Thiamine (vitamin B1) uptake and diphosphate activation (SLC19A2/A3 -> TPK1 -> SLC25A19; THTPA)

Humans cannot synthesise thiamine (vitamin B1) and must take it up from the diet, then convert it to its active cofactor form thiamine diphosphate (ThDP, also called thiamine pyrophosphate, TPP), which is required by pyruvate dehydrogenase, 2-oxoglutarate dehydrogenase, branched-chain 2-oxoacid dehydrogenase and transketolase. Free thiamine is imported across the plasma membrane by the two high-affinity SLC19 thiamine transporters THTR1 (SLC19A2) and THTR2 (SLC19A3). In the cytosol thiamine pyrophosphokinase TPK1 transfers a diphosphate group from ATP (physiologically UTP is the preferred donor) to thiamine, producing ThDP. ThDP is then delivered to the mitochondrial matrix by the inner-membrane carrier SLC25A19 to supply the matrix dehydrogenases. Cellular thiamine triphosphate (ThTP), a minor phosphorylated form, is hydrolysed back to ThDP by the cytosolic thiamine triphosphatase THTPA, contributing to phosphothiamine homeostasis. Defects in this module cause thiamine-responsive megaloblastic anaemia (SLC19A2 / Rogers syndrome), biotin-thiamine-responsive basal ganglia disease (SLC19A3), thiamine metabolism dysfunction syndrome 5 / episodic encephalopathy (TPK1) and Amish lethal microcephaly / THMD4 (SLC25A19).