2.02012-05-31 13:51:14 -06002015-09-13 12:56:11 -0600ECMDB01373M2MDB000362Dephospho-CoADephospho-CoA is a substrate for Ectonucleotide pyrophosphatase/phosphodiesterase 1, Ectonucleotide pyrophosphatase/phosphodiesterase 3 and Ectonucleotide pyrophosphatase/phosphodiesterase 2.3'-dephospho-CoA3'-dephospho-Coenzyme A3'-O-Dephosphono-CoA3'-O-Dephosphono-Coenzyme A3-Dephospho-CoADePCoADephospho-CoADephospho-Coenzyme ADephosphocoenzyme aC21H35N7O13P2S687.554687.148877955[({[(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy}(hydroxy)phosphoryl)oxy][3-hydroxy-2,2-dimethyl-3-({2-[(2-sulfanylethyl)carbamoyl]ethyl}carbamoyl)propoxy]phosphinic acid{[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy(hydroxy)phosphoryl}oxy(3-hydroxy-2,2-dimethyl-3-({2-[(2-sulfanylethyl)carbamoyl]ethyl}carbamoyl)propoxy)phosphinic acid3633-59-8CC(C)(COP(O)(=O)OP(O)(=O)OC[C@H]1O[C@H]([C@H](O)[C@@H]1O)N1C=NC2=C1N=CN=C2N)C(O)C(=O)NCCC(=O)NCCSInChI=1S/C21H35N7O13P2S/c1-21(2,16(32)19(33)24-4-3-12(29)23-5-6-44)8-39-43(36,37)41-42(34,35)38-7-11-14(30)15(31)20(40-11)28-10-27-13-17(22)25-9-26-18(13)28/h9-11,14-16,20,30-32,44H,3-8H2,1-2H3,(H,23,29)(H,24,33)(H,34,35)(H,36,37)(H2,22,25,26)/t11-,14-,15-,16?,20-/m1/s1KDTSHFARGAKYJN-DRCCLKDXSA-NSolidCytosollogp-0.98logs-2.43solubility2.56e+00 g/llogp-5.9pka_strongest_acidic1.86pka_strongest_basic5iupac[({[(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy}(hydroxy)phosphoryl)oxy][3-hydroxy-2,2-dimethyl-3-({2-[(2-sulfanylethyl)carbamoyl]ethyl}carbamoyl)propoxy]phosphinic acidaverage_mass687.554mono_mass687.148877955smilesCC(C)(COP(O)(=O)OP(O)(=O)OC[C@H]1O[C@H]([C@H](O)[C@@H]1O)N1C=NC2=C1N=CN=C2N)C(O)C(=O)NCCC(=O)NCCSformulaC21H35N7O13P2SinchiInChI=1S/C21H35N7O13P2S/c1-21(2,16(32)19(33)24-4-3-12(29)23-5-6-44)8-39-43(36,37)41-42(34,35)38-7-11-14(30)15(31)20(40-11)28-10-27-13-17(22)25-9-26-18(13)28/h9-11,14-16,20,30-32,44H,3-8H2,1-2H3,(H,23,29)(H,24,33)(H,34,35)(H,36,37)(H2,22,25,26)/t11-,14-,15-,16?,20-/m1/s1inchikeyKDTSHFARGAKYJN-DRCCLKDXSA-Npolar_surface_area300.03refractivity151.87polarizability62.51rotatable_bond_count16acceptor_count14donor_count9physiological_charge-2formal_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].PW000828ec00770MetabolicTwo-component systemec02020Metabolic pathwayseco01100Citrate lyase activationThe citrate lyase activation starts with a 3-dephospho-CoA reacting with ATP and a hydrogen ion through a triphosphoribosyl-dephospho-CoA synthase resulting in a adenine and a 2'-(5'-triphospho-alpha-D-ribosyl)-3'-dephospho-CoA. The latter compound in turn reacts with with a citrate lyase acyl-carrier protein through a apo-citrate lyase phosphoribosyl-dephospho-CoA transferase resulting in the release of a pyrophosphate and a hydrogen ion and a holo citrate lyase acyl-carrier protein.This protein complex can either react with a hydrogen ion and a acetate resulting in the release of a water and an acetyl-holo citrate lyase acyl-carrier protein.
The holo acyl-carrier protein creacts with an ATP and an acetate through a citrate lyase synthase resulting in the release of an AMP, a pyrophosphate and an acetyl-holo citrate lyase acyl-ccarrier protein.
The holo citrate lyase acyl-carrier protein can also interact with an S-acetyl phosphopantethiene resulting in the release of a 4-phosphopantethiene and an acetyl-holo citrate lyase acyl-carrier protein.PW002075Metabolic2'-(5'-phosphoribosyl)-3'-dephospho-CoA biosynthesis I (citrate lyase)P2-PWYcoenzyme A biosynthesisCOA-PWYSpecdb::CMs22053Specdb::NmrOneD273418Specdb::NmrOneD273419Specdb::NmrOneD273420Specdb::NmrOneD273421Specdb::NmrOneD273422Specdb::NmrOneD273423Specdb::NmrOneD273424Specdb::NmrOneD273425Specdb::NmrOneD273426Specdb::NmrOneD273427Specdb::NmrOneD273428Specdb::NmrOneD273429Specdb::NmrOneD273430Specdb::NmrOneD273431Specdb::NmrOneD273432Specdb::NmrOneD273433Specdb::NmrOneD273434Specdb::NmrOneD273435Specdb::NmrOneD273436Specdb::NmrOneD273437Specdb::MsMs23369Specdb::MsMs23370Specdb::MsMs23371Specdb::MsMs30167Specdb::MsMs30168Specdb::MsMs30169HMDB01373444485388463C0088215468DEPHOSPHO-COAKeseler, 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 80:2939-2948.18331064Haugen HF, Skrede S: Nucleotide pyrophosphatase and phosphodiesterase I. Demonstration of activity in normal serum, and an increase in cholestatic liver disease. Scand J Gastroenterol. 1976;11(2):121-7.4880http://hmdb.ca/system/metabolites/msds/000/001/235/original/HMDB01373.pdf?1358461914Phosphopantetheine adenylyltransferaseP0A6I6COAD_ECOLIcoaDhttp://ecmdb.ca/proteins/P0A6I6.xmlDephospho-CoA kinaseP0A6I9COAE_ECOLIcoaEhttp://ecmdb.ca/proteins/P0A6I9.xml2-(5''-triphosphoribosyl)-3'-dephosphocoenzyme-A synthaseP77231CITG_ECOLIcitGhttp://ecmdb.ca/proteins/P77231.xmlAdenosine triphosphate + Dephospho-CoA <> ADP + Coenzyme A + Hydrogen ionR00130DEPHOSPHOCOAKIN-RXNAdenosine triphosphate + Dephospho-CoA > 2'-(5-Triphosphoribosyl)-3'-dephospho-CoA + Adenine2.7.8.25-RXNAdenosine triphosphate + Hydrogen ion + Pantetheine 4'-phosphate <> Dephospho-CoA + PyrophosphateR03035PANTEPADENYLYLTRAN-RXNAdenosine triphosphate + Dephospho-CoA <> ADP + Coenzyme AR00130Adenosine triphosphate + Pantetheine 4'-phosphate <> Pyrophosphate + Dephospho-CoAR03035Hydrogen ion + Dephospho-CoA + Adenosine triphosphate > 2'-(5-Triphosphoribosyl)-3'-dephospho-CoA + Adenine2.7.8.25-RXNDephospho-CoA + Adenosine triphosphate > Hydrogen ion + Coenzyme A + ADPDEPHOSPHOCOAKIN-RXNAdenosine triphosphate + Dephospho-CoA <> 2'-(5-Triphosphoribosyl)-3'-dephospho-CoA + AdenineR09675 Pantetheine 4'-phosphate + Adenosine triphosphate + pantotheine 4'-phosphate > Dephospho-CoA + PyrophosphatePW_R002995Adenosine triphosphate + Dephospho-CoA > Adenosine diphosphate + Coenzyme A + ADPPW_R002996Dephospho-CoA + Water <> Pantetheine 4'-phosphate + Adenosine monophosphate + pantotheine 4'-phosphatePW_R0029974'-phosphopantetheine + Adenosine triphosphate + Hydrogen ion + 4'-phosphopantetheine > Pyrophosphate + Dephospho-CoAPW_R003004Dephospho-CoA + Adenosine triphosphate > Hydrogen ion + Adenosine diphosphate + Coenzyme A + ADPPW_R003006Adenosine triphosphate + Hydrogen ion + Pantetheine 4'-phosphate <> Dephospho-CoA + PyrophosphateAdenosine triphosphate + Dephospho-CoA <> ADP + Coenzyme A + Hydrogen ionAdenosine triphosphate + Hydrogen ion + Pantetheine 4'-phosphate <> Dephospho-CoA + Pyrophosphate