The Carnitine Acyltransferases Project
Carnitine acyltransferases catalyze the exchange between acyl-CoA
and acylcarnitines. The enzymes can be divided into three sub-families
based on their substrate preferences: carnitine acetyltransferases
(CrAT), carnitine octanoyltransferases (CrOT), and carnitine
palmitoyltransferases (CPT), with preferences for short-chain,
medium-chain, and long-chain fatty acids, respectively.
The CPTs have crucial roles in the oxidation of long-chain fatty
acids. L-CPT-I and M-CPT-I are located on the outer membrane
of the mitochondria, and convert fatty acyl-CoAs to fatty
acylcarnitines. Upon translocation into the mitochondria,
CPT-II then converts them back to fatty acyl-CoAs, which can
then undergo b-oxidation for energy production.
L-CPT-I is a target for the development of drugs
against type 2 diabetes. At the same time, an agonist of this
enzyme may be efficacious in the control of body weight and
The sequences of the enzymes display signicant homology to
each other (35% identity or better), but they do not show
any recognizable homology to other proteins in the database.
Major findings from this project
- The structure of mouse CrAT has been determined at 1.8 A resolution.
- The backbone fold of CRAT shows unexpected homology to
chloramphenicol acetyltransferase (CAT). However, the quaternary
of the two enzymes are different. CAT is a homo trimer, whereas CrAT
contains two domains that mimics the two subunits of the CAT trimer.
- There is a tunnel that goes through the middle of the protein.
Carnitine and CoA bind to opposite ends of this tunnel.
- The carboxyl group of carnitine is involved in an intricate
network of hydrogen-bonding interactions.
- The CoA molecule is fully extended when bound to CrAT, in
contrast to the folded conformation in the CAT complex.
- The positive charge on carnitine helps stabilize the
oxyanion of the transition state - substrate-assisted catalysis.
- The Met564 residue of CrAT is a determinant of substrate
preference. The M564G mutant has stronger activity with
- The structure of mouse CrOT has been determined at 2.0A
- The structure of rat CPT-II has been determined at 1.9A
- An insert of two helices, with a hydrophobic surface patch,
may mediate the attachment of CPT-II to the inner
- The P50H disease-causing mutation in CPT-II may affect
its membrane localization.
- The structures of CrAT in ternary complex with its substrates
(Michaelis complex) have been determined at up to 1.9A resolution.
Publications from this project
- G. Jogl & L. Tong. (2003). Crystal structure of carnitine
acetyltransferase and implications for the catalytic
mechanism and fatty acid transport.
Cell 112, 113-122.
S. Gobin, L. Thuillier, G. Jogl, A. Faye, L. Tong,
M. Chi, J.-P. Bonnefont, J. Girard, C. Prip-Buus. (2003).
Functional and structural basis of carnitine
palmitoyltransferase 1A deficiency.
J. Biol. Chem. 278, 50428-50434.
Y.-S. Hsiao, G. Jogl & L. Tong. (2004).
Structural and biochemical studies of the
substrate selectivity of carnitine
J. Biol. Chem. 279, 31584-31589.
G. Jogl, Y.-S. Hsiao & L. Tong. (2004).
Structure and function of carnitine
Ann. N.Y. Acad. Sci. 1033, 17-29.
G. Jogl, Y.-S. Hsiao & L. Tong. (2005).
Crystal structure of mouse carnitine octanoyltransferase
and molecular determinants of substrate selectivity.
J. Biol. Chem. 280, 738-744.
Y.-S. Hsiao, G. Jogl, V. Esser & L. Tong. (2006).
Crystal structure of rat carnitine palmitoyltransferase
Biochem. Biophys. Res. Commun. 346, 974-980.
Y.-S. Hsiao, G. Jogl & L. Tong. (2006).
Crystal structures of murine carnitine acetyltransferase
in ternary complexes with its substrates.
J. Biol. Chem. 281, 28480-28487.
Funding for this project
© copyright 2003-2017, Liang Tong.