pyoluteorin
{{Short description|Chemical compound}}
{{Drugbox
| verifiedrevid =
| IUPAC_name = (4,5-Dichloro-1H-pyrrol-2-yl)-(2,6-dihydroxyphenyl)methanone
| image = pyoluteorin.svg
| alt = Molecule of pyoluteorin
| width = 200
| CAS_number_Ref = {{cascite|correct|CAS}}
| CAS_number = 25683-07-2
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 3YM4R964TU
| PubChem = 33137
| ChEBI = 156453
| ChEMBL = 2286204
| ChemSpiderID = 30629
| C=11 | H=7 | N=1 | O=3 | Cl=2
| smiles = C1=CC(=C(C(=C1)O)C(=O)C2=CC(=C(N2)Cl)Cl)O
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 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
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = JPGWTZORMBTNMF-UHFFFAOYSA-N
}}
Pyoluteorin is a natural antibiotic that is biosynthesized from a hybrid nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) pathway.{{cite journal | vauthors = Gross H, Loper JE | title = Genomics of secondary metabolite production by Pseudomonas spp | journal = Natural Product Reports | volume = 26 | issue = 11 | pages = 1408–46 | date = November 2009 | pmid = 19844639 | doi = 10.1039/b817075b }} Pyoluteorin was first isolated in the 1950s from Pseudomonas aeruginosa strains T359 and IFO 3455{{cite journal | vauthors = Takeda R |title=Structure of a new antibiotic, pyoluteorin |journal=Journal of the American Chemical Society |date=1958 |volume=80 |issue=17 |pages=4749–4750 |doi=10.1021/ja01550a093}} and was found to be toxic against oomycetes, bacteria, fungi, and against certain plants.{{cite journal | vauthors = Maurhofer M |title=Influence of Enhanced Antibiotic Production in Pseudomonas fluorescens Strain CHA0 on its Disease Suppressive Capacity |journal=Phytopathology |date=September 10, 1991 |volume=82 |issue=2 |pages=190–195 |doi=10.1094/Phyto-82-190}} Pyoluteorin is most notable for its toxicity against the oomycete Pythium ultimum,{{cite journal | vauthors = Howell CR |title=Suppression of Pythium ultimum-induced damping-off of cotton seedlings by pseudomonas fluorescens and its antibiotic, pyoluteorin |journal=Phytopathology |date=January 16, 1980 |volume=70 |issue=8 |pages=712–715|doi=10.1094/Phyto-70-712 }} 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.{{cite journal | vauthors = Doi K |title=Characterization of pyoluteorin derivatives as Mcl-1 antagonists |journal=Cancer Research |date=October 2014 |volume=74 |issue=19 |pages=1805 |doi=10.1158/1538-7445.AM2014-1805}}
Biosynthesis
Pyoluteorin is synthesized from an NRPS/PKS hybrid pathway. The resorcinol ring is derived from a type I PKS{{cite journal | vauthors = Cuppels DA |title=Biosynthesis of Pyoluteorin: A Mixed Polyketide-Tricarboxylic Acid Cycle Origin Demonstrated by [l,2-13C2]Acetate Incorporation |journal= Zeitschrift für Naturforschung C|date=January 15, 1986 |volume= 41|issue=5–6 |pages=532–536|doi=10.1515/znc-1986-5-607 |doi-access=free }}{{cite journal | vauthors = Nowak-Thompson B, Gould SJ, Loper JE | title = Identification and sequence analysis of the genes encoding a polyketide synthase required for pyoluteorin biosynthesis in Pseudomonas fluorescens Pf-5 | journal = Gene | volume = 204 | issue = 1–2 | pages = 17–24 | date = December 1997 | pmid = 9434161 | doi = 10.1016/S0378-1119(97)00501-5 }} while the dichloropyrrole{{clarify|date=June 2018}} moiety is derived from a type II NRPS.{{cite journal | vauthors = Nowak-Thompson B, Chaney N, Wing JS, Gould SJ, Loper JE | title = Characterization of the pyoluteorin biosynthetic gene cluster of Pseudomonas fluorescens Pf-5 | journal = Journal of Bacteriology | volume = 181 | issue = 7 | pages = 2166–74 | date = April 1999 | pmid = 10094695 | doi = 10.1128/JB.181.7.2166-2174.1999 | pmc = 93630 }} 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.{{cite journal | vauthors = Thomas MG, Burkart MD, Walsh CT | title = Conversion of L-proline to pyrrolyl-2-carboxyl-S-PCP during undecylprodigiosin and pyoluteorin biosynthesis | journal = Chemistry & Biology | volume = 9 | issue = 2 | pages = 171–84 | date = February 2002 | pmid = 11880032 | doi = 10.1016/S1074-5521(02)00100-X | doi-access = free }} 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.{{cite journal | vauthors = Dorrestein PC, Yeh E, Garneau-Tsodikova S, Kelleher NL, Walsh CT | title = Dichlorination of a pyrrolyl-S-carrier protein by FADH2-dependent halogenase PltA during pyoluteorin biosynthesis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 39 | pages = 13843–8 | date = September 2005 | pmid = 16162666 | pmc = 1236592 | doi = 10.1073/pnas.0506964102 | bibcode = 2005PNAS..10213843D | doi-access = free }} 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.
