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MetaCyc Enzyme: pantothenate kinase

Gene: coaA Accession Numbers: EG10922 (MetaCyc), b3974, ECK3966

Synonyms: panK, rts, ts-9

Species: Escherichia coli K-12 substr. MG1655

Subunit composition of pantothenate kinase = [CoaA]2
         pantothenate kinase monomer = CoaA

Summary:
Pantothenate kinase catalyzes the first step in the biosynthesis of coenzyme A, an essential cofactor that is involved in many reactions. It is also the most highly regulated step in the pathway [Jackowski81, Jackowski84].

Pantothenate kinase is sensitive to feedback inhibition by the CoA pool [Song94a, Vallari87]. Mutants that are refractory to feedback inhibition, but retain catalytic activity, have been isolated; these mutants have a higher intracellular CoA content and secrete 4'-phosphopantetheine [Rock03].

The compounds N5-Pan and N7-Pan are competitive inhibitors of pantothenate kinase [Ivey04] and can be utilized as substrates of the CoA biosynthesis pathway [Strauss02]. The phosphopantothenimide moiety is transferred to ACP, rendering it incapable of supporting fatty acid biosynthesis. Thus, N5-Pan and N7-Pan are pro-antibiotics [Zhang04e], explaining earlier results [Clifton70]. Further inhibitors/substrates of pantothenate kinase have been designed and tested [Virga06].

Utilization of two different translation start sites of coaA results in proteins that differ by eight amino acids at the N terminus [Song92, Song94a].

Crystal structures of pantothenate kinase in complex with AMPPNP (a nonhydrolyzable analog of ATP) or CoA have been solved, showing that the phosphate binding sites of CoA and ATP overlap, which explains their kinetic competition [Yun00a]. The N-terminal region forms much of the dimer interface [Yun00a]. The crystal structure of the ternary complex with ADP and patothenate shows induced fit binding of pantothenate; a mechanism of phosphoryl transfer was proposed [Ivey04].

coaA is an essential gene [Gerdes02]. Temperature-sensitive alleles have been isolated [Vallari87a, Flaks66].

Locations: cytosol

Map Position: [4,172,099 <- 4,173,049]

Molecular Weight of Polypeptide: 36.36 kD (from nucleotide sequence)

Molecular Weight of Multimer: 69.0 kD (experimental) [Song94a]

pI: 6.74

Unification Links: ASAP:ABE-0013003 , CGSC:17731 , EchoBASE:EB0915 , EcoGene:EG10922 , EcoliWiki:b3974 , ModBase:P0A6I3 , OU-Microarray:b3974 , PortEco:coaA , PR:PRO_000022308 , Pride:P0A6I3 , Protein Model Portal:P0A6I3 , RefSeq:NP_418405 , RegulonDB:EG10922 , SMR:P0A6I3 , String:511145.b3974 , UniProt:P0A6I3

Relationship Links: InterPro:IN-FAMILY:IPR004566 , InterPro:IN-FAMILY:IPR006083 , InterPro:IN-FAMILY:IPR027417 , Panther:IN-FAMILY:PTHR10285:SF7 , PDB:Structure:1ESM , PDB:Structure:1ESN , PDB:Structure:1SQ5 , Pfam:IN-FAMILY:PF00485

Gene-Reaction Schematic: ?

GO Terms:

Biological Process: GO:0015937 - coenzyme A biosynthetic process Inferred from experiment Inferred by computational analysis [UniProtGOA12, UniProtGOA11, GOA06, GOA01, Vallari87a]
GO:0008152 - metabolic process Inferred by computational analysis [GOA01]
GO:0016310 - phosphorylation Inferred by computational analysis [UniProtGOA11]
Molecular Function: GO:0004594 - pantothenate kinase activity Inferred from experiment Inferred by computational analysis [GOA06, GOA01a, GOA01, Song94a]
GO:0005524 - ATP binding Inferred from experiment Inferred by computational analysis [UniProtGOA11, GOA06, GOA01, Song94a]
GO:0000166 - nucleotide binding Inferred by computational analysis [UniProtGOA11]
GO:0016301 - kinase activity Inferred by computational analysis [UniProtGOA11, GOA01]
GO:0016740 - transferase activity Inferred by computational analysis [UniProtGOA11]
Cellular Component: GO:0005737 - cytoplasm Inferred by computational analysis [UniProtGOA11a, UniProtGOA11, GOA06, GOA01]
GO:0005829 - cytosol Inferred by computational analysis [DiazMejia09]

MultiFun Terms: metabolism biosynthesis of building blocks cofactors, small molecule carriers Coenzyme A and its modification

Credits:
Imported from EcoCyc 16-Sep-2014 by Paley S , SRI International


Enzymatic reaction of: pantothenate kinase

Synonyms: ATP:pantothenate 4'-phosphotransferase

EC Number: 2.7.1.33

(R)-pantothenate + ATP <=> (R)-4'-phosphopantothenate + ADP + H+

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the direction of enzyme catalysis.

The reaction is physiologically favored in the direction shown.

Alternative Substrates for (R)-pantothenate: N5-Pan [Strauss02 ]

Alternative Substrates for ATP: GTP [Vallari87 ]

In Pathways: pantothenate and coenzyme A biosynthesis I , phosphopantothenate biosynthesis I

Credits:
Imported from EcoCyc 16-Sep-2014 by Paley S , SRI International

Summary:
ATP binding to pantothenate kinase is highly cooperative; the Hill coefficient is 1.46 [Song94a].

Cofactors or Prosthetic Groups: Mg2+ [Vallari87]

Inhibitors (Competitive): N5-Pan [Ivey04] , N7-Pan [Ivey04] , coenzyme A [Vallari87, Song94a, Comment 1]

Primary Physiological Regulators of Enzyme Activity: coenzyme A

Kinetic Parameters:

Substrate
Km (μM)
kcat (sec-1)
kcat/Km (sec-1 μM-1)
Citations
(R)-pantothenate
41.0
[Ivey04, BRENDA14]
(R)-pantothenate
9.0
[Vallari87, BRENDA14]
(R)-pantothenate
136.0
[Spry08, BRENDA14]
(R)-pantothenate
36.0, 136.0
[Song94a, BRENDA14]
ATP
136.0
[Spry08, BRENDA14]
ATP
136.0
[Song94a, BRENDA14]
ATP
115.0, 406.0
0.071, 1.14
[Chetnani09, BRENDA14]

pH(opt): 6.3 [Vallari87]


Sequence Features

Feature Class Location Citations Comment
Nucleotide-Phosphate-Binding-Region 95 -> 102
[UniProt10]
UniProt: ATP; Non-Experimental Qualifier: potential;

History:
10/20/97 Gene b3974 from Blattner lab Genbank (v. M52) entry merged into EcoCyc gene EG10922; confirmed by SwissProt match.


References

BRENDA14: BRENDA team (2014). "Imported from BRENDA version existing on Aug 2014." http://www.brenda-enzymes.org.

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

Clifton70: Clifton G, Bryant SR, Skinner CG (1970). "N'-(substituted) pantothenamides, antimetabolites of pantothenic acid." Arch Biochem Biophys 137(2);523-8. PMID: 4909169

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

Flaks66: Flaks JG, Leboy PS, Birge EA, Kurland CG (1966). "Mutations and genetics concerned with the ribosome." Cold Spring Harb Symp Quant Biol 31;623-31. PMID: 4866408

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

GOA01a: GOA, MGI (2001). "Gene Ontology annotation based on Enzyme Commission mapping." Genomics 74;121-128.

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

Ivey04: Ivey RA, Zhang YM, Virga KG, Hevener K, Lee RE, Rock CO, Jackowski S, Park HW (2004). "The structure of the pantothenate kinase.ADP.pantothenate ternary complex reveals the relationship between the binding sites for substrate, allosteric regulator, and antimetabolites." J Biol Chem 279(34);35622-9. PMID: 15136582

Jackowski81: Jackowski S, Rock CO (1981). "Regulation of coenzyme A biosynthesis." J Bacteriol 148(3);926-32. PMID: 6796563

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

Rock03: Rock CO, Park HW, Jackowski S (2003). "Role of feedback regulation of pantothenate kinase (CoaA) in control of coenzyme A levels in Escherichia coli." J Bacteriol 185(11);3410-5. PMID: 12754240

Song92: Song WJ, Jackowski S (1992). "Cloning, sequencing, and expression of the pantothenate kinase (coaA) gene of Escherichia coli." J Bacteriol 1992;174(20);6411-7. PMID: 1328157

Song92a: Song WJ, Jackowski S (1992). "coaA and rts are allelic and located at kilobase 3532 on the Escherichia coli physical map." J Bacteriol 174(5);1705-6. PMID: 1311303

Song94a: Song WJ, Jackowski S (1994). "Kinetics and regulation of pantothenate kinase from Escherichia coli." J Biol Chem 1994;269(43);27051-8. PMID: 7929447

Spry08: Spry C, Kirk K, Saliba KJ (2008). "Coenzyme A biosynthesis: an antimicrobial drug target." FEMS Microbiol Rev 32(1);56-106. PMID: 18173393

Strauss02: Strauss E, Begley TP (2002). "The antibiotic activity of N-pentylpantothenamide results from its conversion to ethyldethia-coenzyme a, a coenzyme a antimetabolite." J Biol Chem 277(50);48205-9. PMID: 12372838

UniProt10: UniProt Consortium (2010). "UniProt version 2010-07 released on 2010-06-15 00:00:00." Database.

UniProtGOA11: UniProt-GOA (2011). "Gene Ontology annotation based on manual assignment of UniProtKB keywords in UniProtKB/Swiss-Prot entries."

UniProtGOA11a: UniProt-GOA (2011). "Gene Ontology annotation based on the manual assignment of UniProtKB Subcellular Location terms in UniProtKB/Swiss-Prot entries."

UniProtGOA12: UniProt-GOA (2012). "Gene Ontology annotation based on UniPathway vocabulary mapping."

Vallari87: Vallari DS, Jackowski S, Rock CO (1987). "Regulation of pantothenate kinase by coenzyme A and its thioesters." J Biol Chem 1987;262(6);2468-71. PMID: 3029083

Vallari87a: Vallari DS, Rock CO (1987). "Isolation and characterization of temperature-sensitive pantothenate kinase (coaA) mutants of Escherichia coli." J Bacteriol 169(12);5795-800. PMID: 2824448

Virga06: Virga KG, Zhang YM, Leonardi R, Ivey RA, Hevener K, Park HW, Jackowski S, Rock CO, Lee RE (2006). "Structure-activity relationships and enzyme inhibition of pantothenamide-type pantothenate kinase inhibitors." Bioorg Med Chem 14(4);1007-20. PMID: 16213731

Yun00a: Yun M, Park CG, Kim JY, Rock CO, Jackowski S, Park HW (2000). "Structural basis for the feedback regulation of Escherichia coli pantothenate kinase by coenzyme A." J Biol Chem 275(36);28093-9. PMID: 10862768

Zhang04e: Zhang YM, Frank MW, Virga KG, Lee RE, Rock CO, Jackowski S (2004). "Acyl carrier protein is a cellular target for the antibacterial action of the pantothenamide class of pantothenate antimetabolites." J Biol Chem 279(49);50969-75. PMID: 15459190


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 SRI International Pathway Tools version 18.5 on Mon Nov 24, 2014, BIOCYC13B.