Pig Liver Carnitine Palmitoyltransferase
CHIMERA STUDIES SHOW THAT BOTH THE N- AND C-TERMINAL REGIONS OF
THE ENZYME ARE IMPORTANT FOR THE UNUSUAL HIGH MALONYL-CoA
SENSITIVITY*
Carine
Nicot
,
Joana
Relat,
Gebre
Woldegiorgis§,
Diego
Haro, and
Pedro F.
Marrero¶
From the Department of Biochemistry and Molecular
Biology, School of Pharmacy, University of Barcelona, 08028 Barcelona, Spain and the § Department of Biochemistry and
Molecular Biology, Oregon Graduate Institute School of
Science and Engineering, Oregon Health and Science University,
Beaverton, Oregon 97006 8921
Pig and rat liver carnitine palmitoyltransferase
I (L-CPTI) share common Km values for palmitoyl-CoA
and carnitine. However, they differ widely in their sensitivity to
malonyl-CoA inhibition. Thus, pig L-CPTI has an
IC50 for malonyl-CoA of 141 nM, while that of
rat L-CPTI is 2 µM. Using chimeras between rat L-CPTI and
pig L-CPTI, we show that the entire C-terminal region behaves as a
single domain, which dictates the overall malonyl-CoA sensitivity of
this enzyme. The degree of malonyl-CoA sensitivity is determined by the
structure adopted by this domain. Using deletion mutation analysis, we
show that malonyl-CoA sensitivity also depends on the interaction of
this single domain with the first 18 N-terminal amino acid residues. We
conclude that pig and rat L-CPTI have different malonyl-CoA
sensitivity, because the first 18 N-terminal amino acid residues
interact differently with the C-terminal domain. This is the first
study that describes how interactions between the C- and N-terminal
regions can determine the malonyl-CoA sensitivity of L-CPTI enzymes
using active C-terminal chimeras.
*
This research was supported by the Fundació la
Marató de TV3 (to P. M.), the Dirección General de
Investigación Científica y Técnica Grant PB97-0958
(to D. H.), and National Institutes of Health Grant HL52571 (to
G. W.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
¶
To whom correspondence should be addressed: Departamento de
Bioquímica y Biología Molecular, Facultad de Farmacia,
Universidad de Barcelona., Av. Diagonal, 643, Barcelona 08028, Spain.
Tel.: 34-93-403-45-00; Fax: 34-93-402-18-96; E-mail:
pmar@farmacia.far.ub.es.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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