If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
|Superclasses:||Biosynthesis → Cofactors, Prosthetic Groups, Electron Carriers Biosynthesis → Coenzyme A Biosynthesis|
|Biosynthesis → Cofactors, Prosthetic Groups, Electron Carriers Biosynthesis → Vitamins Biosynthesis|
Some taxa known to possess this pathway include : Escherichia coli K-12 substr. MG1655
Expected Taxonomic Range: Bacteria
Coenzyme A (CoA) is a cofactor of ubiquitous occurrence in plants, bacteria, and animals needed in a large number of enzymatic reactions central to intermediary metabolism, including the oxidation of fatty acids, carbohydrates, and amino acids. Coenzyme A is the common acyl carrier in prokaryotic and eukaryotic cells required for a multitude of reactions for both biosynthetic and degradative pathways amongst others forming derivatives that are key intermediates in energy metabolism [Rubio06].
The biosynthesis of CoA is of equal importance with regard to its recognition as a target for antibacterial drug discovery and to the association of human neurodegenerative disorder with mutations in EC 22.214.171.124, pantothenate kinase [Leonardi05].
About This Pathway
The CoA biosynthesis precursor 3-methyl-2-oxobutanoate is an intermediate in the synthesis of L-valine (see L-valine biosynthesis). This compound is converted in two steps to (R)-pantoate, as shown in phosphopantothenate biosynthesis I. 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 126.96.36.199, pantoate—β-alanine ligase (AMP-forming) followed by EC 188.8.131.52, pantothenate kinase, as described in phosphopantothenate biosynthesis I and phosphopantothenate biosynthesis II. However, in archaea the order is reversed, and EC 184.108.40.206, pantoate kinase acts before EC 220.127.116.11, 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 18.104.22.168, 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].
Unification Links: EcoCyc:PANTOSYN-PWY
Rubio06: Rubio S, Larson TR, Gonzalez-Guzman M, Alejandro S, Graham IA, Serrano R, Rodriguez PL (2006). "An Arabidopsis mutant impaired in coenzyme A biosynthesis is sugar dependent for seedling establishment." Plant Physiol 140(3);830-43. PMID: 16415216
Albert98: Albert A, Dhanaraj V, Genschel U, Khan G, Ramjee MK, Pulido R, Sibanda BL, von Delft F, Witty M, Blundell TL, Smith AG, Abell C (1998). "Crystal structure of aspartate decarboxylase at 2.2 A resolution provides evidence for an ester in protein self-processing." Nat Struct Biol 5(4);289-93. PMID: 9546220
Badger05: Badger J, Sauder JM, Adams JM, Antonysamy S, Bain K, Bergseid MG, Buchanan SG, Buchanan MD, Batiyenko Y, Christopher JA, Emtage S, Eroshkina A, Feil I, Furlong EB, Gajiwala KS, Gao X, He D, Hendle J, Huber A, Hoda K, Kearins P, Kissinger C, Laubert B, Lewis HA, Lin J, Loomis K, Lorimer D, Louie G, Maletic M, Marsh CD, Miller I, Molinari J, Muller-Dieckmann HJ, Newman JM, Noland BW, Pagarigan B, Park F, Peat TS, Post KW, Radojicic S, Ramos A, Romero R, Rutter ME, Sanderson WE, Schwinn KD, Tresser J, Winhoven J, Wright TA, Wu L, Xu J, Harris TJ (2005). "Structural analysis of a set of proteins resulting from a bacterial genomics project." Proteins 60(4);787-96. PMID: 16021622
Butland05: Butland G, Peregrin-Alvarez JM, Li J, Yang W, Yang X, Canadien V, Starostine A, Richards D, Beattie B, Krogan N, Davey M, Parkinson J, Greenblatt J, Emili A (2005). "Interaction network containing conserved and essential protein complexes in Escherichia coli." Nature 433(7025);531-7. PMID: 15690043
Chakrabarti10: Chakrabarti KS, Thakur KG, Gopal B, Sarma SP (2010). "X-ray crystallographic and NMR studies of pantothenate synthetase provide insights into the mechanism of homotropic inhibition by pantoate." FEBS J 277(3);697-712. PMID: 20059543
Chetnani09: Chetnani B, Das S, Kumar P, Surolia A, Vijayan M (2009). "Mycobacterium tuberculosis pantothenate kinase: possible changes in location of ligands during enzyme action." Acta Crystallogr D Biol Crystallogr 65(Pt 4);312-25. PMID: 19307712
Ciulli06: Ciulli A, Williams G, Smith AG, Blundell TL, Abell C (2006). "Probing hot spots at protein-ligand binding sites: a fragment-based approach using biophysical methods." J Med Chem 49(16);4992-5000. PMID: 16884311
Ciulli07: Ciulli A, Chirgadze DY, Smith AG, Blundell TL, Abell C (2007). "Crystal structure of Escherichia coli ketopantoate reductase in a ternary complex with NADP+ and pantoate bound: substrate recognition, conformational change, and cooperativity." J Biol Chem 282(11);8487-97. PMID: 17229734
Ciulli07a: Ciulli A, Lobley CM, Tuck KL, Smith AG, Blundell TL, Abell C (2007). "pH-tuneable binding of 2'-phospho-ADP-ribose to ketopantoate reductase: a structural and calorimetric study." Acta Crystallogr D Biol Crystallogr 63(Pt 2);171-8. PMID: 17242510
Cronan82: Cronan JE, Littel KJ, Jackowski S (1982). "Genetic and biochemical analyses of pantothenate biosynthesis in Escherichia coli and Salmonella typhimurium." J Bacteriol 149(3);916-22. PMID: 7037743
Daugherty02: Daugherty M, Polanuyer B, Farrell M, Scholle M, Lykidis A, de Crecy-Lagard V, Osterman A (2002). "Complete reconstitution of the human coenzyme A biosynthetic pathway via comparative genomics." J Biol Chem 277(24);21431-9. PMID: 11923312
deNadal98: de Nadal E, Clotet J, Posas F, Serrano R, Gomez N, Arino J (1998). "The yeast halotolerance determinant Hal3p is an inhibitory subunit of the Ppz1p Ser/Thr protein phosphatase." Proc Natl Acad Sci U S A 95(13);7357-62. PMID: 9636153
Diaz91: Diaz E, Anton DL (1991). "Alkylation of an active-site cysteinyl residue during substrate-dependent inactivation of Escherichia coli S-adenosylmethionine decarboxylase." Biochemistry 1991;30(16);4078-81. PMID: 2018773
DiazMejia09: Diaz-Mejia JJ, Babu M, Emili A (2009). "Computational and experimental approaches to chart the Escherichia coli cell-envelope-associated proteome and interactome." FEMS Microbiol Rev 33(1);66-97. PMID: 19054114
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