2.02012-05-31 14:33:57 -06002015-06-04 17:06:03 -0600ECMDB20223M2MDB0010682'-(5-Triphosphoribosyl)-3'-dephospho-CoA2'-(5-triphosphoribosyl)-3'-dephospho-CoA is a member of the chemical class known as Purine Ribonucleoside Triphosphates. These are purine ribobucleotides with triphosphate group linked to the ribose moiety. 2'-(5''-Triphosphoribosyl)-3'-dephospho-CoA2-5-TRIPHOSPHORIBOSYL-3-DEPHOSPHO-2-5-Triphosphoribosyl-3-dephospho-CoAC26H46N7O26P5S1059.6091059.090127929(2R)-4-({[({[(2R,3R,4R,5R)-5-(6-amino-9H-purin-9-yl)-4-{[(2S,3R,4S,5R)-3,4-dihydroxy-5-({[hydroxy({[hydroxy(phosphonooxy)phosphoryl]oxy})phosphoryl]oxy}methyl)oxolan-2-yl]oxy}-3-hydroxyoxolan-2-yl]methoxy}(hydroxy)phosphoryl)oxy](hydroxy)phosphoryl}oxy)-2-hydroxy-3,3-dimethyl-N-{2-[(2-sulfanylethyl)-C-hydroxycarbonimidoyl]ethyl}butanimidic acid(2R)-4-[({[(2R,3R,4R,5R)-5-(6-aminopurin-9-yl)-4-{[(2S,3R,4S,5R)-3,4-dihydroxy-5-[({hydroxy[hydroxy(phosphonooxy)phosphoryl]oxyphosphoryl}oxy)methyl]oxolan-2-yl]oxy}-3-hydroxyoxolan-2-yl]methoxy(hydroxy)phosphoryl}oxy(hydroxy)phosphoryl)oxy]-2-hydroxy-3,3-dimethyl-N-{2-[(2-sulfanylethyl)-C-hydroxycarbonimidoyl]ethyl}butanimidic acid[H][C@](O)(C(O)=NCCC(O)=NCCS)C(C)(C)COP(O)(=O)OP(O)(=O)OC[C@@]1([H])O[C@@]([H])(N2C=NC3=C(N)N=CN=C23)[C@]([H])(O[C@]2([H])O[C@]([H])(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@]([H])(O)[C@@]2([H])O)[C@]1([H])OInChI=1S/C26H46N7O26P5S/c1-26(2,20(38)23(39)29-4-3-14(34)28-5-6-65)9-53-63(47,48)58-61(43,44)52-8-13-17(36)19(24(54-13)33-11-32-15-21(27)30-10-31-22(15)33)56-25-18(37)16(35)12(55-25)7-51-62(45,46)59-64(49,50)57-60(40,41)42/h10-13,16-20,24-25,35-38,65H,3-9H2,1-2H3,(H,28,34)(H,29,39)(H,43,44)(H,45,46)(H,47,48)(H,49,50)(H2,27,30,31)(H2,40,41,42)/t12-,13-,16-,17-,18-,19-,20+,24-,25+/m1/s1NFWZJXFBUKDGOX-JIRKQKIOSA-NCytosollogp-0.20logs-1.76solubility1.83e+01 g/llogp-3.7pka_strongest_acidic0.85iupac(2R)-4-({[({[(2R,3R,4R,5R)-5-(6-amino-9H-purin-9-yl)-4-{[(2S,3R,4S,5R)-3,4-dihydroxy-5-({[hydroxy({[hydroxy(phosphonooxy)phosphoryl]oxy})phosphoryl]oxy}methyl)oxolan-2-yl]oxy}-3-hydroxyoxolan-2-yl]methoxy}(hydroxy)phosphoryl)oxy](hydroxy)phosphoryl}oxy)-2-hydroxy-3,3-dimethyl-N-{2-[(2-sulfanylethyl)-C-hydroxycarbonimidoyl]ethyl}butanimidic acidaverage_mass1059.609mono_mass1059.090127929smiles[H][C@](O)(C(O)=NCCC(O)=NCCS)C(C)(C)COP(O)(=O)OP(O)(=O)OC[C@@]1([H])O[C@@]([H])(N2C=NC3=C(N)N=CN=C23)[C@]([H])(O[C@]2([H])O[C@]([H])(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@]([H])(O)[C@@]2([H])O)[C@]1([H])OformulaC26H46N7O26P5SinchiInChI=1S/C26H46N7O26P5S/c1-26(2,20(38)23(39)29-4-3-14(34)28-5-6-65)9-53-63(47,48)58-61(43,44)52-8-13-17(36)19(24(54-13)33-11-32-15-21(27)30-10-31-22(15)33)56-25-18(37)16(35)12(55-25)7-51-62(45,46)59-64(49,50)57-60(40,41)42/h10-13,16-20,24-25,35-38,65H,3-9H2,1-2H3,(H,28,34)(H,29,39)(H,43,44)(H,45,46)(H,47,48)(H,49,50)(H2,27,30,31)(H2,40,41,42)/t12-,13-,16-,17-,18-,19-,20+,24-,25+/m1/s1inchikeyNFWZJXFBUKDGOX-JIRKQKIOSA-Npolar_surface_area505.52refractivity211.98polarizability87.74rotatable_bond_count25acceptor_count26donor_count14physiological_charge-5formal_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 systemec02020Citrate 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-PWYSpecdb::NmrOneD270578Specdb::NmrOneD270579Specdb::NmrOneD270580Specdb::NmrOneD270581Specdb::NmrOneD270582Specdb::NmrOneD270583Specdb::NmrOneD270584Specdb::NmrOneD270585Specdb::NmrOneD270586Specdb::NmrOneD270587Specdb::NmrOneD270588Specdb::NmrOneD270589Specdb::NmrOneD270590Specdb::NmrOneD270591Specdb::NmrOneD270592Specdb::NmrOneD270593Specdb::NmrOneD270594Specdb::NmrOneD270595Specdb::NmrOneD270596Specdb::NmrOneD270597Specdb::MsMs29507Specdb::MsMs29508Specdb::MsMs29509Specdb::MsMs36065Specdb::MsMs36066Specdb::MsMs3606725203684C197712-5-TRIPHOSPHORIBOSYL-3-DEPHOSPHO-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-D590.21097882van 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 80:2939-2948.18331064Apo-citrate lyase phosphoribosyl-dephospho-CoA transferaseP0A6G5CITX_ECOLIcitXhttp://ecmdb.ca/proteins/P0A6G5.xml2-(5''-triphosphoribosyl)-3'-dephosphocoenzyme-A synthaseP77231CITG_ECOLIcitGhttp://ecmdb.ca/proteins/P77231.xmlAdenosine triphosphate + Dephospho-CoA > 2'-(5-Triphosphoribosyl)-3'-dephospho-CoA + Adenine2.7.8.25-RXNHydrogen ion + Dephospho-CoA + Adenosine triphosphate > 2'-(5-Triphosphoribosyl)-3'-dephospho-CoA + Adenine2.7.8.25-RXN2'-(5-Triphosphoribosyl)-3'-dephospho-CoA + citrate lyase apo-[acyl-carrier-protein] > citrate lyase holo-[acyl-carrier-protein] + PyrophosphateAdenosine triphosphate + Dephospho-CoA <> 2'-(5-Triphosphoribosyl)-3'-dephospho-CoA + AdenineR09675 2'-(5-Triphosphoribosyl)-3'-dephospho-CoA <> PyrophosphateR10706 2'-(5-Triphosphoribosyl)-3'-dephospho-CoA + [an apo citrate-lyase acyl-carrier protein] > Pyrophosphate + Hydrogen ion + [a holo citrate lyase acyl-carrier protein]PW_R006061