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The Skaggs Institute For Chemical Biology
Scientific Report 1997-1998


Chemical Physiology


B.F. Cravatt, D.K. Giang, K. Kustedjo, M.P. Patricelli

Our laboratory is interested in understanding complex physiology and behavior at the level of chemistry and molecules. At the center of cross talk between different physiologic processes are endogenous compounds that act as a molecular mode for intersystem communication. However, many of these molecular messages remain unknown, and even in the cases in which the participating molecules have been defined, the mechanisms by which these compounds function are for the most part still a mystery.

Our current efforts focus on a family of chemical messengers termed the fatty acid amides, which affect many physiologic functions, including sleep, thermoregulation, sensitivity to pain, and angiogenesis. In particular, one member of this family, oleamide, accumulates selectively in the cerebrospinal fluid of tired animals. This finding suggests that oleamide may function as a molecular indicator of the organism's need for sleep, and, indeed, rats treated with oleamide fall asleep.

The in vivo levels of chemical messengers such as fatty acid amides must be tightly regulated to maintain proper control over the influence of the messengers on brain and body physiology. We are characterizing one mechanism by which the level of fatty acid amides can be regulated in vivo. The enzyme fatty acid amide hydrolase (FAAH), degrades 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 physiologic responses in excess of their intended purpose.

We are using genetic, biochemical, and synthetic chemistry techniques to study the role that FAAH plays in the dynamic regulation of fatty acid amide levels in vivo. We are also interested in proteins responsible for the biosynthesis of fatty acid amides and for the selective uptake of the amides into cells and in determining novel molecular sites of action for these compounds.

A related effort 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 toward understanding the different functions of these N-myristoyltransferases, including their enzymology, intracellular targeting, and regulated expression. Because myristoylated proteins are implicated in the generation of pathologic changes 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.

Publications

Giang, D.K., Cravatt, B.F. A second mammalian N-myristoyltransferase. J. Biol. Chem. 273:6595, 1998.

Guan, X., Cravatt, B.F., Ehring, G.R., Hall, J.E., Boger, D.L., Lerner, R.A., Gilula, N.B. The sleep-inducing lipid oleamide deconvolutes gap junction communication and calcium wave transmission in glial cells. J. Cell Biol. 139:1785, 1997.

Patricelli, M.P., Lashuel, H.A., Giang, D.K., Kelly, J.W., Cravatt, B.F. Comparative characterization of a wild-type and transmembrane domain­deleted fatty acid amide hydrolase: Identification of the transmembrane domain as a site for oligomerization. Biochemistry, in press.

Patricelli, M.P., Patterson, J.P., Boger, D.L., Cravatt, B.F. An endogenous sleep-inducing compound is a novel competitive inhibitor of fatty acid amide hydrolase (FAAH). Bioorg. Med. Chem. Lett. 8:613, 1998.

Thomas, E.A., Cravatt, B.F., Danielson, P.E., Gilula, N.B., Sutcliffe, J.G. Fatty acid amide hydrolase (FAAH), the degradative enzyme for anandamide and oleamide, has selective distribution in neurons within the rat central nervous system. J. Neurosci. Res. 50:1047, 1997.

 

 







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