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

Identifiers
IUPAC name (4,5-Dichloro-1H-pyrrol-2-yl)-(2,6-dihydroxyphenyl)methanone
CAS Number	25683-07-2 Y
PubChem CID	33137
ChemSpider	30629
UNII	3YM4R964TU
ChEBI	CHEBI:156453
ChEMBL	ChEMBL2286204
CompTox Dashboard (EPA)	DTXSID30180384
Chemical and physical data
Formula	C11H7Cl2NO3
Molar mass	272.08 g·mol−1
3D model (JSmol)	Interactive image
SMILES C1=CC(=C(C(=C1)O)C(=O)C2=CC(=C(N2)Cl)Cl)O
InChI 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 Y Key:JPGWTZORMBTNMF-UHFFFAOYSA-N Y

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^{[clarification needed]} 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.