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MetaCyc Pathway: phosphopantothenate biosynthesis III
Inferred from experiment

Pathway diagram: phosphopantothenate biosynthesis III

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.

Superclasses: BiosynthesisCofactors, Prosthetic Groups, Electron Carriers BiosynthesisVitamins BiosynthesisPantothenate Biosynthesis

Some taxa known to possess this pathway include : Thermococcus kodakarensis

Expected Taxonomic Range: Archaea

(R)-4'-phosphopantothenate is the universal precursor for the synthesis of the 4'-phosphopantetheine moiety of coenzyme A and acyl carrier protein. Only plants and microorganisms (including some eukaryotic microbes, such as Saccharomyces cerevisiae) can synthesize pantothenate de novo - animals require a dietary supplement. The enzymes of this pathway are therefore considered to be antimicrobial drug targets.

The starting compound for pantothenate biosynthesis, 3-methyl-2-oxobutanoate, is derived from the L-valine biosynthesis pathway. The first committed step in the pathway is the transfer of a methyl group to 2-keto-isovalerate by 3-methyl-2-oxobutanoate hydroxymethyltransferase. The product of this reaction, 2-dehydropantoate, is subsequently reduced by 2-dehydropantoate 2-reductase to (R)-pantoate.

The next steps, as found in bacteria/eukaryotes, consist of the ATP hydrolysis-dependent condensation of R-pantoate with β-alanine to form (R)-pantothenate, followed by the phosphorylation of the latter to (R)-4'-phosphopantothenate. While archaebacteria are known to produce coenzyme A, and archaeal genomes harbor homologs for most of the enzymes involved in this pathway, homologs of the bacterial/eukaryotic pantothenate synthetase and pantothenate kinase, which catalyze these last two steps, are missing. The puzzle has been solved with the discovery of two new enzymes - pantoate kinase and 4-phosphopantoate-β-alanine ligase. Apparently, the order of these two steps (condensation and phosphorylation) has been reversed in archaea [Yokooji09].

The two enzymes have been purified and characterized, and their activities verified. Homologs of both genes are widely distributed among the archaea, suggesting that this is the predominant pathway for 4'-phosphopantothenate biosynthesis in the archaea [Yokooji09].

Variants: phosphopantothenate biosynthesis I, phosphopantothenate biosynthesis II

Created 21-Oct-2010 by Caspi R, SRI International


Yokooji09: Yokooji Y, Tomita H, Atomi H, Imanaka T (2009). "Pantoate kinase and phosphopantothenate synthetase, two novel enzymes necessary for CoA biosynthesis in the Archaea." J Biol Chem 284(41);28137-45. PMID: 19666462

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

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

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

Elischewski99: Elischewski F, Puhler A, Kalinowski J (1999). "Pantothenate production in Escherichia coli K12 by enhanced expression of the panE gene encoding ketopantoate reductase." J Biotechnol 75(2-3);135-46. PMID: 10553653

Latendresse13: Latendresse M. (2013). "Computing Gibbs Free Energy of Compounds and Reactions in MetaCyc."

Maden00: Maden BE (2000). "Tetrahydrofolate and tetrahydromethanopterin compared: functionally distinct carriers in C1 metabolism." Biochem J 350 Pt 3;609-29. PMID: 10970772

MatakVinkovic01: Matak-Vinkovic D, Vinkovic M, Saldanha SA, Ashurst JL, von Delft F, Inoue T, Miguel RN, Smith AG, Blundell TL, Abell C (2001). "Crystal structure of Escherichia coli ketopantoate reductase at 1.7 A resolution and insight into the enzyme mechanism." Biochemistry 40(48);14493-500. PMID: 11724562

Miller13: Miller CN, LoVullo ED, Kijek TM, Fuller JR, Brunton JC, Steele SP, Taft-Benz SA, Richardson AR, Kawula TH (2013). "PanG, a new ketopantoate reductase involved in pantothenate synthesis." J Bacteriol 195(5);965-76. PMID: 23243306

RaemakersFranke89: Raemakers-Franken PC, Voncken FG, Korteland J, Keltjens JT, van der Drift C, Vogels GD (1989). "Structural characterization of tatiopterin, a novel pterin isolated from Methanogenium tationis." Biofactors 2(2);117-22. PMID: 2624671

RaemakersFranke91: Raemakers-Franken PC, van Elderen CH, van der Drift C, Vogels GD (1991). "Identification of a novel tatiopterin derivative in Methanogenium tationis." Biofactors 3(2);127-30. PMID: 1910453

RaemakersFranke91a: Raemakers-Franken PC, Bongaerts R, Fokkens R, van der Drift C, Vogels GD (1991). "Characterization of two pterin derivatives isolated from Methanoculleus thermophilicum." Eur J Biochem 200(3);783-7. PMID: 1915350

vanBeelen84: van Beelen P, Stassen AP, Bosch JW, Vogels GD, Guijt W, Haasnoot CA (1984). "Elucidation of the structure of methanopterin, a coenzyme from Methanobacterium thermoautotrophicum, using two-dimensional nuclear-magnetic-resonance techniques." Eur J Biochem 138(3);563-71. PMID: 6319137

White93: White RH (1993). "Structures of the modified folates in the extremely thermophilic archaebacterium Thermococcus litoralis." J Bacteriol 175(11);3661-3. PMID: 8501071

Zheng00: Zheng R, Blanchard JS (2000). "Kinetic and mechanistic analysis of the E. coli panE-encoded ketopantoate reductase." Biochemistry 2000;39(13);3708-17. PMID: 10736170

Zheng00a: Zheng R, Blanchard JS (2000). "Identification of active site residues in E. coli ketopantoate reductase by mutagenesis and chemical rescue." Biochemistry 39(51);16244-51. PMID: 11123955

Zheng03: Zheng R, Blanchard JS (2003). "Substrate specificity and kinetic isotope effect analysis of the Eschericia coli ketopantoate reductase." Biochemistry 42(38);11289-96. PMID: 14503879

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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 Sun Feb 14, 2016, biocyc14.