News and Publications

Chemical Physiology

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 the 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 (Fig. 1). 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, enzymologic, 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.

Related efforts focus on developing novel chemical approaches for understanding the physiologic and pathologic roles played by members of the serine hydrolase family of enzymes. Serine hydrolases are a large and diverse class of enzymes with numerous endogenous functions. We are synthesizing and using tagged chemical probes to monitor the collective catalytic states of these enzymes directly in crude cell and tissue samples. Using this rapid and global experimental strategy, we hope to greatly accelerate both the assignment of protein function and the indentification of potential pharmaceutical targets for diseases such as caner.

Publications

Boger, D.L., Henriksen, S.J., Cravatt, B.F. Oleamide: An endogenous sleep-inducing lipid and prototypical member of a new class of biological signaling molecules. Curr. Pharm. Des. 4:303, 1999.

Egertova, M., Giang, D.K., Cravatt, B.F., Elphick, M.R. A new perspective on cannabinoid signalling: Complimentary localization of fatty acid amide hydrolase and the CB1 receptor in rat brain. Proc. R. Soc. Lond. B Biol. Sci. 265:2081, 1998.

Patricelli, M.P., Lashuel, H.A., Giang, D.K., Kelly, J.W., Cravatt, B.F. Comparative characterization of a wild type and transmembrane domain-deleted fatty acid amide hydrolase: Identification of the transmembrane domain as a site for oligomerization. Biochemistry 37:15177, 1998.

Patricelli, M.P., Lovato, M.A., Cravatt, B.F. Chemical and mutagenic investigations of fatty acid amide hydrolase: Evidence for a family of serine hydrolases with distinct catalytic properties. Biochemistry 38:9804, 1999.

Thomas, E.A., Cravatt, B.F., Sutcliffe, J.G. The endogenous lipid oleamide activates serotonin 5-HT₇ neurons in mouse thalamus and hypothalamus. J. Neurochem. 72:2370, 1999.

Wan, M., Cravatt B.F., Huijun, Z.R., Xianyu, Z., Francke, U. Conserved chromosomal location and genomic structure of human and mouse fatty-acid amide hydrolase genes and evaluationof clasper as a candidate neurological mutation. Genomics 54:408, 1998.