Pyoluteorin

Pyoluteorin is a natural antibiotic that is biosynthesized from a hybrid nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) pathway.[1] Pyoluteorin was first isolated in the 1950s from Pseudomonas aeruginosa strains T359 and IFO 3455[2] and was found to be toxic against oomycetes, bacteria, fungi, and against certain plants.[3] Pyoluteorin is most notable for its toxicity against the oomycete Pythium ultimum,[4] which is a plant pathogen that causes a global loss in agriculture. Currently, pyoluteorin derivatives are being studied as an Mcl-1 antagonist in order to target cancers that have elevated Mcl-1 levels.[5]

Pyoluteorin
Molecule of pyoluteorin
Identifiers
  • (4,5-Dichloro-1H-pyrrol-2-yl)-(2,6-dihydroxyphenyl)methanone
CAS Number
PubChem CID
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC11H7Cl2NO3
Molar mass272.08 g·mol−1
3D model (JSmol)
  • C1=CC(=C(C(=C1)O)C(=O)C2=CC(=C(N2)Cl)Cl)O
  • InChI=InChI=1S/C11H7Cl2NO3/c12-5-4-6(14-11(5)13)10(17)9-7(15)2-1-3-8(9)16/h1-4,14-16H checkY
  • Key:JPGWTZORMBTNMF-UHFFFAOYSA-N checkY

Biosynthesis

Pyoluteorin is synthesized from an NRPS/PKS hybrid pathway. The resorcinol ring is derived from a type I PKS[6][7] while the dichloropyrrole moiety is derived from a type II NRPS.[8] Pyoluteorin biosynthesis begins with the activation of L-proline to prolyl-AMP by the adenylation domain PltF. With prolyl-AMP still in the active site, the active form of the peptidyl carrier protein PltL binds to PltF. Then PltF catalyzes the aminoacylation of PltL by attaching L-proline to the thiol of the 4’phosphopantetheine arm of PltL.[9] Next, the dehydrogenase PltE desaturates the prolyl moiety on PltL to create pyrrolyl-PltL. The halogenation domain PltA then dichlorinates the pyrrole moiety first at position 5 and then at position 4 in a FADH2 dependent manner.[10] The dichloropyrroyl residue is then transferred to the type I PKS PltB and PltC, however, the mechanism of transfer is unknown. The addition of 3 malonyl-CoA monomers, cyclization, and release by the thioesterase PltG gives pyoluteorin.

Pyoluteorin biosynthesis. Asterisk denotes inactive domain.

References
  1. Gross H, Loper JE (November 2009). "Genomics of secondary metabolite production by Pseudomonas spp". Natural Product Reports. 26 (11): 1408–46. doi:10.1039/b817075b. PMID 19844639.
  2. Takeda R (1958). "Structure of a new antibiotic, pyoluteorin". Journal of the American Chemical Society. 80 (17): 4749–4750. doi:10.1021/ja01550a093.
  3. Maurhofer M (September 10, 1991). "Influence of Enhanced Antibiotic Production in Pseudomonas fluorescens Strain CHA0 on its Disease Suppressive Capacity". Phytopathology. 82 (2): 190–195. doi:10.1094/Phyto-82-190.
  4. Howell CR (January 16, 1980). "Suppression of Pythium ultimum-induced damping-off of cotton seedlings by pseudomonas fluorescens and its antibiotic, pyoluteorin". Phytopathology. 70 (8): 712–715. doi:10.1094/Phyto-70-712.
  5. Doi K (October 2014). "Characterization of pyoluteorin derivatives as Mcl-1 antagonists". Cancer Research. 74 (19): 1805. doi:10.1158/1538-7445.AM2014-1805.
  6. Cuppels DA (January 15, 1986). "Biosynthesis of Pyoluteorin: A Mixed Polyketide-Tricarboxylic Acid Cycle Origin Demonstrated by [l,2-13C2]Acetate Incorporation". Zeitschrift für Naturforschung C. 41 (5–6): 532–536. doi:10.1515/znc-1986-5-607.
  7. Nowak-Thompson B, Gould SJ, Loper JE (December 1997). "Identification and sequence analysis of the genes encoding a polyketide synthase required for pyoluteorin biosynthesis in Pseudomonas fluorescens Pf-5". Gene. 204 (1–2): 17–24. doi:10.1016/S0378-1119(97)00501-5. PMID 9434161.
  8. Nowak-Thompson B, Chaney N, Wing JS, Gould SJ, Loper JE (April 1999). "Characterization of the pyoluteorin biosynthetic gene cluster of Pseudomonas fluorescens Pf-5". Journal of Bacteriology. 181 (7): 2166–74. doi:10.1128/JB.181.7.2166-2174.1999. PMC 93630. PMID 10094695.
  9. Thomas MG, Burkart MD, Walsh CT (February 2002). "Conversion of L-proline to pyrrolyl-2-carboxyl-S-PCP during undecylprodigiosin and pyoluteorin biosynthesis". Chemistry & Biology. 9 (2): 171–84. doi:10.1016/S1074-5521(02)00100-X. PMID 11880032.
  10. Dorrestein PC, Yeh E, Garneau-Tsodikova S, Kelleher NL, Walsh CT (September 2005). "Dichlorination of a pyrrolyl-S-carrier protein by FADH2-dependent halogenase PltA during pyoluteorin biosynthesis". Proceedings of the National Academy of Sciences of the United States of America. 102 (39): 13843–8. Bibcode:2005PNAS..10213843D. doi:10.1073/pnas.0506964102. PMC 1236592. PMID 16162666.
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