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MetaCyc Pathway: coenzyme A biosynthesis I
Inferred from experimentTraceable author statement to experimental support

Enzyme View:

Pathway diagram: coenzyme A biosynthesis I

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: BiosynthesisCofactors, Prosthetic Groups, Electron Carriers BiosynthesisCoenzyme A Biosynthesis

Some taxa known to possess this pathway include : Arabidopsis thaliana col, Escherichia coli K-12 substr. MG1655, Saccharomyces cerevisiae

Expected Taxonomic Range: Archaea, Bacteria , Eukaryota

General Background

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, 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, pantoate—β-alanine ligase (AMP-forming) followed by EC, pantothenate kinase, as described in phosphopantothenate biosynthesis I and phosphopantothenate biosynthesis II. However, in archaea the order is reversed, and EC, pantoate kinase acts before EC, 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, 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, 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].

Superpathways: pantothenate and coenzyme A biosynthesis II (plants), pantothenate and coenzyme A biosynthesis I, pantothenate and coenzyme A biosynthesis III

Variants: coenzyme A biosynthesis II (mammalian)

Unification Links: AraCyc:COA-PWY, EcoCyc:COA-PWY

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


Arino02: Arino J (2002). "Novel protein phosphatases in yeast." Eur J Biochem 269(4);1072-7. PMID: 11856338

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

Kupke03: Kupke T, Hernandez-Acosta P, Culianez-Macia FA (2003). "4'-phosphopantetheine and coenzyme A biosynthesis in plants." J Biol Chem 278(40);38229-37. PMID: 12860978

Leonardi05: Leonardi R, Zhang YM, Rock CO, Jackowski S (2005). "Coenzyme A: back in action." Prog Lipid Res 44(2-3);125-53. PMID: 15893380

Osterman09: Osterman AL (2009). "Genomic variations on a CoA biosynthetic theme." Nat Chem Biol 5(12);871-2. PMID: 19915531

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

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

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

BRENDA14: BRENDA team (2014). Imported from BRENDA version existing on Aug 2014.

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

GOA01: GOA, MGI (2001). "Gene Ontology annotation based on Enzyme Commission mapping." Genomics 74;121-128.

GOA01a: GOA, DDB, FB, MGI, ZFIN (2001). "Gene Ontology annotation through association of InterPro records with GO terms."

GOA06: GOA, SIB (2006). "Electronic Gene Ontology annotations created by transferring manual GO annotations between orthologous microbial proteins."

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

Ishihama08: Ishihama Y, Schmidt T, Rappsilber J, Mann M, Hartl FU, Kerner MJ, Frishman D (2008). "Protein abundance profiling of the Escherichia coli cytosol." BMC Genomics 9;102. PMID: 18304323

Izard02: Izard T (2002). "The crystal structures of phosphopantetheine adenylyltransferase with bound substrates reveal the enzyme's catalytic mechanism." J Mol Biol 315(4);487-95. PMID: 11812124

Izard03: Izard T (2003). "A novel adenylate binding site confers phosphopantetheine adenylyltransferase interactions with coenzyme A." J Bacteriol 185(14);4074-80. PMID: 12837781

Izard99: 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

Izard99a: Izard T, Geerlof A (1999). "The crystal structure of a novel bacterial adenylyltransferase reveals half of sites reactivity." EMBO J 1999;18(8);2021-30. PMID: 10205156

Jackowski84: Jackowski S, Rock CO (1984). "Metabolism of 4'-phosphopantetheine in Escherichia coli." J Bacteriol 158(1);115-20. PMID: 6370952

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

Kupke01: Kupke T (2001). "Molecular characterization of the 4'-phosphopantothenoylcysteine decarboxylase domain of bacterial Dfp flavoproteins." J Biol Chem 2001;276(29);27597-604. PMID: 11358972

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Report Errors or Provide Feedback
Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
Page generated by Pathway Tools version 19.5 (software by SRI International) on Tue May 3, 2016, biocyc14.