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- Title
A characteristic Glu17 residue of pig carnitine palmitoyltransferase 1 is responsible for the low K<sub>m</sub> for carnitine and the low sensitivity to malonyl-CoA inhibition of the enzyme.
- Authors
Relat, Joana; Pujol-Vidal, Magdalena; Haro, Diego; Marrero, Pedro F.
- Abstract
Human carnitine palmitoyltransferase 1B (CPT1B) is a highly malonyl-CoA-sensitive enzyme (IC50 = 0.097 μm) and has a positive determinant (residues 18–28) of malonyl-CoA inhibition. By contrast, rat carnitine palmitoyltransferase 1A is less sensitive to malonyl-CoA inhibition (IC50 = 1.9 μm), and has both a positive (residues 1–18) and a negative (residues 18–28) determinant of its inhibition. Interestingly, pig CPT1B shows a low degree of malonyl-CoA sensitivity (IC50 = 0.804 μm). Here, we examined whether any additional molecular determinants affect malonyl-CoA inhibition of CPT1B. We show that the malonyl-CoA sensitivity of CPT1B is determined by the length (either 50 or 128 residues) of the N-terminal region constructed by recombining pig and human enzymes. We also show that the N-terminal region of pig CPT1B carries a single positive determinant of malonyl-CoA sensitivity, but that this is located between residues 1 and 18 of the N-terminal segment. Importantly, we found a single amino acid variation (D17E) relevant to malonyl-CoA sensitivity. Thus, Asp17 is specifically involved, under certain assay conditions , in the high malonyl-CoA sensitivity of the human enzyme, whereas the naturally occurring variation, Glu17, is responsible for both the low malonyl-CoA sensitivity and high carnitine affinity characteristics of the pig enzyme. This is the first demonstration that a single naturally occurring amino acid variation can alter CPT1B enzymatic properties.
- Subjects
ENZYMES; CATALYSTS; RESPONSE inhibition; CARNITINE; VITAMIN B complex
- Publication
FEBS Journal, 2009, Vol 276, Issue 1, p210
- ISSN
1742-464X
- Publication type
Article
- DOI
10.1111/j.1742-4658.2008.06774.x