News and Publications
The Skaggs Institute for Chemical Biology
Scientific Report 1998-1999
B.F. Cravatt, D.K. Giang, K. Kustedjo, M.P. Patricelli, M.H. Bracey, Y. Liu
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.
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,
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.