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Structure and Function of Carnitine Acyltransferases
Author(s) -
JOGL GERWALD,
HSIAO YUSHAN,
TONG LIANG
Publication year - 2004
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1320.002
Subject(s) - carnitine , acyltransferases , carnitine o palmitoyltransferase , coenzyme a , chemistry , active site , transferase , biochemistry , carnitine palmitoyltransferase i , acetylcarnitine , enzyme , acetyltransferases , oxyanion hole , stereochemistry , biosynthesis , beta oxidation , reductase , acetylation , gene
A bstract : Carnitine acyltransferases catalyze the exchange of acyl groups between carnitine and coenzyme A (CoA). These enzymes include carnitine acetyltransferase (CrAT), carnitine octanoyltransferase (CrOT), and carnitine palmitoyltransferases (CPTs). CPT‐I and CPT‐II are crucial for the β‐oxidation of long‐chain fatty acids in the mitochondria by enabling their transport across the mitochondrial membrane. The activity of CPT‐I is inhibited by malonyl‐CoA, a crucial regulatory mechanism for fatty acid oxidation. Mutation or dysregulation of the CPT enzymes has been linked to many serious, even fatal human diseases, and these enzymes are promising targets for the development of therapeutic agents against type 2 diabetes and obesity. We have determined the crystal structures of murine CrAT, alone and in complex with its substrate carnitine or CoA. The structure contains two domains. Surprisingly, these two domains share the same backbone fold, which is also similar to that of chloramphenicol acetyltransferase and dihydrolipoyl transacetylase. The active site is located at the interface between the two domains, in a tunnel that extends through the center of the enzyme. Carnitine and CoA are bound in this tunnel, on opposite sides of the catalytic His343 residue. The structural information provides a molecular basis for understanding the catalysis by carnitine acyltransferases and for designing their inhibitors. In addition, our structural information suggests that the substrate carnitine may assist the catalysis by stabilizing the oxyanion in the reaction intermediate.