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EcoSal Plus

Domain 3:

Metabolism

Biosynthesis of Pantothenic Acid and Coenzyme A

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  • Authors: Roberta Leonardi1, and Suzanne Jackowski2
  • Editor: Thomas J. Begley3
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Department of Infectious Diseases, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105-2794; 2: Department of Infectious Diseases, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105-2794; 3: University at Albany, Rensselear, NY
  • Received 13 February 2007 Accepted 01 June 2007 Published 13 August 2007
  • Address correspondence to Suzanne Jackowski suzanne.jackowski@stjude.org
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  • Abstract:

    Pantothenate is vitamin B5 and is the key precursor for the biosynthesis of coenzyme A (CoA), a universal and essential cofactor involved in a myriad of metabolic reactions, including the synthesis of phospholipids, the synthesis and degradation of fatty acids, and the operation of the tricarboxylic acid cycle. CoA is also the only source of the phosphopantetheine prosthetic group for enzymes that shuttle intermediates between the active sites of enzymes involved in fatty acid, nonribosomal peptide, and polyketide synthesis. Pantothenate can be synthesized de novo and/or transported into the cell through a pantothenatepermease. Pantothenate uptake is essential for those organisms that lack the genes to synthesize this vitamin. The intracellular levels of CoA are controlled by the balance between synthesis and degradation. In particular, CoA is assembled in five enzymatic steps, starting from the phosphorylation of pantothenate to phosphopantothenatecatalyzed by pantothenate kinase, the product of the coaA gene. In some bacteria, the production of phosphopantothenate by pantothenate kinase is the rate limiting and most regulated step in the biosynthetic pathway. CoA synthesis additionally networks with other vitamin-associated pathways, such as thiamine and folic acid.

  • Citation: Leonardi R, Jackowski S. 2007. Biosynthesis of Pantothenic Acid and Coenzyme A, EcoSal Plus 2007; doi:10.1128/ecosalplus.3.6.3.4

Key Concept Ranking

Major Facilitator Superfamily
0.50757575
Fatty Acid Biosynthesis
0.44129664
Amino Acid Synthesis
0.4392689
Bacterial Proteins
0.4291912
0.50757575

References

1. Miller SL, Schlesinger G. 1993. Prebiotic syntheses of vitamin coenzymes: II. Pantoic acid, pantothenic acid, and the composition of coenzyme A. J Mol Evol 36:308–314.[PubMed]
2. 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 184:4555–4572. [PubMed][CrossRef]
3. Cronan JE Jr, Littel KJ, Jackowski S. 1982. Genetic and biochemical analyses of pantothenate biosynthesis in Escherichia coli and Salmonella typhimurium. J Bacteriol 149:916–922.[PubMed]
4. Song W-J, Jackowski S. 1992. Cloning, sequencing, and expression of the pantothenate kinase (coaA) gene of Escherichia coli. J Bacteriol 174:6411–6417.[PubMed]
5. Vadali RV, Bennett GN, San KY. 2004. Cofactor engineering of intracellular CoA/acetyl-CoA and its effect on metabolic flux redistribution in Escherichia coli. Metab Eng 6:133–139. [PubMed][CrossRef]
6. Enos-Berlage JL, Downs DM. 1997. Mutations in sdh (succinate dehydrogenase genes) alter the thiamine requirement of Salmonella typhimurium. J Bacteriol 179:3989–3996.[PubMed]
7. Chassagnole C, Diano A, Letisse F, Lindley ND. 2003. Metabolic network analysis during fed-batch cultivation of Corynebacterium glutamicum for pantothenic acid production: first quantitative data and analysis of by-product formation. J Biotechnol 104:261–272. [PubMed][CrossRef]
8. Begley TP, Kinsland C, Strauss E. 2001. The biosynthesis of coenzyme A in bacteria. Vitam Horm 61:157–171. [PubMed][CrossRef]
9. Jackowski S. 1996. Biosynthesis of pantothenic acid and coenzyme A, p 687–694. In Neidhardt FC, Curtiss R, Gross CA, Ingraham JL, Lin ECC, Low KB, Magasanik B, Reznikoff W, Riley M, Schaechter M, and Umbarger HE (ed), Escherichia coli and Salmonella typhimurium: Cellular and Molecular Biology. American Society for Microbiology, Washington, D.C.
10. Tahiliani AG, Beinlich CJ. 1991. Pantothenic acid in health and disease. Vitam Horm 46:165–228. [PubMed][CrossRef]
11. Epelbaum S, LaRossa RA, VanDyk TK, Elkayam T, Chipman DM, Barak Z. 1998. Branched-chain amino acid biosynthesis in Salmonella typhimurium: a quantitative analysis. J Bacteriol 180:4056–4067.[PubMed]
12. Lobley CM, Schmitzberger F, Kilkenny ML, Whitney H, Ottenhof HH, Chakauya E, Webb ME, Birch LM, Tuck KL, Abell C, Smith AG, Blundell TL. 2003. Structural insights into the evolution of the pantothenate-biosynthesis pathway. Biochem Soc Trans 31:563–571. [PubMed][CrossRef]
13. Leigh JA. 1983. Levels of water-soluble vitamins in methanogenic and non-methanogenic bacteria. Appl Environ Microbiol 45:800–803.[PubMed]
14. Noll KM, Barber TS. 1988. Vitamin contents of archaebacteria. J Bacteriol 170:4315–4321.[PubMed]
15. Huser AT, Chassagnole C, Lindley ND, Merkamm M, Guyonvarch A, Elisakova V, Patek M, Kalinowski J, Brune I, Puhler A, Tauch A. 2005. Rational design of a Corynebacterium glutamicum pantothenate production strain and its characterization by metabolic flux analysis and genome-wide transcriptional profiling. Appl Environ Microbiol 71:3255–3268. [PubMed][CrossRef]
16. Sahm H, Eggeling L. 1999. D-Pantothenate synthesis in Corynebacterium glutamicum and use of panBC and genes encoding L-valine synthesis for D-pantothenate overproduction. Appl Environ Microbiol 65:1973–1979.[PubMed]
17. Powers SG, Snell EE. 1976. Ketopantoate hydroxymethyltransferase. II. Physical, catalytic, and regulatory properties. J Biochem (Tokyo) 251:3786–3793.
18. Maas WK, Vogel H. 1953. α-Oxoisovaleric acid, a precursor of pantothenic acid in Escherichia coli. J Bacteriol 65:388–393.[PubMed]
19. Whalen WA, Berg CM. 1982. Analysis of an avtA::Mu d1(Ap lac) mutant: Metabolic role of transaminase C. J Bacteriol 150:739–746.[PubMed]
20. Jones CE, Brook JM, Buck D, Abell C, Smith AG. 1993. Cloning and sequencing of the Escherichia coli panB gene, which encodes ketopantoate hydroxymethyltransferase, and overexpression of the enzyme. J Bacteriol 175:2125–2130.[PubMed]
21. Powers SG, Snell EE. 1979. Purification and properties of ketopantoate hydroxymethyltransferase. Methods Enzymol 62:204–209. [PubMed][CrossRef]
22. Sugantino M, Zheng R, Yu M, Blanchard JS. 2003. Mycobacterium tuberculosis ketopantoate hydroxymethyltransferase: tetrahydrofolate-independent hydroxymethyltransferase and enolization reactions with alpha-keto acids. Biochemistry 42:191–199. [PubMed][CrossRef]
23. von DF, Inoue T, Saldanha SA, Ottenhof HH, Schmitzberger F, Birch LM, Dhanaraj V, Witty M, Smith AG, Blundell TL, Abell C. 2003. Structure of E. coli ketopantoate hydroxymethyl transferase complexed with ketopantoate and Mg2+, solved by locating 160 selenomethionine sites. Structure (Camb.) 11:985–996. [PubMed][CrossRef]
24. Chaudhuri BN, Sawaya MR, Kim CY, Waldo GS, Park MS, Terwilliger TC, Yeates TO. 2003. The crystal structure of the first enzyme in the pantothenate biosynthetic pathway, ketopantoate hydroxymethyltransferase, from M tuberculosis. Structure (Camb.) 11:753–764. [PubMed][CrossRef]
25. Webb ME, Smith AG, Abell C. 2004. Biosynthesis of pantothenate. Nat Prod Rep 21:695–721. [PubMed][CrossRef]
26. Teller JH, Powers SG, Snell EE. 1976. Ketopantoate hydroxymethyltransferase I. Purification and role in pantothenate biosynthesis. J Biol Chem 251:3780–3785.[PubMed]
27. Vallari DS, Jackowski S, Rock CO. 1987. Regulation of pantothenate kinase by coenzyme A and its thioesters. J Biol Chem 262:2468–2471.[PubMed]
28. Rubio A, Downs DM. 2002. Elevated levels of ketopantoate hydroxymethyltransferase (PanB) lead to a physiologically significant coenzyme A elevation in Salmonella enterica serovar Typhimurium. J Bacteriol 184:2827–2832. [PubMed][CrossRef]
29. Shimizu S, Kataoka M, Chung MC-M, Yamada H. 1988. Ketopantoic acid reductase of Pseudomonas maltophilia 845. J Biol Chem 263:12077–12084.[PubMed]
30. Frodyma ME, Downs D. 1998. ApbA, the ketopantoate reductase enzyme of Salmonella typhimurium, is required for the synthesis of thiamine via the alternative pyrimidine biosynthetic pathway. J Biol Chem 273:5572–5576. [PubMed][CrossRef]
31. Matak-Vinkovic D, Vinkovic M, Saldanha SA, Ashurst JL, von DF, 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 40:14493–14500. [PubMed][CrossRef]
32. Zheng R, Blanchard JS. 2000. Kinetic and mechanistic analysis of the E. coli panE-encoded ketopantoate reductase. Biochemistry 39:3708–3717. [PubMed][CrossRef]
33. Zheng R, Blanchard JS. 2000. Identification of active site residues in E. coli ketopantoate reductase by mutagenesis and chemical rescue. Biochemistry 39:16244–16251. [PubMed][CrossRef]
34. 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 282:8487–8497. [PubMed][CrossRef]
35. Lobley CM, Ciulli A, Whitney HM, Williams G, Smith AG, Abell C, Blundell TL. 2005. The crystal structure of Escherichia coli ketopantoate reductase with NADP+ bound. Biochemistry 44:8930–8939. [PubMed][CrossRef]
36. Merkamm M, Chassagnole C, Lindley ND, Guyonvarch A. 2003. Ketopantoate reductase activity is only encoded by ilvC in Corynebacterium glutamicum. J Biotechnol 104:253–260. [PubMed][CrossRef]
37. Primerano DA, Burns RO. 1982. Metabolic basis for the isoleucine, pantothenate or methionine requirement of ilvG strains of Salmonella typhimurium. J Bacteriol 150:1202–1211.[PubMed]
38. Primerano DA, Burns RO. 1983. Role of acetohydroxy acid isomeroreductase in biosynthesis of pantothenic acid in Salmonella typhimurium. J Bacteriol 153:259–269.[PubMed]
39. Frodyma ME, Downs D. 1998. The panE gene, encoding ketopantoate reductase, maps at 10 minutes and is allelic to apbA in Salmonella typhimurium. J Bacteriol 180:4757–4759.[PubMed]
40. Frodyma M, Rubio A, Downs DM. 2000. Reduced flux through the purine biosynthetic pathway results in an increased requirement for coenzyme A in thiamine synthesis in Salmonella enterica serovar typhimurium. J Bacteriol 182:236–240. [PubMed][CrossRef]
41. 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 75:135–146. [PubMed][CrossRef]
42. David WE, Lichstein HC. 1950. Aspartic acid decarboxylase in bacteria. Proc Exp Biol Med 73:216–218.
43. Virtanen AI, Laine T. 1937. The decarboxylation of D-lysine and L-aspartic acid. Enzymologia 8:266–270.
44. Williamson JM, Brown GM. 1979. Purification and properties of L-aspartate-α-decarboxylase, an enzyme that catalyzes the formation of β-alanine in Escherichia coli. J Biol Chem 254:8074–8082.[PubMed]
45. Cronan JE, Jr. 1980. β-Alanine synthesis in Escherichia coli. J Bacteriol 141:1291–1297.[PubMed]
46. Williamson JM. 1985. L-Aspartate α-decarboxylase. Methods Enzymol 113:589–595. [PubMed][CrossRef]
47. Lee BI, Suh SW. 2004. Crystal structure of the schiff base intermediate prior to decarboxylation in the catalytic cycle of aspartate alpha-decarboxylase. J Mol Biol 340:1–7. [PubMed][CrossRef]
48. 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 Å resolution provides evidence for an ester in protein self-processing. Nat Struct Biol 5:289–293. [PubMed][CrossRef]
49. Ramjee MK, Genschel U, Abell C, Smith AG. 1997. Escherichia coli L-aspartate-alpha-decarboxylase: preprotein processing and observation of reaction intermediates by electrospray mass spectrometry. Biochem J 323(Pt 3):661–669.
50. Chopra S, Pai H, Ranganathan A. 2002. Expression, purification, and biochemical characterization of Mycobacterium tuberculosis aspartate decarboxylase, PanD. Protein Expr Purif 25:533–540. [PubMed][CrossRef]
51. Schmitzberger F, Kilkenny ML, Lobley CM, Webb ME, Vinkovic M, Matak-Vinkovic D, Witty M, Chirgadze DY, Smith AG, Abell C, Blundell TL. 2003. Structural constraints on protein self-processing in L-aspartate-alpha-decarboxylase. EMBO J 22:6193–6204. [PubMed][CrossRef]
52. LaRossa RA, Van Dyk TK. 1989. Leaky pantothenate and thiamin mutations of Salmonella typhimurium conferring suphometuron methyl sensitivity. J Gen Microbiol 135(Pt 8):2209–2222.
53. Cosloy SD, McFall E. 1973. Metabolism of D-serine in Escherichia coli K-12: mechanism of growth inhibition. J Bacteriol 114:685–694.[PubMed]
54. Durham NN, Milligan R. 1961. Reversal of the D-serine inhibition of growth and division in a Flavobacterium. Biochem Biophys Res Commun 5:144–147. [PubMed][CrossRef]
55. Durham NN, Milligan R. 1962. Mechanism of growth inhibition by D-serine in a Flavobacterium. Biochem Biophys Res Commun 7:342–345. [CrossRef]
56. Grula EA, Grula MM. 1963. Inhibition in the synthesis of beta-alanine by D-serine. Biochim Biophys Acta 74:776–778. [PubMed][CrossRef]
57. Maas WK, Davis BD. 1950. Pantothenate studies. I. Interference by D-serine and L-aspartic acid with pantothenate biosynthesis in Escherichia coli J Bacteriol 60:733–745.[PubMed]
58. Shive W, Macow J. 1946. Biochemical transformations as determined by competitive analogue-metabolite growth inhibitions. J Biol Chem 162:451–462.
59. Slotnick IJ. 1956. Dihydrouracil as a growth factor for a mutant strain of Escherichia coli. J Bacteriol 72:276–277.[PubMed]
60. Slotnick IJ, Weinfeld H. 1957. Dihydrouracil as a growth factor for mutant strains of Escherichia coli. J Bacteriol 73:122–125.[PubMed]
61. Dusch N, Puhler A, Kalinowski J. 1999. Expression of the Corynebacterium glutamicum panD gene encoding L-aspartate-alpha-decarboxylase leads to pantothenate overproduction in Escherichia coli. Appl Environ Microbiol 65:1530–1539.[PubMed]
62. Schneider F, Kramer R, Burkovski A. 2004. Identification and characterization of the main beta-alanine uptake system in Escherichia coli. Appl Microbiol Biotechnol 65:576–582. [PubMed][CrossRef]
63. Maas WK. 1952. Pantothenate studies III. Description of the extracted pantothenate-synthesizing enzyme of Escherichia coli. J Biol Chem 198:23–32.[PubMed]
64. Miyatake K, Nakano Y, Kitaoka S. 1979. Pantothenate synthetase from Escherichia coli [D-pantoate:β-alanine ligase (AMP-forming), EC 6.3.2.1]. Methods Enzymol 62:215–219. [PubMed][CrossRef]
65. Zheng R, Blanchard JS. 2001. Steady-state and pre-steady-state kinetic analysis of Mycobacterium tuberculosis pantothenate synthetase. Biochemistry 40:12904–12912. [PubMed][CrossRef]
66. Williams L, Zheng R, Blanchard JS, Raushel FM. 2003. Positional isotope exchange analysis of the pantothenate synthetase reaction. Biochemistry 42:5108–5113. [PubMed][CrossRef]
67. Wang S, Eisenberg D. 2006. Crystal structure of the pantothenate synthetase from Mycobacterium tuberculosis, snapshots of the enzyme in action. Biochemistry 45:1554–1561. [PubMed][CrossRef]
68. Wang S, Eisenberg D. 2003. Crystal structures of a pantothenate synthetase from M. tuberculosis and its complexes with substrates and a reaction intermediate. Protein Sci 12:1097–1108. [PubMed][CrossRef]
69. Goulding CW, Apostol M, Anderson DH, Gill HS, Smith CV, Kuo MR, Yang JK, Waldo GS, Suh SW, Chauhan R, Kale A, Bachhawat N, Mande SC, Johnston JM, Lott JS, Baker EN, Arcus VL, Leys D, McLean KJ, Munro AW, Berendzen J, Sharma V, Park MS, Eisenberg D, Sacchettini J, Alber T, Rupp B, Jacobs W, Jr, Terwilliger TC. 2002. The TB structural genomics consortium: providing a structural foundation for drug discovery. Curr Drug Targets Infect Disord 2:121–141. [PubMed][CrossRef]
70. Zheng R, Dam TK, Brewer CF, Blanchard JS. 2004. Active site residues in Mycobacterium tuberculosis pantothenate synthetase required in the formation and stabilization of the adenylate intermediate. Biochemistry 43:7171–7178. [PubMed][CrossRef]
71. Tuck KL, Saldanha SA, Birch LM, Smith AG, Abell C. 2006. The design and synthesis of inhibitors of pantothenate synthetase. Org Biomol Chem 4:3598–3610. [PubMed][CrossRef]
72. White EL, Southworth K, Ross L, Cooley S, Gill RB, Sosa MI, Manouvakhova A, Rasmussen L, Goulding C, Eisenberg D, Fletcher TM III. 2007. A novel inhibitor of Mycobacterium tuberculosis pantothenate synthetase. J Biomol Screen 12:100–105. [PubMed][CrossRef]
73. Merkel WK, Nichols BP. 1996. Characterization and sequence of the Escherichia coli panBCD gene cluster. FEMS Microbiol Lett 143:247–252. [PubMed][CrossRef]
74. Baba T, Ara T, Hasegawa M, Takai Y, Okumura Y, Baba M, Datsenko KA, Tomita M, Wanner BL, Mori H. 2006. Construction of Escherichia coli K-12 in-frame, single-gene knockout mutants: the Keio collection. Mol Syst Biol 2:2006. [CrossRef]
75. Davis BD. 1950. Studies on nutritionally deficient bacterial mutants isolated by means of penicillin. Experimentia 6:41–50. [CrossRef]
76. Jackowski S, Rock CO. 1981. Regulation of coenzyme A biosynthesis. J Bacteriol 148:926–932.[PubMed]
77. Baigori M, Grau R, Morbidoni HR, de Mendoza D. 1991. Isolation and characterization of Bacillus subtilis mutants blocked in the synthesis of pantothenic acid. J Bacteriol 173:4240–4242.[PubMed]
78. Nakamura H, Tamura Z. 1973. Pantothenate uptake in Escherichia coli K-12. J Nutr Sci Vitaminol 19:389–400.
79. Vanet A, Plumbridge JA, Alix J-H. 1993. Cotranscription of two genes necessary for ribosomal protein L11 methylation (prmA) and pantothenate transport (panF) in Escherichia coli K-12. J Bacteriol 175:7178–7188.[PubMed]
80. Jackowski S, Alix J-H. 1990. Cloning, sequence, and expression of the pantothenate permease (panF) gene of Escherichia coli. J Bacteriol 172:3842–3848.[PubMed]
81. Jung H. 2002. The sodium/substrate symporter family: structural and functional features. FEBS Lett 529:73–77. [PubMed][CrossRef]
82. Reizer J, Reizer A, Saier MH, Jr. 1990. The Na+/pantothenate symporter (PanF) of Escherichia coli is homologous to the Na+/proline symporter (PutP) of E. coli and the Na+/glucose symporters of mammals. Res Microbiol 141:1069–1072. [PubMed][CrossRef]
83. Vallari DS, Rock CO. 1985. Pantothenate transport in Escherichia coli. J Bacteriol 162:1156–1161.[PubMed]
84. Dunn SD, Snell EE. 1979. Isolation of temperature-sensitive pantothenate kinase mutants of Salmonella typhimurium and mapping of the coaA gene. J Bacteriol 140:805–808.[PubMed]
85. Vallari DS, Rock CO. 1985. Isolation and characterization of Escherichia coli pantothenate permease (panF) mutants. J Bacteriol 164:136–142.[PubMed]
86. Sambandamurthy VK, Derrick SC, Jalapathy KV, Chen B, Russell RG, Morris SL, Jacobs WR, Jr. 2005. Long-term protection against tuberculosis following vaccination with a severely attenuated double lysine and pantothenate auxotroph of Mycobacterium tuberculosis. Infect Immun 73:1196–1203. [PubMed][CrossRef]
87. Sambandamurthy VK, Wang X, Chen B, Russell RG, Derrick S, Collins FM, Morris SL, Jacobs WR. 2002. A pantothenate auxotroph of Mycobacterium tuberculosis is highly attenuated and protects mice against tuberculosis. Nat Med 8:1174. [CrossRef]
88. Brown GM. 1959. The metabolism of pantothenic acid. J Biol Chem 234:370–378.[PubMed]
89. Dunn SD, Snell EE. 1977. Abstr. J Supramol Struct 6:136.
90. Vallari DS, Rock CO. 1987. Isolation and characterization of temperature-sensitive pantothenate kinase (coaA) mutants of Escherichia coli. J Bacteriol 169:5795–5800.[PubMed]
91. Flaks JG, Leboy S, Birge EA, Kurland CG. 1966. Mutations and genetics concerned with the ribosome. Cold Spring Harbor Symp Quant Biol 31:623–631.[PubMed]
92. Song W-J, Jackowski S. 1992. coaA and rts are allelic and located at kilobase 3532 on the Escherichia coli physical map. J Bacteriol 174:1705–1706.[PubMed]
93. Flamm JA, Friesen JD, Otsuka JA. 1988. The nucleotide sequence of the Escherichia coli rts gene. Gene 74:555–558. [PubMed][CrossRef]
94. Chen X, Shen D, Zhou B. 2006. Analysis of the temperature-sensitive mutation of Escherichia coli pantothenate kinase reveals YbjN as a possible protein stabilizer. Biochem Biophys Res Commun 345:834–842. [PubMed][CrossRef]
95. Song W-J, Jackowski S. 1994. Kinetics and regulation of pantothenate kinase from Escherichia coli. J Biol Chem 269:27051–27058.[PubMed]
96. Yun M, Park C-G, Kim J-Y, Rock CO, Jackowski S, Park H-W. 2000. Structural basis for the feedback regulation of Escherichia coli pantothenate kinase by coenzyme A. J Biol Chem 275:28093–28099.[PubMed]
97. Ivey RA, Zhang Y-M, Virga KG, Hevener K, Lee RE, Rock CO, Jackowski S, Park H-W. 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 279:35622–35629. [PubMed][CrossRef]
98. Clifton G, Bryant SR, Skinner CG. 1970. N′-(substituted) pantothenamides, antimetabolites of pantothenic acid. Arch Biochem Biophys 137:523–528. [PubMed][CrossRef]
99. 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 277:48205–48209. [PubMed][CrossRef]
100. Virga KG, Zhang Y-M, Leonardi R, Ivey RA, Hevener K, Park H-W, Jackowski S, Rock CO, Lee RE. 2006. Structure-activity relationships and enzyme inhibition of pantothenamide-type pantothenate kinase inhibitors. Bioorg Med Chem 14:1007–1020. [PubMed][CrossRef]
101. Zhang Y-M, 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 279:50969–50975. [PubMed][CrossRef]
102. Choudhry AE, Mandichak TL, Broskey JP, Egolf RW, Kinsland C, Begley TP, Seefeld MA, Ku TW, Brown JR, Zalacain M, Ratnam K. 2003. Inhibitors of pantothenate kinase: novel antibiotics for staphylococcal infections. Antimicrob Agents Chemother 47:2051–2055. [PubMed][CrossRef]
103. Leonardi R, Chohnan S, Zhang Y-M, Virga KG, Lee RE, Rock CO, Jackowski S. 2005. A pantothenate kinase from Staphylococcus aureus refractory to feedback regulation by coenzyme A. J Biol Chem 280:3314–3322. [PubMed][CrossRef]
104. Hong BS, Yun MK, Zhang Y-M, Chohnan S, Rock CO, White SW, Jackowski S, Park HW, Leonardi R. 2006. Prokaryotic type II and type III pantothenate kinases: the same monomer fold creates dimers with distinct catalytic properties. Structure 14:1251–1261. [PubMed][CrossRef]
105. Newton GL, Arnold K, Price MS, Sherrill C, delCardayre SB, Aharonowitz Y, Cohen G, Davies J, Fahey RC, Davis C. 1996. Distribution of thiols in microorganisms: mycothiol is a major thiol in most actinomycetes. J Bacteriol 178:1990–1995.[PubMed]
106. delCardayre SB, Stock KP, Newton GL, Fahey RC, Davies JE. 1998. Coenzyme A disulfide reductase, the primary low molecular weight disulfide reductase from Staphylococcus aureus. Purification and characterization of the native enzyme. J Biol Chem 273:5744–5751. [PubMed][CrossRef]
107. delCardayre SB, Davies JE. 1998. Staphylococcus aureus coenzyme A disulfide reductase, a new subfamily of pyridine nucleotide-disulfide oxidoreductase. J Biol Chem 273:5752–5757. [PubMed][CrossRef]
108. Nicely NI, Parsonage D, Paige C, Newton GL, Fahey RC, Leonardi R, Jackowski S, Mallett TC, Claiborne A. 2007. Structure of the type III pantothenate kinase from Bacillus anthracis at 2.0 Å resolution: implications for coenzyme A-dependent redox biology. Biochemistry 46:3234–3245. [PubMed][CrossRef]
109. Genschel U. 2004. Coenzyme a biosynthesis: reconstruction of the pathway in archaea and an evolutionary scenario based on comparative genomics. Mol Biol Evol 21:1242–1251. [PubMed][CrossRef]
110. Osterman A, Overbeek R. 2003. Missing genes in metabolic pathways: a comparative genomics approach. Curr Opin Chem Biol 7:238–251. [PubMed][CrossRef]
111. Yocum RR, Patterson TA. 2004. U.S. Patent 6,830,898.
112. Brand LA, Strauss E. 2005. Characterization of a new pantothenate kinase isoform from Helicobacter pylori. J Biol Chem 280:20185–20188. [PubMed][CrossRef]
113. Yang H, Abeles RH. 1987. Purification and properties of Escherichia coli 4′-phosphopantothenoylcysteine decarboxylase: presence of covalently bound pyruvate. Biochemistry 26:4076–4081. [PubMed][CrossRef]
114. Spitzer ED, Jimenez-Billini HE, Weiss B. 1988. beta-Alanine auxotrophy associated with dfp, a locus affecting DNA synthesis in Escherichia coli. J Bacteriol 170:872–876.[PubMed]
115. Spitzer ED, Weiss B. 1985. dfp Gene of Escherichia coli K-12, a locus affecting DNA synthesis, codes for a flavoprotein. J Bacteriol 164:994–1003.[PubMed]
116. 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 275:31838–31846. [PubMed][CrossRef]
117. Strauss E, Kinsland C, Ge Y, McLafferty FW, Begley TP. 2001. Phosphopantothenoylcysteine synthetase from Escherichia coli. Identification and characterization of the last unidentified coenzyme A biosynthetic enzyme in bacteria. J Biol Chem 276:13513–13516. [PubMed][CrossRef]
118. Kupke T. 2001. Molecular characterization of the 4′-phosphopantothenoylcysteine decarboxylase domain of bacterial Dfp flavoproteins. J Biol Chem 276:27597–27604. [PubMed][CrossRef]
119. Kupke T. 2002. Molecular characterization of the 4′-phosphopantothenoylcysteine synthetase domain of bacterial dfp flavoproteins. J Biol Chem 277:36137–36145. [PubMed][CrossRef]
120. Strauss E, Begley TP. 2001. Mechanistic studies on phosphopantothenoylcysteine decarboxylase. J Am Chem Soc 123:6449–6450. [PubMed][CrossRef]
121. Strauss E, Begley TP. 2003. Stereochemical studies on phosphopantothenoylcysteine decarboxylase from Escherichia coli. Bioorg Med Chem Lett 13:339–342. [PubMed][CrossRef]
122. Strauss E, Zhai H, Brand LA, McLafferty FW, Begley TP. 2004. Mechanistic studies on phosphopantothenoylcysteine decarboxylase: trapping of an enethiolate intermediate with a mechanism-based inactivating agent. Biochemistry 43:15520–15533. [PubMed][CrossRef]
123. Kupke T. 2004. Active-site residues and amino acid specificity of the bacterial 4′-phosphopantothenoylcysteine synthetase CoaB. Eur J Biochem 271:163–172. [PubMed][CrossRef]
124. Stanitzek S, Augustin MA, Huber R, Kupke T, Steinbacher S. 2004. Structural basis of CTP-dependent peptide bond formation in coenzyme A biosynthesis catalyzed by Escherichia coli PPC synthetase. Structure (Camb.) 12:1977–1988. [PubMed][CrossRef]
125. Manoj N, Strauss E, Begley TP, Ealick SE. 2003. Structure of human phosphopantothenoylcysteine synthetase at 2.3 Å resolution. Structure 11:927–936. [PubMed][CrossRef]
126. Abiko Y, Suzuki T, Shimizu M. 1967. Investigations on pantothenic acid and its related compounds XI. Biochemical studies 6 A final stage in the biosynthesis of CoA. J Biochem (Tokyo) 61:309–312.[PubMed]
127. Hoagland MB, Novelli GD. 1954. Biosynthesis of coenzyme A from phosphopantetheine and of pantetheine from pantothenate. J Biol Chem 207:767–773.[PubMed]
128. Martin DP, Drueckhammer DG. 1993. Separate enzymes catalyze the final two steps of coenzyme A biosynthesis in Brevibacterium ammoniagenes: purification of panthetheine phosphate adenylyltransferase. Biochem Biophys Res Commun 192:1155–1161. [PubMed][CrossRef]
129. Geerlof A, Lewendon A, Shaw WV. 1999. Purification and characterization of phosphopantetheine adenylyltransferase from Escherichia coli. J Biol Chem 274:27105–27111. [PubMed][CrossRef]
130. Jackowski S, Rock CO. 1984. Metabolism of 4′-phosphopantetheine in Escherichia coli. J Bacteriol 158:115–120.
131. Rock CO, Park H-W, Jackowski S. 2003. Role of feedback regulation of pantothenate kinase (CoaA) in the control of coenzyme A levels in Escherichia coli. J Bacteriol 185:3410–3415. [PubMed][CrossRef]
132. Vallari DS, Jackowski S. 1988. Biosynthesis and degradation both contribute to the regulation of coenzyme A content in Escherichia coli. J Bacteriol 170:3961–3966.[PubMed]
133. Izard T. 2002. The crystal structures of phosphopantetheine adenylyltransferase with bound substrates reveal the enzyme’s catalytic mechanism. J Mol Biol 315:487–495. [PubMed][CrossRef]
134. Izard T. 2003. A novel adenylate binding site confers phosphopantetheine adenylyltransferase interactions with coenzyme A. J Bacteriol 185:4074–4080. [PubMed][CrossRef]
135. Izard T, Geerlof A. 1999. The crystal structure of a novel bacterial adenylyltransferase reveals half of sites reactivity. EMBO J 18:2021–2030. [PubMed][CrossRef]
136. Bork P, Holm L, Koonin EV, Sander C. 1995. The cytidylyltransferase superfamily: identification of the nucleotide-binding site and fold prediction. Prot Struct Funct Genet 22:259–266. [CrossRef]
137. Morris VK, Izard T. 2004. Substrate-induced asymmetry and channel closure revealed by the apoenzyme structure of Mycobacterium tuberculosis phosphopantetheine adenylyltransferase. Protein Sci 13:2547–2552. [PubMed][CrossRef]
138. Takahashi H, Inagaki E, Fujimoto Y, Kuroishi C, Nodake Y, Nakamura Y, Arisaka F, Yutani K, Kuramitsu S, Yokoyama S, Yamamoto M, Miyano M, Tahirov TH. 2004. Structure and implications for the thermal stability of phosphopantetheine adenylyltransferase from Thermus thermophilus. Acta Crystallogr D Biol Crystallogr 60:97–104. [PubMed][CrossRef]
139. Aghajanian S, Worrall DM. 2002. Identification and characterization of the gene encoding the human phosphopantetheine adenylyltransferase and dephospho-CoA kinase bifunctional enzyme (CoA synthase). Biochem J 365:13–18.[PubMed]
140. Daugherty M, Polanuyer B, Farrell M, Scholle M, Lykidis A, Crecy-Lagard V, Osterman A. 2002. Complete reconstitution of the human coenzyme A biosynthetic pathway via comparative genomics. J Biol Chem 277:21431–21439. [PubMed][CrossRef]
141. Worrall DM, Tubbs PK. 1983. A bifunctional enzyme complex in coenzyme A biosynthesis: purification of 4′ pantetheine phosphate adenylyltransferase and dephospho-CoA kinase. J Biochem (Tokyo) 215:153–157.
142. Zhyvoloup A, Nemazanyy I, Babych O, Panasyuk G, Pobigailo N, Vudmaska M, Naidenov V, Kukharenko O, Palchevskii S, Savinska L, Ovcharenko G, Verdier F, Valovka T, Fenton T, Rebholz H, Wang ML, Shepherd P, Matsuka G, Filonenko V, Gout IT. 2002. Molecular cloning of CoA synthase: the missing link in CoA biosynthesis. J Biol Chem 277:22107–22110. [PubMed][CrossRef]
143. Zhao L, Allanson NM, Thomson SP, Maclean JK, Barker JJ, Primrose WU, Tyler PD, Lewendon A. 2003. Inhibitors of phosphopantetheine adenylyltransferase. Eur J Med Chem 38:345–349. [PubMed][CrossRef]
144. Mishra P, Park PK, Drueckhammer DG. 2001. Identification of yacE (coaE) as the structural gene for dephosphocoenzyme A kinase in Escherichia coli K-12. J Bacteriol 183:2774–2778. [PubMed][CrossRef]
145. O’Toole N, Barbosa JA, Li Y, Hung LW, Matte A, Cygler M. 2003. Crystal structure of a trimeric form of dephosphocoenzyme A kinase from Escherichia coli. Protein Sci 12:327–336. [PubMed][CrossRef]
146. Obmolova G, Teplyakov A, Bonander N, Eisenstein E, Howard AJ, Gilliland GL. 2001. Crystal structure of dephospho-coenzyme A kinase from Haemophilus influenzae. J Struct Biol 136:119–125. [PubMed][CrossRef]
147. Seto A, Murayama K, Toyama M, Ebihara A, Nakagawa N, Kuramitsu S, Shirouzu M, Yokoyama S. 2005. ATP-induced structural change of dephosphocoenzyme A kinase from Thermus thermophilus HB8. Proteins 58:235–242. [PubMed][CrossRef]
148. Jackowski S, Rock CO. 1986. Consequences of reduced intracellular coenzyme A content in Escherichia coli. J Bacteriol 166:866–871.[PubMed]
149. Jackowski S, Rock CO. 1984. Turnover of the 4′-phosphopantetheine prosthetic group of acyl carrier protein. J Biol Chem 259:1891–1895.[PubMed]
150. Vadali RV, Bennett GN, San KY. 2004. Enhanced isoamyl acetate production upon manipulation of the acetyl-CoA node in Escherichia coli. Biotechnol Prog 20:692–697. [PubMed][CrossRef]
151. Fahey RC. 2001. Novel thiols of prokaryotes. Annu Rev Microbiol 55:333–356. [PubMed][CrossRef]
152. Fahey RC, Brown WC, Adams WB, Worsham MB. 1978. Occurrence of glutathione in bacteria. J Bacteriol 133:1126–1129.[PubMed]
153. Swerdlow RD, Green CL, Setlow B, Setlow P. 1979. Identification of an NADH-linked disulfide reductase from Bacillus megaterium specific for disulfides containing pantethine 4′,4″-diphosphate moieties. J Biol Chem 254:6835–6837.
154. Swerdlow RD, Setlow P. 1983. Purification and characterization of a Bacillus megaterium disulfide reductase specific for disulfides containing pantethine 4′,4″-diphosphate. J Bacteriol 153:475–484.[PubMed]
155. Setlow B, Setlow P. 1977. Levels of acetyl coenzyme A, reduced and oxidized coenzyme A, and coenzyme A in disulfide linkage to protein in dormant and germinated spores and growing and sporulating cells of Bacillus megaterium. J Bacteriol 132:444–452.[PubMed]
156. Loewen PC. 1976. Novel nucleotides from E. coli isolated and partially characterized Biochem Biophys Res Commun 70:1210–1218. [PubMed][CrossRef]
157. Loewen PC. 1978. Levels of coenzyme A-glutathione mixed disulfide in Escherichia coli. Can J Biochem 56:753–759.[PubMed]
158. Lowry OH, Carter J, Ward JB, Glaser L. 1971. The effect of carbon and nitrogen sources on the level of metabolic intermediates in Escherichia coli. J Biol Chem 246:6511–6521.[PubMed]
159. Kleinkauf H. 2000. The role of 4′-phosphopantetheine in the biosynthesis of fatty acids, polyketides and peptides. Biofactors 11:91–92. [CrossRef]
160. Lambalot RH, Gehring AM, Flugel RS, Zuber P, LaCelle M, Marahiel MA, Reid R, Khosla C, Walsh CT. 1996. A new enzyme superfamily. Chem Biol 3:923–936. [PubMed][CrossRef]
161. Mootz HD, Finking R, Marahiel MA. 2001. 4′-Phosphopantetheine transfer in primary and secondary metabolism of Bacillus subtilis. J Biol Chem 276:37289–37298. [PubMed][CrossRef]
162. Elovson J, Vagelos PR. 1968. Acyl carrier protein X. Acyl carrier protein synthetase. J Biol Chem 243:3603–3611.[PubMed]
163. Lambalot RH, Walsh CT. 1995. Cloning, overproduction, and characterization of the Escherichia coli holo-acyl carrier protein synthase. J Biol Chem 270:24658–24661. [PubMed][CrossRef]
164. Flugel RS, Hwangbo Y, Lambalot RH, Cronan JE, Jr, Walsh CT. 2000. Holo-(Acyl carrier protein) synthase and phosphopantetheinyl transfer in Escherichia coli. J Biol Chem 275:959–968. [PubMed][CrossRef]
165. De Lay NR, Cronan JE. 2006. A genome rearrangement has orphaned the Escherichia coli K-12 AcpT phosphopantetheinyl transferase from its cognate Escherichia coli O157:H7 substrates. Mol Microbiol 61:232–242. [PubMed][CrossRef]
166. Barekzi N, Joshi S, Irwin S, Ontl T, Schweizer HP. 2004. Genetic characterization of pcpS, encoding the multifunctional phosphopantetheinyl transferase of Pseudomonas aeruginosa. Microbiology 150:795–803. [PubMed][CrossRef]
167. Thomas J, Cronan JE, Jr. 2005. The enigmatic acyl carrier protein phosphodiesterase of Escherichia coli: Genetic and enzymological characterization. J Biol Chem 280:34675–34683. [PubMed][CrossRef]
168. Thomas J, Rigden DJ, Cronan JE. 2007. Acyl carrier protein phosphodiesterase (AcpH) of Escherichia coli is a non-canonical member of the HD phosphatase/phosphodiesterase family. Biochemistry 46:129–136. [PubMed][CrossRef]
169. Vagelos PR, Larabee AR. 1967. Acyl carrier protein. IX. Acyl carrier protein hydrolase. J Biol Chem 242:1776–1781.[PubMed]
170. Alberts AW, Vagelos PR. 1966. Acyl carrier protein VIII. Studies of acyl carrier protein and coenzyme A in Escherichia coli pantothenate or β-alanine auxotrophs. J Biol Chem 241:5201–5204.[PubMed]
171. Kang LW, Gabelli SB, Bianchet MA, Xu WL, Bessman MJ, Amzel LM. 2003. Structure of a coenzyme A pyrophosphatase from Deinococcus radiodurans: a member of the nudix family. J Bacteriol 185:4110. [CrossRef]
172. Xu W, Shen J, Dunn CA, Desai S, Bessman MJ. 2001. The Nudix hydrolases of Deinococcus radiodurans. Mol Microbiol 39:286–290. [PubMed][CrossRef]
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/content/journal/ecosalplus/10.1128/ecosalplus.3.6.3.4
2007-08-13
2017-05-29

Abstract:

Pantothenate is vitamin B5 and is the key precursor for the biosynthesis of coenzyme A (CoA), a universal and essential cofactor involved in a myriad of metabolic reactions, including the synthesis of phospholipids, the synthesis and degradation of fatty acids, and the operation of the tricarboxylic acid cycle. CoA is also the only source of the phosphopantetheine prosthetic group for enzymes that shuttle intermediates between the active sites of enzymes involved in fatty acid, nonribosomal peptide, and polyketide synthesis. Pantothenate can be synthesized de novo and/or transported into the cell through a pantothenatepermease. Pantothenate uptake is essential for those organisms that lack the genes to synthesize this vitamin. The intracellular levels of CoA are controlled by the balance between synthesis and degradation. In particular, CoA is assembled in five enzymatic steps, starting from the phosphorylation of pantothenate to phosphopantothenatecatalyzed by pantothenate kinase, the product of the coaA gene. In some bacteria, the production of phosphopantothenate by pantothenate kinase is the rate limiting and most regulated step in the biosynthetic pathway. CoA synthesis additionally networks with other vitamin-associated pathways, such as thiamine and folic acid.

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Figures

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Figure 1

Pantoate formation begins with the transfer of a methyl group to α-ketoisovalerate by ketopantoate hydroxymethyltransferase, the gene product, followed by reduction by ketopantoate reductase, the gene product. The α-ketoisovalerate is an intermediate in valine biosynthesis, and the relative demand for the amino acid versus pantothenate determines the interconversion between the two metabolites. The branched-chain-amino-acid transferase, the product of the gene, converts valine back to α-ketoisovalerate. β-Alanine is formed from aspartate by aspartate-1-decarboxylase, the product of the gene. Pantothenate is formed by the ATP-dependent condensation of β-alanine and pantoate by pantothenate synthetase, the gene product. Pantothenate is used for CoA biosynthesis or exits from the bacterium.

Citation: Leonardi R, Jackowski S. 2007. Biosynthesis of Pantothenic Acid and Coenzyme A, EcoSal Plus 2007; doi:10.1128/ecosalplus.3.6.3.4
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Image of Figure 2
Figure 2

Pantothenate is either synthesized de novo ( Fig. 1 ) or actively taken up into cells by a unidirectional sodium-dependent permease, the gene product. The exit of pantothenate is independent of permease activity. Pantothenate kinase isoforms type I, II, and III are the products of the gene(s) and phosphorylate pantothenate. Cysteine and CTP are then added to 4′-phosphopantothenate in a two-step reaction to yield 4′-phosphopantetheine by the bifunctional product of the gene. The phosphopantetheine adenylyltransferase, the gene product, adds the adenine moiety to 4′-phosphopantetheine to form dephospho-CoA, which in turn is phosphorylated by dephospho-CoA kinase, the product of the gene, to form CoA. The CoA either becomes acylated by a fatty acid or organic acid or donates the 4′-phosphopantetheine moiety to a protein, such as acyl carrier protein (ACP), to activate it. The transfer of the 4′-phosphopantetheine prosthetic group is catalyzed by the product of the gene. The prosthetic group is cleaved from the protein by an ACP-specific phosphodiesterase encoded by the gene. The 4′-phosphopantetheine metabolic intermediate either is utilized for CoA synthesis or exits from the cell. Intact 4′-phosphopantetheine is not taken up by the bacterium.

Citation: Leonardi R, Jackowski S. 2007. Biosynthesis of Pantothenic Acid and Coenzyme A, EcoSal Plus 2007; doi:10.1128/ecosalplus.3.6.3.4
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Tables

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Table 1

Intracellular CoA pool composition in

Citation: Leonardi R, Jackowski S. 2007. Biosynthesis of Pantothenic Acid and Coenzyme A, EcoSal Plus 2007; doi:10.1128/ecosalplus.3.6.3.4

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