Thiamine pyrophosphate (TPP or ThPP), or thiamine diphosphate (ThDP), or cocarboxylase is a thiamine (vitamin B1) derivative which is produced by the enzyme thiamine diphosphokinase. Thiamine pyrophosphate is a cofactor that is present in all living systems, in which it catalyzes several biochemical reactions. Thiamine pyrophosphate is synthesized in the cytosol and is required in the cytosol for the activity of transketolase and in the mitochondria for the activity of pyruvate-, oxoglutarate- and branched chain keto acid dehydrogenases. To date, the yeast ThPP carrier (Tpc1p) the human Tpc and the Drosophila melanogaster have been identified as being responsible for the mitochondrial transport of ThPP and ThMP. It was first discovered as an essential nutrient (vitamin) in humans through its link with the peripheral nervous system disease beriberi, which results from a deficiency of thiamine in the diet. TPP works as a coenzyme in many enzymatic reactions, such as: Pyruvate dehydrogenase complex Pyruvate decarboxylase in ethanol fermentation Alpha-ketoglutarate dehydrogenase complex Branched-chain amino acid dehydrogenase complex 2-hydroxyphytanoyl-CoA lyase Transketolase Chemistry Chemically, TPP consists of a pyrimidine ring which is connected to a thiazole ring, which is in turn connected to a pyrophosphate (diphosphate) functional group. The part of TPP molecule that is most commonly involved in reactions is the thiazole ring, which contains nitrogen and sulfur. Thus, the thiazole ring is the "reagent portion" of the molecule. The C2 of this ring is capable of acting as an acid by donating its proton and forming a carbanion. Normally, reactions that form carbanions are highly unfavorable, but the positive charge on the tetravalent nitrogen just adjacent to the carbanion stabilizes the negative charge, making the reaction much more favorable. A compound with positive and negative charges on adjacent atoms is called an ylide, so sometimes the carbanion form of TPP is referred to as the "ylide form". Reaction mechanisms In several reactions, including that of pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, and transketolase, TPP catalyses the reversible decarboxylation reaction (aka cleavage of a substrate compound at a carbon-carbon bond connecting a carbonyl group to an adjacent reactive group—usually a carboxylic acid or an alcohol). It achieves this in four basic steps: The carbanion of the TPP ylid nucleophilically attacks the carbonyl group on the substrate. (This forms a single bond between the TPP and the substrate.) The target bond on the substrate is broken, and its electrons are pushed towards the TPP. This creates a