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This review addresses progress of carnitine palmitoyltransferase targeted pharmaceuticals in diabetes and the challenges ahead. Since the discovery of carnitine palmitoyltransferase (CPT), there are lots of publications on its role in disease. The wide tissue expression, functional and biological roles have documented the physiological importance of these enzymes both in health and disease. Thus, over the years, studies have revealed essential importance of CPT1 in mammalian pathophysiology revealing CPT1 as potential drug targets. Starting from a brief description of the main functional features of CPTs, their roles in physiology and pathophysiology of different human diseases, this review describes the main classes of small molecules which are able to regulate CPT1 for diagnostic and therapeutic applications.

The transport properties of mitochondria are such that net potassium flux across the inner membrane determines mitochondrial volume. It has been known that K+ uptake is mediated by diffusive leak driven by the high electrical membrane potential maintained by redox-driven, electrogenic proton ejection and that regulated K+ efflux is mediated by an 82-kDa inner membrane K+/H+ antiporter. There is also long-standing suggestive evidence for the existence of an inner membrane protein designed to catalyze electrophoretic K+ uptake into mitochondria. We report reconstitution of a highly purified inner membrane protein fraction from rat liver and beef heart mitochondria that catalyzes electrophoretic K+ flux in liposomes and channel activity in planar lipid bilayers. The unit conductance of the channel at saturating [K+] is about 30 pS. Reconstituted K+ flux is inhibited with high affinity by ATP and ADP in the presence of divalent cations and by glibenclamide in the absence of divalent cations. The mitochondrial ATP-dependent K+ channel is selective for K+, with a Km of 32 mM, and does not transport Na+. K+ transport depends on voltage in a manner consistent with a channel activity that is not voltage-regulated. Thus, the mitochondrial ATP-dependent K+ channel exhibits properties that are remarkably similar to those of the ATP-dependent K+ channels of plasma membranes.

The uncoupling protein is one of a family of mitochondrial transport proteins involved in energy metabolism. It dissipates oxidative energy to generate heat, either by catalyzing proton transport directly or by catalyzing fatty acid anion transport, thus enabling fatty acids to act as cycling protonophores. This transport process is tightly regulated by purine nucleotides. We have expressed uncoupling protein in yeast and examined its proton transport activity after its reconstitution into proteoliposomes. A directed change of Arg276 to Leu or Gln completely abolished nucleotide inhibition of protonophoretic action of the reconstituted mutant uncoupling proteins without affecting the transport process. Arg276 is the first residue of functional importance to be identified in uncoupling protein. Mutation of the homologous residue in the yeast ADP/ATP translocator prevented the growth of yeast on a nonfermentable carbon source, presumably by interfering with nucleotide exchange (Nelson, D. R., Lawson, J. E., Klingenberg, M., and Douglas, M. G. (1993) J. Mol. Biol. 230, 1159-1170). Demonstration of the essential role of a single homologous residue in protein-nucleotide interaction within these two transporters is the first direct evidence that uncoupling protein and the ADP/ATP translocator belong to the same gene family.