News and Publications
The Skaggs Institute For Chemical Biology
Scientific Report 1997-1998
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.
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,
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.