Table 6.

Key metabolic enzymes that use thiamine pyrophosphate as a cofactor.^{5,62,65,70–75,77}

Enzyme	HGNC approved gene symbol	Cytogenic location	Subcellular location	Pathway/function	Magnesium as a further cofactor	Functions of metabolic products and resulting other pathways intermediates	Clinical implication in deficiency states
TK EC 2.2.1.1	TKT	3p21.1	Cytosol, extracellular exosome, nucleus, peroxisome, vesicles	Pentose phosphate pathway	Yes	Substrates in the glycolytic pathways Generation of d-ribose-5-P → Nucleotide synthesis → RNA/DNA synthesis NADPH as a reducing agent for fatty acid and acetylcholine synthesis, maintenance of myelin sheaths Aromatic amino acid synthesis	↓ energy supply ↓ nucleotide synthesis ↓ fatty acid synthesis → facilitating demyelination ↑oxidative stress Amino acid imbalance
TK protein 1 EC 2.2.1.1	TKTL 1	Xq28	Cytosol, nucleus	As TK	Yes	May structurally alter TPP to change TPP affinity for TK78	Unclear
PDHG EC 1.2.4.1	PDHA1	Xp22.12	Mitochondrion, nucleus, PDHG complex (GO:0045254)a	Glycolysis (rate-limiting co-factor)	Yes	Fatty acid, ketone bodies and acetylcholine synthesis, maintenance of myelin sheaths Generation of Acetyl CoA Generation of citrate, the first component in the TCA cycle	↓ fatty acid synthesis → demyelination ↓ Energy (ATP) production Leigh phenotype
α-ketoglutarate dehydrogenase α-KGDH/OGDC EC 1.2.4.2	OGDH	7p13	Mitochondrion, nucleus, OGDC (GO: 0045252)a	TCA (citric acid) cycle	Yes	Energy production (ATP) Generation of succinyl CoA	↑ nitric oxide and peroxidase activity →oxidative stress ↓ energy production Lactate acidosis and ↑focal extracellular glutamate → oedema → excitotoxicity → BBB permeability → neuronal death
BCKDH E1 subunit α EC 1.2.4.4	BCKDHA	19q13.2	Mitochondrion	Degradation of branched chain amino acids, valine, leucine and isoleucine, facilitating the oxidative decarboxylation step	Yes	Isobuturyl CoA, α-methylbuturyl CoA, isovaleryl CoA → acetyl CoA, acetoacetate, succinyl CoA → Fatty acid, ketone bodies and acetylcholine synthesis, maintenance of myelin sheaths	↓ fatty acid synthesis → demyelination ↑ Valine, leucine and isoleucine and corresponding α-ketoacids → maple syrup urine disease
2-hydroxyacyl CoA lyase 1 (HACL1) EC 4.1.-.-	HACL1	3p25.1	Cytosol, peroxisomes	Oxidation of 3-methyl branched fatty acids such as phytanic acid and 2-hydroxy fatty acids (α-oxidation)	Yes	Formate → CO2	Peroxisome biogenesis defects → impeding the breakdown of certain nutrients including amino acids degeneration and β-oxidation of fatty acids ↑ phytanic acid → Refsum disease

^aNote that this term represents a location and not a function.

ATP, adenosine triphosphate; BCKDH, branched chain α-keto acid dehydrogenase; Co A, coenzyme A; EC, Enzyme Commission numbers; GO, gene ontology; HGNC, HUGO Gene Nomenclature Committee; NADPH, nicotinamide adenine dinucleotide phosphate (hydrogenated, i.e. reduced form); ODGC, oxoglutarate dehydrogenase complex; P, phosphate; PDHG, pyruvate dehydrogenase; TCA cycle, tricarboxylic acid cycle; TK, transketolase; TPP, thiamine pyrophosphate.