The regulated uncoupling of oxidative phosphorylation is a biologically useful means of generating heat. The uncoupling of oxidative phosphorylation is a means of generating heat to maintain body temperature in hibernating animals, in some newborn animals (including human beings), and in mammals adapted to cold. Brown adipose tissue, which is very rich in mitochondria (often referred to as brown fat mitochondria), is specialized for this process of non shivering thermogenesis. The inner mitochondrial membrane of these mitochondria contains a large amount of uncoupling protein (UCP), here UCP-1, or Thermogenin, a dimer of 33-kd subunits that resembles ATP-ADP translocase. UCP-1 forms a pathway for the flow of protons from the cytosol to the matrix. In essence, UCP-1 generates heat by short-circuiting the mitochondrial proton battery. This UCP-1 channel is activated by fatty acids (as in the given case) – Figure-2.
Initially, pyruvate and thiamine pyrophosphate (TPP or vitamin B 1 ) are bound by pyruvate dehydrogenase subunits. The thiazolium ring of TPP is in a zwitterionic form, and the anionic C2 carbon performs a nucleophilic attack on the C2 (ketone) carbonyl of pyruvate. The resulting hemithioacetal undergoes decarboxylation to produce an acyl anion equivalent (see cyanohydrin or aldehyde-dithiane umpolung chemistry, as well as benzoin condensation ). This anion attacks S1 of an oxidized lipoate species that is attached to a lysine residue. In a ring-opening S N 2-like mechanism, S2 is displaced as a sulfide or sulfhydryl moiety. Subsequent collapse of the tetrahedral hemithioacetal ejects thiazole, releasing the TPP cofactor and generating a thioacetate on S1 of lipoate. The E1-catalyzed process is the rate-limiting step of the whole pyruvate dehydrogenase complex.