This view shows enzymes only for those organisms listed below, in the list of taxa known to possess the pathway. If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
Synonyms: CoA biosynthesis
|Superclasses:||Biosynthesis → Cofactors, Prosthetic Groups, Electron Carriers Biosynthesis → Coenzyme A Biosynthesis|
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 220.127.116.11, 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 18.104.22.168, pantoate—β-alanine ligase (AMP-forming) followed by EC 22.214.171.124, pantothenate kinase, as described in phosphopantothenate biosynthesis I and phosphopantothenate biosynthesis II. However, in archaea the order is reversed, and EC 126.96.36.199, pantoate kinase acts before EC 188.8.131.52, 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 184.108.40.206, 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].
About this pathway in yeast
The conversion of R-4'-phosphopantothenoyl-L-cysteine to 4'-phosphopantetheine is catalyzed by EC 220.127.116.11, phosphopantothenoylcysteine decarboxylase. In Saccharomyces cerevisiae this is a unique heterotrimeric enzyme encoded by three genes, CAB3, SIS2 and VHS3 which although similar in structure are irreplaceable and fulfill distinctive essential functions in the protein complex. Two of the three genes, SIS2 and VHS3, are moonlighting proteins which are not only involved as PPCDC subunits in CoA biosynthesis but also known to be inhibitors/negative regulators of the serine/threonine protein phosphatase Ppz1 [deNadal98, Arino02, Ruiz04]. Hence, this enzyme complex stands as an example of cross-talks between metabolic and signaling pathways indicating the possibility of exerting regulatory influence from one pathway to another [Osterman09].
Variants: coenzyme A biosynthesis II (mammalian)
Created 07-Oct-2003 by Arnaud M , SRI International
Reviewed 24-Oct-2006 by Foerster H , TAIR
Revised 12-Jun-2008 by Keseler I , SRI International
Revised 05-Mar-2013 by Foerster H , Boyce Thompson Institute
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
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
Ruiz04: Ruiz A, Munoz I, Serrano R, Gonzalez A, Simon E, Arino J (2004). "Functional characterization of the Saccharomyces cerevisiae VHS3 gene: a regulatory subunit of the Ppz1 protein phosphatase with novel, phosphatase-unrelated functions." J Biol Chem 279(33);34421-30. PMID: 15192104
Ruiz09: Ruiz A, Gonzalez A, Munoz I, Serrano R, Abrie JA, Strauss E, Arino J (2009). "Moonlighting proteins Hal3 and Vhs3 form a heteromeric PPCDC with Ykl088w in yeast CoA biosynthesis." Nat Chem Biol 5(12);920-8. PMID: 19915539
Steinbacher03: Steinbacher S, Hernandez-Acosta P, Bieseler B, Blaesse M, Huber R, Culianez-Macia FA, Kupke T (2003). "Crystal structure of the plant PPC decarboxylase AtHAL3a complexed with an ene-thiol reaction intermediate." J Mol Biol 327(1);193-202. PMID: 12614618
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
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
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
Ferrando95: Ferrando A, Kron SJ, Rios G, Fink GR, Serrano R (1995). "Regulation of cation transport in Saccharomyces cerevisiae by the salt tolerance gene HAL3." Mol Cell Biol 15(10);5470-81. PMID: 7565698
Freiberg01: Freiberg C, Wieland B, Spaltmann F, Ehlert K, Brotz H, Labischinski H (2001). "Identification of novel essential Escherichia coli genes conserved among pathogenic bacteria." J Mol Microbiol Biotechnol 3(3);483-9. PMID: 11361082
Geerlof99: Geerlof A, Lewendon A, Shaw WV (1999). "Purification and characterization of phosphopantetheine adenylyltransferase from Escherichia coli." J Biol Chem 1999;274(38);27105-11. PMID: 10480925
Gerdes02: Gerdes SY, Scholle MD, D'Souza M, Bernal A, Baev MV, Farrell M, Kurnasov OV, Daugherty MD, Mseeh F, Polanuyer BM, Campbell JW, Anantha S, Shatalin KY, Chowdhury SA, Fonstein MY, Osterman AL (2002). "From genetic footprinting to antimicrobial drug targets: examples in cofactor biosynthetic pathways." J Bacteriol 184(16);4555-72. PMID: 12142426
Hare01: Hare RS, Walker SS, Dorman TE, Greene JR, Guzman LM, Kenney TJ, Sulavik MC, Baradaran K, Houseweart C, Yu H, Foldes Z, Motzer A, Walbridge M, Shimer GH, Shaw KJ (2001). "Genetic footprinting in bacteria." J Bacteriol 183(5);1694-706. PMID: 11160101
Izard99a: Izard T, Geerlof A, Lewendon A, Barker JJ (1999). "Cubic crystals of phosphopantetheine adenylyltransferase from Escherichia coli." Acta Crystallogr D Biol Crystallogr 1999;55 ( Pt 6);1226-8. PMID: 10329792
Kupke00: Kupke T, Uebele M, Schmid D, Jung G, Blaesse M, Steinbacher S (2000). "Molecular characterization of lantibiotic-synthesizing enzyme EpiD reveals a function for bacterial Dfp proteins in coenzyme A biosynthesis." J Biol Chem 2000;275(41);31838-46. PMID: 10922366
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