2.02012-05-31 13:03:32 -06002015-06-03 15:53:40 -0600ECMDB01016M2MDB000227D-4'-PhosphopantothenateD-4'-Phosphopantothenate is a product of the phosphorylatation of Pantothenate by Pantothenate kinase. It is an intermediate in coenzyme A (CoA) biosynthesis pathway. Coenzyme A is a cofactor of ubiquitous occurrence in plants, bacteria, and animals. It is needed in a large number of enzymatic reactions central to intermediary metabolism, including the oxidation of fatty acids, carbohydrates, and amino acids. Only plants and microorganisms like E. coli are capable of synthesizing this compound de novo. (R)-4'-phosphopantothenate(R)-4'-phosphopantothenic acid4'-P-Pantothenate4'-P-Pantothenic acid4'-Phosphopantothenate4'-Phosphopantothenic acid4'PPAD-4'-PhosphopantothenateD-4'-Phosphopantothenic acidC9H18NO8P299.2149299.0770030693-{2-hydroxy-3-methyl-3-[(phosphonooxy)methyl]butanamido}propanoic acid3-{2-hydroxy-3-methyl-3-[(phosphonooxy)methyl]butanamido}propanoic acidCC(C)(COP(O)(O)=O)C(O)C(=O)NCCC(O)=OInChI=1S/C9H18NO8P/c1-9(2,5-18-19(15,16)17)7(13)8(14)10-4-3-6(11)12/h7,13H,3-5H2,1-2H3,(H,10,14)(H,11,12)(H2,15,16,17)XHFVGHPGDLDEQO-UHFFFAOYSA-NSolidCytosollogp-2.14logs-1.55solubility8.51e+00 g/llogp-1.5pka_strongest_acidic1.79pka_strongest_basic-3.8iupac3-{2-hydroxy-3-methyl-3-[(phosphonooxy)methyl]butanamido}propanoic acidaverage_mass299.2149mono_mass299.077003069smilesCC(C)(COP(O)(O)=O)C(O)C(=O)NCCC(O)=OformulaC9H18NO8PinchiInChI=1S/C9H18NO8P/c1-9(2,5-18-19(15,16)17)7(13)8(14)10-4-3-6(11)12/h7,13H,3-5H2,1-2H3,(H,10,14)(H,11,12)(H2,15,16,17)inchikeyXHFVGHPGDLDEQO-UHFFFAOYSA-Npolar_surface_area153.39refractivity62.38polarizability26.6rotatable_bond_count8acceptor_count7donor_count5physiological_charge-3formal_charge0Pantothenate and CoA biosynthesisThe CoA biosynthesis requires compounds from two other pathways: aspartate metabolism and valine biosynthesis. It requires a Beta-Alanine and R-pantoate.
The compound (R)-pantoate is generated in two reactions, as shown by the interaction of alpha-ketoisovaleric acid, 5,10 methylene-THF and water through a 3-methyl-2-oxobutanoate hydroxymethyltransferase resulting in a tetrahydrofolic acid and a 2-dehydropantoate. This compound interacts with hydrogen through a NADPH driven acetohydroxy acid isomeroreductase resulting in the release of NADP and R-pantoate.
On the other hand L-aspartic acid interacts with a hydrogen ion and gets decarboxylated through an Aspartate 1- decarboxylase resulting in a carbon dioxide and a Beta-alanine.
Beta-alanine and R-pantoate interact with an ATP driven pantothenate synthetase resulting in pyrophosphate, AMP, hydrogen ion and pantothenic acid.
Pantothenic acid is phosphorylated through a ATP-driven pantothenate kinase resulting in a ADP, a hydrogen ion and D-4'-Phosphopantothenate. This compound interacts with a CTP and a L-cysteine resulting in a fused 4'-phosphopantothenoylcysteine decarboxylase and phosphopantothenoylcysteine synthetase resulting in a hydrogen ion, a pyrophosphate, a CMP and 4-phosphopantothenoylcysteine.
The latter compound interacts with a hydrogen ion through a fused 4'-phosphopantothenoylcysteine decarboxylase and phosphopantothenoylcysteine synthetase resulting in a carbon dioxide release and a 4-phosphopantetheine. This compound interacts with an ATP, hydrogen ion and an phosphopantetheine adenylyltransferase resulting in a release of pyrophosphate, and dephospho-CoA.
Dephospho-CoA reacts with an ATP driven dephospho-CoA kinase resulting in a ADP , a hydrogen ion and a Coenzyme A.
. The latter is converted into (R)-4'-phosphopantothenate is two steps, involving a β-alanine ligase and a kinase. In most organsims the ligase acts before the kinase (EC 6.3.2.1, pantoate—β-alanine ligase (AMP-forming) followed by EC 2.7.1.33, pantothenate kinase, as described in phosphopantothenate biosynthesis I and phosphopantothenate biosynthesis II. However, in archaea the order is reversed, and EC 2.7.1.169, pantoate kinase acts before EC 6.3.2.36, 4-phosphopantoate—β-alanine ligase, as described in phosphopantothenate biosynthesis III.
The kinases are feedback inhibited by CoA itself, accounting for the primary regulatory mechanism of CoA biosynthesis. The addition of L-cysteine to (R)-4'-phosphopantothenate, resulting in the formation of R-4'-phosphopantothenoyl-L-cysteine (PPC), is followed by decarboxylation of PPC to 4'-phosphopantetheine. The ultimate reaction is catalyzed by EC 2.7.1.24, dephospho-CoA kinase, which converts 4'-phosphopantetheine to CoA. All enzymes of this pathway are essential for growth.
The reactions in the biosynthetic route towards CoA are identical in most organisms, although there are differences in the functionality of the involved enzymes. In plants every step is catalyzed by single monofunctional enzymes, whereas in bacteria and mammals bifunctional enzymes are often employed [Rubio06].PW000828ec00770Metabolicbeta-Alanine metabolismThe Beta-Alanine Metabolism starts with a product of Aspartate metabolism. Aspartate is decarboxylated by aspartate 1-decarboxylase, releasing carbon dioxide and Beta-alanine. Beta alanine is then metabolized through a pantothenate synthetase resulting in Pantothenic acid undergoes phosphorylation through a ATP driven pantothenate kinase, resulting in D-4-phosphopantothenate.
Pantothenate (vitamin B5) is the universal precursor for the synthesis of the 4'-phosphopantetheine moiety of coenzyme A and acyl carrier protein. Only plants and microorganismscan synthesize pantothenate de novo - animals require a dietary supplement. The enzymes of this pathway are therefore considered to be antimicrobial drug targets.PW000896ec00410MetabolicMetabolic pathwayseco01100phosphopantothenate biosynthesis IPANTO-PWYcoenzyme A biosynthesisCOA-PWYSpecdb::CMs3456Specdb::CMs37893Specdb::NmrOneD314561Specdb::NmrOneD314562Specdb::NmrOneD314563Specdb::NmrOneD314564Specdb::NmrOneD314565Specdb::NmrOneD314566Specdb::NmrOneD314567Specdb::NmrOneD314568Specdb::NmrOneD314569Specdb::NmrOneD314570Specdb::NmrOneD314571Specdb::NmrOneD314572Specdb::NmrOneD314573Specdb::NmrOneD314574Specdb::NmrOneD314575Specdb::NmrOneD314576Specdb::NmrOneD314577Specdb::NmrOneD314578Specdb::NmrOneD314579Specdb::NmrOneD314580Specdb::MsMs23426Specdb::MsMs23427Specdb::MsMs23428Specdb::MsMs30224Specdb::MsMs30225Specdb::MsMs30226HMDB0101641635128C03492159054-P-PANTOTHENATEKeseler, 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-D590.21097882Kanehisa, 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-D114.22080510van 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 370:17-25.17765195Winder, C. L., Dunn, W. B., Schuler, S., Broadhurst, D., Jarvis, R., Stephens, G. M., Goodacre, R. (2008). "Global metabolic profiling of Escherichia coli cultures: an evaluation of methods for quenching and extraction of intracellular metabolites." Anal Chem 80:2939-2948.18331064Pantothenate kinaseP0A6I3COAA_ECOLIcoaAhttp://ecmdb.ca/proteins/P0A6I3.xmlCoenzyme A biosynthesis bifunctional protein coaBCP0ABQ0COABC_ECOLIcoaBChttp://ecmdb.ca/proteins/P0ABQ0.xmlD-4'-Phosphopantothenate + Cytidine triphosphate + L-Cysteine > 4-Phosphopantothenoylcysteine + Cytidine monophosphate + Hydrogen ion + PyrophosphateR04231P-PANTOCYSLIG-RXNAdenosine triphosphate + Pantothenic acid <> D-4'-Phosphopantothenate + ADP + Hydrogen ionR03018PANTOTHENATE-KIN-RXNAdenosine triphosphate + Pantothenic acid <> ADP + D-4'-PhosphopantothenateR03018PANTOTHENATE-KIN-RXNAdenosine triphosphate + D-4'-Phosphopantothenate + L-Cysteine <> Adenosine monophosphate + Pyrophosphate + 4-PhosphopantothenoylcysteineR04230Cytidine triphosphate + D-4'-Phosphopantothenate + L-Cysteine <> Cytidine monophosphate + Pyrophosphate + 4-PhosphopantothenoylcysteineR04231Pantothenic acid + Adenosine triphosphate > Hydrogen ion + D-4'-Phosphopantothenate + ADPPANTOTHENATE-KIN-RXNPantothenic acid + Adenosine triphosphate + Pantothenic acid > D-4'-Phosphopantothenate + Adenosine diphosphate + D-4'-Phosphopantothenate + ADPPW_R002990Cytidine triphosphate + D-4'-Phosphopantothenate + L-Cysteine + D-4'-Phosphopantothenate > Cytidine monophosphate + Pyrophosphate + 4-Phosphopantothenoylcysteine + Cytidine monophosphatePW_R002991Pantothenic acid + Adenosine triphosphate + Pantothenic acid > Adenosine diphosphate + Hydrogen ion + D-4'-Phosphopantothenate + ADP + D-4'-PhosphopantothenatePW_R003002D-4'-Phosphopantothenate + Cytidine triphosphate + L-Cysteine + D-4'-Phosphopantothenate > Cytidine monophosphate + Pyrophosphate + Hydrogen ion + 4-Phosphopantothenoylcysteine + Cytidine monophosphatePW_R003003D-4'-Phosphopantothenate + Cytidine triphosphate + L-Cysteine >4 4-Phosphopantothenoylcysteine + Cytidine monophosphate + Hydrogen ion + PyrophosphateD-4'-Phosphopantothenate + Cytidine triphosphate + L-Cysteine >4 4-Phosphopantothenoylcysteine + Cytidine monophosphate + Hydrogen ion + Pyrophosphate