivity, and angiogenesis. In particular, one member of this family, oleamide, has been identified as a compound that accumulates selectively in the cerebrospinal fluid of tired animals, suggesting that oleamide may function as a molecular indicator of the organism's need for sleep. Indeed, upon treatment with oleamide, rats have been shown to fall asleep.
The in vivo levels of chemical messengers like the fatty acid amides must be tightly regulated to maintain proper control over their influence on brain and body physiology. We are characterizing one mechanism by which the level of fatty acid amides can be regulated in vivo, an enzyme termed fatty acid amide hydrolase (FAAH), which serves to degrade the fatty acid amides to inactive metabolites. Thus, FAAH effectively terminates the signaling messages conveyed by fatty acid amides, possibly ensuring that these molecules do not generate physiological responses in excess of their intended purpose. We are presently studying the role that FAAH plays in the dynamic regulation of fatty acid amide levels in vivo through the use of both genetic and synthetic chemistry techniques. Our lab is also interested in proteins responsible for both the biosynthesis of fatty acid amides and their selective uptake into cells, as well as in identifying novel molecular sites of action for these compounds.
A related effort underway in our group is the study of enzymes involved in the cotranslational fatty acid amidation of proteins. In particular, we are characterizing a family of enzymes termed N-myristoyltransferases, which catalyze the transfer of myristic acid to the N-termini of many signaling proteins. Efforts are being directed towards understanding the different functions of these N-myristoyltransferases, including their enzymology, intracellular targeting, and regulated expression. Given that myristoylated proteins are implicated in the generation of pathologies ranging from tumorigenesis to viral infection, we hope that the characterization and pharmaceutical targeting of myristoyltransferases may lead to effective drug treatments for such diseases.