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J Biol Chem, Vol. 274, Issue 14, 9421-9426, April 2, 1999
From the Department of Biochemistry and Molecular Biology, Oregon
Graduate Institute of Science and Technology,
Portland, Oregon 97291-1000
We have recently shown by deletion mutation
analysis that the conserved first 18 N-terminal amino acid residues of
rat liver carnitine palmitoyltransferase I (L-CPTI) are essential for
malonyl-CoA inhibition and binding (Shi, J., Zhu, H., Arvidson, D. N., Cregg, J. M., and Woldegiorgis, G. (1998)
Biochemistry 37, 11033-11038). To identify specific
residue(s) involved in malonyl-CoA binding and inhibition of L-CPTI, we
constructed two more deletion mutants, 
12 and 6, and three
substitution mutations within the conserved first six amino acid
residues. Mutant L-CPTI, lacking either the first six N-terminal amino
acid residues or with a change of glutamic acid 3 to alanine, was
expressed at steady-state levels similar to wild type and had near wild
type catalytic activity. However, malonyl-CoA inhibition of these
mutant enzymes was reduced 100-fold, and high affinity malonyl-CoA
binding was lost. A mutant L-CPTI with a change of histidine 5 to
alanine caused only partial loss of malonyl-CoA inhibition, whereas a
mutant L-CPTI with a change of glutamine 6 to alanine had wild type
properties. These results demonstrate that glutamic acid 3 and
histidine 5 are necessary for malonyl-CoA binding and inhibition of
L-CPTI by malonyl-CoA but are not required for catalysis.
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