Showing Metabocard for thiamine diphosphate (BASm0003812)

Common Name

Thiamine diphosphate

Description

Thiamine pyrophosphate (CAS: 154-87-0) is the active form of thiamine, and it serves as a cofactor for several enzymes involved primarily in carbohydrate catabolism. These enzymes are important in the biosynthesis of several cell constituents, including neurotransmitters, and for the production of reducing equivalents used in oxidant stress defences. The enzymes are also important for the synthesis of pentoses used as nucleic acid precursors. The chemical structure of TPP is that of an aromatic methylaminopyrimidine ring, linked via a methylene bridge to a methylthiazolium ring with a pyrophosphate group attached to a hydroxyethyl side chain. In non-enzymatic model studies, it has been demonstrated that the thiazolium ring can catalyze reactions that are similar to those of TPP-dependent enzymes but several orders of magnitude slower. Using infrared and NMR spectrophotometry it has been shown that the dissociation of the proton from C2 of the thiazolium ring is necessary for catalysis; the abstraction of the proton leads to the formation of a carbanion with the potential for a nucleophilic attack on the carbonyl group of the substrate. In all TPP-dependent enzymes, the abstraction of the proton from the C2 atom is the first step in catalysis, which is followed by a nucleophilic attack of this carbanion on the substrate. Subsequent cleavage of a C-C bond releases the first product with the formation of a second carbanion (enamine). This formation is the second feature of TPP catalysis common to all TPP-dependent enzymes. Depending on the enzyme and the substrate(s), the reaction intermediates and products differ. Methyl-branched fatty acids, as phytanic acid, undergo peroxisomal beta-oxidation in which they are shortened by 1 carbon atom. This process includes four steps: activation, 2-hydroxylation, thiamine pyrophosphate-dependent cleavage, and aldehyde dehydrogenation. In the third step, 2-hydroxy-3-methylacyl-CoA is cleaved in the peroxisomal matrix by 2-hydroxyphytanoyl-CoA lyase (2-HPCL), which uses thiamine pyrophosphate (TPP) as a cofactor. The thiamine pyrophosphate dependence of the third step is unique in peroxisomal mammalian enzymology. Human pathology due to a deficient alpha-oxidation is mostly linked to mutations in the gene coding for the second enzyme of the sequence, phytanoyl-CoA hydroxylase (EC 1.14.11.18) (PMID:12694175 , 11899071 , 9924800 ).

Structure

Molecular Formula

C₁₂H₁₉N₄O₇P₂S

Average Mass

425.31400

Monoisotopic Mass

425.04497

IUPAC Name

3-[(4-amino-2-methylpyrimidin-5-yl)methyl]-5-(2-{[hydroxy(phosphonooxy)phosphoryl]oxy}ethyl)-4-methyl-1,3-thiazol-3-ium

Traditional Name

Thiamine diphosphate

CAS Registry Number

0136-09-04

SMILES

Cc1ncc(C[n+]2csc(CCOP(=O)([O-])OP(=O)([O-])[O-])c2C)c(N)n1

InChI Identifier

InChI=1S/C12H18N4O7P2S/c1-8-11(3-4-22-25(20,21)23-24(17,18)19)26-7-16(8)6-10-5-14-9(2)15-12(10)13/h5,7H,3-4,6H2,1-2H3,(H4-,13,14,15,17,18,19,20,21)/p+1

InChI Key

AYEKOFBPNLCAJY-UHFFFAOYSA-O

CHEBI ID

CHEBI:58937

HMDB ID

HMDB0001372

Pathways

Name	SMPDB/PathBank
Valine, leucine and isoleucine degradation
Pyruvate metabolism
Lysine degradation
Propanoate metabolism
Oxidation of Branched Chain Fatty Acids
Citric Acid Cycle
Thiamine Metabolism
2-Methyl-3-Hydroxybutryl CoA Dehydrogenase Deficiency
3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency
3-Methylglutaconic Aciduria Type I
3-Methylglutaconic Aciduria Type III
3-Methylglutaconic Aciduria Type IV
Beta-Ketothiolase Deficiency
Glutaric Aciduria Type I
Leigh Syndrome
Malonic Aciduria
Maple Syrup Urine Disease
Methylmalonic Aciduria
Methylmalonic Aciduria Due to Cobalamin-Related Disorders
Pyruvate Dehydrogenase Complex Deficiency
Propionic Acidemia
3-Methylcrotonyl Coa Carboxylase Deficiency Type I
Isovaleric Aciduria
Saccharopinuria/Hyperlysinemia II
Pyruvate Decarboxylase E1 Component Deficiency (PDHE1 Deficiency)
Methylmalonate Semialdehyde Dehydrogenase Deficiency
Phytanic Acid Peroxisomal Oxidation
Refsum Disease
Threonine and 2-Oxobutanoate Degradation
Transfer of Acetyl Groups into Mitochondria
Malonyl-coa decarboxylase deficiency
3-hydroxyisobutyric acid dehydrogenase deficiency
3-hydroxyisobutyric aciduria
Isobutyryl-coa dehydrogenase deficiency
Isovaleric acidemia
Hyperlysinemia I, Familial
Hyperlysinemia II or Saccharopinuria
Congenital lactic acidosis
Fumarase deficiency
Mitochondrial complex II deficiency
2-ketoglutarate dehydrogenase complex deficiency
Pyruvate dehydrogenase deficiency (E3)
Pyruvate dehydrogenase deficiency (E2)
Primary hyperoxaluria II, PH2
Pyruvate kinase deficiency
Pyridoxine dependency with seizures
Warburg Effect
2-aminoadipic 2-oxoadipic aciduria
The oncogenic action of 2-hydroxyglutarate
The Oncogenic Action of Succinate
The Oncogenic Action of Fumarate
Glutaminolysis and Cancer
The oncogenic action of L-2-hydroxyglutarate in Hydroxygluaricaciduria
The oncogenic action of D-2-hydroxyglutarate in Hydroxygluaricaciduria

State

Solid

Water Solubility

1.52e-01 g/l

logP

-1.21

logS

-3.48

pKa (Strongest Acidic)

1.78

pKa (Strongest Basic)

5.53

Hydrogen Acceptor Count

Hydrogen Donor Count

Polar Surface Area

168.97 Å²

Rotatable Bond Count

Physiological Charge

-1

Formal Charge

Refractivity

95.15 m³·mol⁻¹

Polarizability

36.96

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