2.0 2012-05-31 13:51:11 -0600 2015-09-13 12:56:11 -0600 ECMDB01372 M2MDB000361 Thiamine pyrophosphate Thiamine pyrophosphate (TPP) is the active form of thiamine, and it serves as a cofactor for several enzymes involved primarily in carbohydrate catabolism. The enzymes are important in the biosynthesis of a number of cell constituents and for the production of reducing equivalents used in oxidant stress defenses and in biosyntheses and for 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 catalyse reactions which 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 (ylid) 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 formation of a second carbanion (2-greek small letter alpha-carbanion or enamine). The formation of this 2-greek small letter alpha-carbanion 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 cofactor. (PMID: 12694175, 11899071, 9924800) TDP Thaimine pyrophosphate Thaimine pyrophosphoric acid Thiamin diphosphate Thiamin diphosphoric acid Thiamin pyrophosphate Thiamin pyrophosphoric acid Thiamin-PPi Thiamine diphosphate Thiamine diphosphoric acid Thiamine pyrophosphate Thiamine pyrophosphoric acid Thiamine-PPi Thiamine-pyrophosphate Thiamine-pyrophosphoric acid ThiamineDP ThPP TPP C12H19N4O7P2S 425.314 425.044967696 3-[(4-amino-2-methylpyrimidin-5-yl)methyl]-5-(2-{[hydroxy(phosphonooxy)phosphoryl]oxy}ethyl)-4-methyl-1,3-thiazol-3-ium thiamin pyrophosphate 154-87-0 CC1=C(CCO[P@](O)(=O)OP(O)(O)=O)SC=[N+]1CC1=CN=C(C)N=C1N 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 AYEKOFBPNLCAJY-UHFFFAOYSA-O Solid Cytosol logp -1.21 ALOGPS logs -3.48 ALOGPS solubility 1.52e-01 g/l ALOGPS logp -5.8 ChemAxon pka_strongest_acidic 1.78 ChemAxon pka_strongest_basic 5.53 ChemAxon iupac 3-[(4-amino-2-methylpyrimidin-5-yl)methyl]-5-(2-{[hydroxy(phosphonooxy)phosphoryl]oxy}ethyl)-4-methyl-1,3-thiazol-3-ium ChemAxon average_mass 425.314 ChemAxon mono_mass 425.044967696 ChemAxon smiles CC1=C(CCO[P@](O)(=O)OP(O)(O)=O)SC=[N+]1CC1=CN=C(C)N=C1N ChemAxon formula C12H19N4O7P2S ChemAxon inchi 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 ChemAxon inchikey AYEKOFBPNLCAJY-UHFFFAOYSA-O ChemAxon polar_surface_area 168.97 ChemAxon refractivity 95.15 ChemAxon polarizability 36.96 ChemAxon rotatable_bond_count 8 ChemAxon acceptor_count 8 ChemAxon donor_count 4 ChemAxon physiological_charge -1 ChemAxon formal_charge 1 ChemAxon Citrate cycle (TCA cycle) ec00020 Butanoate metabolism ec00650 Glycolysis / Gluconeogenesis ec00010 Pyruvate metabolism ec00620 Thiamine metabolism ec00730 Valine, leucine and isoleucine degradation ec00280 Metabolic pathways eco01100 Vitamin B1/Thiamine PW000892 Metabolic Thiamin diphosphate biosynthesis PW002028 Metabolic pyruvate to cytochrome bd terminal oxidase electron transfer The reaction of pyruvate to cytochrome bd terminal oxidase electron transfer starts with 2 pyruvate and 2 water molecules reacting in a pyruvate oxidase resulting in the release of 4 electrons into the inner membrane, and releasing 2 carbon dioxide molecules , 2 acetate and 4 hydrogen ion into the cytosol. 2 ubiquinone,4 hydrogen ion and 4 electron ion react resulting in the release of 2 ubiquinol . The 2 ubiquinol in turn release 4 hydrogen ions into the periplasmic space through a cytochrome bd-I terminal oxidase and releasing 4 electrons through the enzyme. Oxygen and 4 hydrogen ion reacts with the 4 electrons resulting in 2 water molecules. PW002087 Metabolic thiamin diphosphate biosynthesis I (E. coli) PWY-6894 Specdb::CMs 21217 Specdb::CMs 146535 Specdb::NmrOneD 1691 Specdb::NmrOneD 87892 Specdb::NmrOneD 87893 Specdb::NmrOneD 87894 Specdb::NmrOneD 87895 Specdb::NmrOneD 87896 Specdb::NmrOneD 87897 Specdb::NmrOneD 87898 Specdb::NmrOneD 87899 Specdb::NmrOneD 87900 Specdb::NmrOneD 87901 Specdb::NmrOneD 87902 Specdb::NmrOneD 87903 Specdb::NmrOneD 87904 Specdb::NmrOneD 87905 Specdb::NmrOneD 87906 Specdb::NmrOneD 87907 Specdb::NmrOneD 87908 Specdb::NmrOneD 87909 Specdb::NmrOneD 87910 Specdb::NmrOneD 87911 Specdb::NmrOneD 166374 Specdb::NmrOneD 166669 Specdb::MsMs 1541 Specdb::MsMs 1542 Specdb::MsMs 1543 Specdb::MsMs 5210 Specdb::MsMs 5211 Specdb::MsMs 5212 Specdb::MsMs 5213 Specdb::MsMs 5214 Specdb::MsMs 5215 Specdb::MsMs 5216 Specdb::MsMs 5217 Specdb::MsMs 5218 Specdb::MsMs 5219 Specdb::MsMs 178236 Specdb::MsMs 178237 Specdb::MsMs 178238 Specdb::MsMs 180552 Specdb::MsMs 180553 Specdb::MsMs 180554 Specdb::MsMs 437451 Specdb::MsMs 437452 Specdb::MsMs 437453 Specdb::MsMs 437454 Specdb::MsMs 437455 Specdb::MsMs 445905 Specdb::NmrTwoD 1632 HMDB01372 1132 1100 C00068 9532 THIAMINE-PYROPHOSPHATE TPP Thiamine pyrophosphate Keseler, I. M., Collado-Vides, J., Santos-Zavaleta, A., Peralta-Gil, M., Gama-Castro, S., Muniz-Rascado, L., Bonavides-Martinez, C., Paley, S., Krummenacker, M., Altman, T., Kaipa, P., Spaulding, A., Pacheco, J., Latendresse, M., Fulcher, C., Sarker, M., Shearer, A. G., Mackie, A., Paulsen, I., Gunsalus, R. P., Karp, P. D. (2011). "EcoCyc: a comprehensive database of Escherichia coli biology." Nucleic Acids Res 39:D583-D590. 21097882 Kanehisa, M., Goto, S., Sato, Y., Furumichi, M., Tanabe, M. (2012). "KEGG for integration and interpretation of large-scale molecular data sets." Nucleic Acids Res 40:D109-D114. 22080510 van der Werf, M. J., Overkamp, K. M., Muilwijk, B., Coulier, L., Hankemeier, T. (2007). "Microbial metabolomics: toward a platform with full metabolome coverage." Anal Biochem 370:17-25. 17765195 Casteels, M., Foulon, V., Mannaerts, G. P., Van Veldhoven, P. P. (2003). "Alpha-oxidation of 3-methyl-substituted fatty acids and its thiamine dependence." Eur J Biochem 270:1619-1627. 12694175 Foulon V, Sniekers M, Huysmans E, Asselberghs S, Mahieu V, Mannaerts GP, Van Veldhoven PP, Casteels M: Breakdown of 2-hydroxylated straight chain fatty acids via peroxisomal 2-hydroxyphytanoyl-CoA lyase: a revised pathway for the alpha-oxidation of straight chain fatty acids. J Biol Chem. 2005 Mar 18;280(11):9802-12. Epub 2005 Jan 11. 15644336 Singleton CK, Martin PR: Molecular mechanisms of thiamine utilization. Curr Mol Med. 2001 May;1(2):197-207. 11899071 Molina JA, Jimenez-Jimenez FJ, Hernanz A, Fernandez-Vivancos E, Medina S, de Bustos F, Gomez-Escalonilla C, Sayed Y: Cerebrospinal fluid levels of thiamine in patients with Alzheimer's disease. J Neural Transm. 2002 Jul;109(7-8):1035-44. 12111441 Shimon I, Almog S, Vered Z, Seligmann H, Shefi M, Peleg E, Rosenthal T, Motro M, Halkin H, Ezra D: Improved left ventricular function after thiamine supplementation in patients with congestive heart failure receiving long-term furosemide therapy. Am J Med. 1995 May;98(5):485-90. 7733128 Floridi A, Pupita M, Palmerini CA, Fini C, Alberti Fidanza A: Thiamine pyrophosphate determination in whole blood and erythrocytes by high performance liquid chromatography. Int J Vitam Nutr Res. 1984;54(2-3):165-71. 6500839 Essama-Tjani JC, Guilland JC, Fuchs F, Lombard M, Richard D: Changes in thiamin, riboflavin, niacin, beta-carotene, vitamins, C, A, D and E status of French Elderly Subjects during the first year of institutionalization. Int J Vitam Nutr Res. 2000 Mar;70(2):54-64. 10804457 Warnock LG: The measurement of erythrocyte thiamin pyrophosphate by high-performance liquid chromatography. Anal Biochem. 1982 Nov 1;126(2):394-7. 7158773 Lynch PL, Trimble ER, Young IS: High-performance liquid chromatographic determination of thiamine diphosphate in erythrocytes using internal standard methodology. J Chromatogr B Biomed Sci Appl. 1997 Nov 7;701(1):120-3. 9389346 Naito E, Ito M, Yokota I, Saijo T, Ogawa Y, Kuroda Y: Diagnosis and molecular analysis of three male patients with thiamine-responsive pyruvate dehydrogenase complex deficiency. J Neurol Sci. 2002 Sep 15;201(1-2):33-7. 12163191 Baines M: Improved high performance liquid chromatographic determination of thiamin diphosphate in erythrocytes. Clin Chim Acta. 1985 Nov 29;153(1):43-8. 4075519 Duffy P, Morris H, Neilson G: Thiamin status of a Melanesian population. Am J Clin Nutr. 1981 Aug;34(8):1584-92. 7270482 Kjosen B, Seim SH: The transketolase assay of thiamine in some diseases. Am J Clin Nutr. 1977 Oct;30(10):1591-6. 910736 Winston AP, Jamieson CP, Madira W, Gatward NM, Palmer RL: Prevalence of thiamin deficiency in anorexia nervosa. Int J Eat Disord. 2000 Dec;28(4):451-4. 11054793 Levy S, Herve C, Delacoux E, Erlinger S: Thiamine deficiency in hepatitis C virus and alcohol-related liver diseases. Dig Dis Sci. 2002 Mar;47(3):543-8. 11911339 Talwar D, Davidson H, Cooney J, St JO'Reilly D: Vitamin B(1) status assessed by direct measurement of thiamin pyrophosphate in erythrocytes or whole blood by HPLC: comparison with erythrocyte transketolase activation assay. Clin Chem. 2000 May;46(5):704-10. 10794754 Fidanza F, Simonetti MS, Floridi A, Codini M, Fidanza R: Comparison of methods for thiamin and riboflavin nutriture in man. Int J Vitam Nutr Res. 1989;59(1):40-7. 2722424 Tate JR, Nixon PF: Measurement of Michaelis constant for human erythrocyte transketolase and thiamin diphosphate. Anal Biochem. 1987 Jan;160(1):78-87. 3565758 Frank T, Bitsch R, Maiwald J, Stein G: High thiamine diphosphate concentrations in erythrocytes can be achieved in dialysis patients by oral administration of benfontiamine. Eur J Clin Pharmacol. 2000 Jun;56(3):251-7. 10952481 Lavoie J, Butterworth RF: Reduced activities of thiamine-dependent enzymes in brains of alcoholics in the absence of Wernicke's encephalopathy. Alcohol Clin Exp Res. 1995 Aug;19(4):1073-7. 7485819 Schenk G, Duggleby RG, Nixon PF: Properties and functions of the thiamin diphosphate dependent enzyme transketolase. Int J Biochem Cell Biol. 1998 Dec;30(12):1297-318. 9924800 Zabrodskaya, S. V.; Oparin, D. A.; Ostrovskii, Yu. M. Selective synthesis of thiamine diphosphate. Zhurnal Obshchei Khimii (1989), 59(1), 226-7. http://hmdb.ca/system/metabolites/msds/000/001/234/original/HMDB01372.pdf?1358462487 Acetolactate synthase isozyme 3 large subunit P00893 ILVI_ECOLI ilvI http://ecmdb.ca/proteins/P00893.xml Acetolactate synthase isozyme 3 small subunit P00894 ILVH_ECOLI ilvH http://ecmdb.ca/proteins/P00894.xml Acetolactate synthase isozyme 1 large subunit P08142 ILVB_ECOLI ilvB http://ecmdb.ca/proteins/P08142.xml Acetolactate synthase isozyme 1 small subunit P0ADF8 ILVN_ECOLI ilvN http://ecmdb.ca/proteins/P0ADF8.xml Acetolactate synthase isozyme 2 small subunit P0ADG1 ILVM_ECOLI ilvM http://ecmdb.ca/proteins/P0ADG1.xml Phosphatase nudJ P0AEI6 NUDJ_ECOLI nudJ http://ecmdb.ca/proteins/P0AEI6.xml 2-oxoglutarate dehydrogenase E1 component P0AFG3 ODO1_ECOLI sucA http://ecmdb.ca/proteins/P0AFG3.xml Pyruvate dehydrogenase E1 component P0AFG8 ODP1_ECOLI aceE http://ecmdb.ca/proteins/P0AFG8.xml Thiamine-monophosphate kinase P0AGG0 THIL_ECOLI thiL http://ecmdb.ca/proteins/P0AGG0.xml 4-alpha-L-fucosyltransferase P56258 WECF_ECOLI wecF http://ecmdb.ca/proteins/P56258.xml Adenosine triphosphate + Thiamine monophosphate <> ADP + Thiamine pyrophosphate R00617 THI-P-KIN-RXN Water + Thiamine pyrophosphate > Hydrogen ion + Phosphate + Thiamine monophosphate RXN0-3542 Pyruvic acid + Thiamine pyrophosphate <> 2-(a-Hydroxyethyl)thiamine diphosphate + Carbon dioxide R00014 alpha-Ketoglutarate + Thiamine pyrophosphate <> 3-carboxy-1-hydroxypropylthiamine diphosphate + Carbon dioxide R00621 2-Acetolactate + Thiamine pyrophosphate <> 2-(a-Hydroxyethyl)thiamine diphosphate + Pyruvic acid R03050 2-(a-Hydroxyethyl)thiamine diphosphate + Enzyme N6-(lipoyl)lysine <> [Dihydrolipoyllysine-residue acetyltransferase] S-acetyldihydrolipoyllysine + Thiamine pyrophosphate R03270 3-carboxy-1-hydroxypropylthiamine diphosphate + Enzyme N6-(lipoyl)lysine <> [Dihydrolipoyllysine-residue succinyltransferase] S-succinyldihydrolipoyllysine + Thiamine pyrophosphate R03316 (S)-2-Acetolactate + Thiamine pyrophosphate <> 2-(a-Hydroxyethyl)thiamine diphosphate + Pyruvic acid R04672 2-Ketobutyric acid + 2-(a-Hydroxyethyl)thiamine diphosphate <> 2-Aceto-2-hydroxy-butyrate + Thiamine pyrophosphate R04673 2-(a-Hydroxyethyl)thiamine diphosphate + Pyruvate-dehydrogenase-lipoate > Thiamine pyrophosphate + Pyruvate-dehydrogenase-acetylDHlipoyl RXN-12508 Hydrogen ion + Pyruvic acid + Thiamine pyrophosphate > 2-(a-Hydroxyethyl)thiamine diphosphate + Carbon dioxide R00014 RXN-12583 Hydrogen ion + Thiamine pyrophosphate + ADP <> adenosine thiamine triphosphate + Phosphate RXN0-5291 Thiamine monophosphate + Adenosine triphosphate > Thiamine pyrophosphate + ADP THI-P-KIN-RXN TDP-Fuc4NAc + Und-PP-GlcNAc-ManNAcA > Thiamine pyrophosphate + Und-PP-GlcNAc-ManNAcA-Fuc4NAc Thiamine monophosphate + Adenosine triphosphate + Thiamine monophosphate > Thiamine pyrophosphate + Adenosine diphosphate + ADP PW_R003337 Adenosine triphosphate + Thiamine monophosphate <> ADP + Thiamine pyrophosphate