TPK1 (thiamin pyrophosphokinase 1) catalyzes the phosphorylation of thiamine to thiamine pyrophosphate (TPP), a critical cofactor for mitochondrial energy metabolism 1. The enzyme preferentially uses uridine 5'-triphosphate (UTP) as its phosphoryl donor, directly linking pyrimidine metabolism to TPP biosynthesis and vitamin B1 utilization 1. By generating TPP, TPK1 indirectly supports pyruvate dehydrogenase (PDH) activity and the tricarboxylic acid cycle, thereby maintaining pyruvate oxidation and de novo lipogenesis 1. While TPK1 can utilize ATP and CTP in vitro, these substrates show significantly lower efficiency without established physiological relevance 1. Mutations in TPK1 cause thiamine metabolism dysfunction syndrome 5 and episodic encephalopathy type, with thiamine supplementation (30 mg/kg/day) improving clinical outcomes 2. Lower TPK1 plasma levels are associated with increased Parkinson's disease risk, highlighting its role in neurological health 3. Deep intronic TPK1 variants can cause secondary pyruvate dehydrogenase complex deficiency through aberrant splicing 4. Additionally, common TPK1 intronic variants associate with birth weight variation in normal humans 5.