Pig Liver Carnitine Palmitoyltransferase I, with LowKmfor Carnitine and High Sensitivity to Malonyl-CoA Inhibition, Is a Natural Chimera of Rat Liver and Muscle Enzymes†

Biochemistry ◽  
2001 ◽  
Vol 40 (7) ◽  
pp. 2260-2266 ◽  
Author(s):  
Carine Nicot ◽  
Fausto G. Hegardt ◽  
Gebre Woldegiorgis ◽  
Diego Haro ◽  
Pedro F. Marrero
Keyword(s):  
Rat Liver ◽  
High Sensitivity ◽  
Carnitine Palmitoyltransferase ◽  
Muscle Enzymes ◽  
Pig Liver ◽  
Malonyl Coa ◽  
Carnitine Palmitoyltransferase I

scholarly journals Identification of Conserved Amino Acid Residues in Rat Liver Carnitine Palmitoyltransferase I Critical for Malonyl-CoA Inhibition

2002 ◽  
Vol 278 (11) ◽  
pp. 9058-9063 ◽  
Author(s):  
Montserrat Morillas ◽  
Paulino Gómez-Puertas ◽  
Assia Bentebibel ◽  
Eva Sellés ◽  
Nuria Casals ◽  
...  
Keyword(s):  
Amino Acid ◽  
Rat Liver ◽  
Carnitine Palmitoyltransferase ◽  
Amino Acid Residues ◽  
Malonyl Coa ◽  
Carnitine Palmitoyltransferase I

scholarly journals Roles of the N- and C-terminal domains of carnitine palmitoyltransferase I isoforms in malonyl-CoA sensitivity of the enzymes: insights from expression of chimaeric proteins and mutation of conserved histidine residues

1998 ◽  
Vol 335 (3) ◽  
pp. 513-519 ◽  
Author(s):  
S. Todd SWANSON ◽  
Daniel W. FOSTER ◽  
J. Denis McGARRY ◽  
Nicholas F. BROWN
Keyword(s):  
Carnitine Palmitoyltransferase ◽  
Mitochondrial Outer Membrane ◽  
Irreversible Inhibitor ◽  
Muscle Enzymes ◽  
Histidine Residues ◽  
Terminal Domain ◽  
Malonyl Coa ◽  
Carnitine Palmitoyltransferase I ◽  
Cpt I ◽  
Terminal Domains

The mitochondrial outer membrane enzyme carnitine palmitoyltransferase I (CPT I) plays a major role in the regulation of fatty acid entry into the mitochondrial matrix for β-oxidation by virtue of its inhibition by malonyl-CoA. Two isoforms of CPT I, the liver type (L) and muscle type (M), have been identified, the latter being 100 times more sensitive to malonyl-CoA and having a much higher Km for the substrate carnitine. Here we have examined the roles of different regions of the CPT I molecules in their response to malonyl-CoA, etomoxir (an irreversible inhibitor) and carnitine. To this end, we analysed the properties of engineered rat CPT I constructs in which (a) the N-terminal domain of L-CPT I was deleted, (b) the N-terminal domains of L- and M-CPT I were switched, or (c) each of three conserved histidine residues located towards the N-terminus in L-CPT I was mutated. Several novel points emerged: (1) whereas the N-terminal domain is critical for a normal malonyl-CoA response, it does not itself account for the widely disparate sensitivities of the liver and muscle enzymes to the inhibitor; (2) His-5 and/or His-140 probably play a direct role in the malonyl-CoA response, but His-133 does not; (3) the truncated, chimaeric and point- mutant variants of the enzyme all bound the covalent, active-site- directed ligand, etomoxir; and (4) only the most radical alteration of L-CPT I, i.e. deletion of the N-terminal 82 residues, affected the response to carnitine. We conclude that the N-terminal domain of CPT I plays an essential, but permissive, role in the inhibition of the enzyme by malonyl-CoA. By contrast, the larger C-terminal region dictates the degree of sensitivity to malonyl-CoA, as well as the response to carnitine; it is also sufficient for etomoxir binding. Additionally, further weight is added to the notion that one or more histidine residues may be involved in the CPT I–malonyl-CoA interaction.

scholarly journals The Extreme C Terminus of Rat Liver Carnitine Palmitoyltransferase I Is Not Involved in Malonyl-CoA Sensitivity but in Initial Protein Folding

2002 ◽  
Vol 277 (49) ◽  
pp. 47184-47189 ◽  
Author(s):  
Yong Pan ◽  
Isabelle Cohen ◽  
Fanny Guillerault ◽  
Bruno Fève ◽  
Jean Girard ◽  
...  
Keyword(s):  
Protein Folding ◽  
Rat Liver ◽  
Carnitine Palmitoyltransferase ◽  
C Terminus ◽  
Malonyl Coa ◽  
Carnitine Palmitoyltransferase I

scholarly journals Reversible sensitization and desensitization of carnitine palmitoyltransferase I to inhibition by malonyl-CoA in isolated rat liver mitochondria. Significance for the mechanism of malonyl-CoA-induced sensitization

1983 ◽  
Vol 214 (3) ◽  
pp. 1027-1030 ◽  
Author(s):  
V A Zammit
Keyword(s):  
Rat Liver ◽  
Reduced Glutathione ◽  
Thiol Group ◽  
Liver Mitochondria ◽  
Carnitine Palmitoyltransferase ◽  
Rat Liver Mitochondria ◽  
Nitrobenzoic Acid ◽  
Malonyl Coa ◽  
Carnitine Palmitoyltransferase I ◽  
Cpt I

Preincubation of rat liver mitochondria with 5,5′-dithiobis-(2-nitrobenzoic acid) (Nbs2) followed by removal of excess reagent by washing the mitochondria with 0.5 mM-reduced glutathione resulted in a desensitization of carnitine palmitoyltransferase (CPT) I activity to malonyl-CoA inhibition. The effect was not observed if mitochondria were washed with 0.5 mM-dithiothreitol. The desensitization effect of Nbs2 could be reversed by a second incubation in the presence of 8 microM-malonyl-CoA. In addition, malonyl-CoA, when present simultaneously with Nbs2, protected CPT I activity against the desensitization effect of the thiol-group reagent. These results suggest that malonyl-CoA exerts an effect on one or more thiol groups of the enzyme, and that this effect is related to the ability of the metabolite to sensitize CPT I to malonyl-CoA inhibition.

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