Structural insight into function and regulation of carnitine palmitoyltransferase.
The control of fatty acid translocation across the mitochondrial membrane is mediated by the carnitine palmitoyltransferase (CPT) system. Modulation of its functionality has simultaneous effects on fatty acid and glucose metabolism. This encourages use of the CPT system as drug target for reduction of gluconeogenesis and restoration of lipid homeostasis, which are beneficial in the treatment of type 2 diabetes mellitus and obesity. Recently, crystal structures of CPT-2 were determined in uninhibited forms and in complexes with inhibitory substrate-analogs with anti-diabetic properties in animal models and in clinical studies. The CPT-2 crystal structures have advanced understanding of CPT structure-function relationships and will facilitate discovery of novel inhibitors by structure-based drug design. However, a number of unresolved questions regarding the biochemistry and pharmacology of CPT enzymes remain and are addressed in this review.
F. Hoffmann-La Roche AG, Pharma Research Discovery Technologies, 4070 Basel, Switzerland.
Arne C
AC
Rufer
Ralf
R
Thoma
Michael
M
Hennig
D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D051336:Mitochondrial Membranes / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D008970:Molecular Weight; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational; D014018:Tissue Distribution
D005227:Fatty Acids; D007527:Isoenzymes; D002334:Carnitine O-Palmitoyltransferase