Pyoluteorin is a natural

antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention of ...

that is biosynthesized from a hybrid nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) pathway. Pyoluteorin was first isolated in the 1950s from '' Pseudomonas aeruginosa'' strains T359 and IFO 3455 and was found to be toxic against oomycetes, bacteria, fungi, and against certain plants. Pyoluteorin is most notable for its toxicity against the oomycete ''

Pythium ultimum ''Pythium ultimum'' is a plant pathogen. It causes the damping off and root rot diseases of hundreds of diverse plant hosts including corn, soybean, potato, wheat, fir, and many ornamental species. ''P. ultimum'' belongs to the peronospora ...

'', which is a

plant pathogen Plant pathology (also phytopathology) is the scientific study of diseases in plants caused by pathogens (infectious organisms) and environmental conditions (physiological factors). Organisms that cause infectious disease include fungi, oomyc ...

that causes a global loss in agriculture. Currently, pyoluteorin derivatives are being studied as an Mcl-1

antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...

in order to target cancers that have elevated Mcl-1 levels.

Biosynthesis

Pyoluteorin is synthesized from an NRPS/PKS hybrid pathway. The resorcinol ring is derived from a type I PKS while the dichloropyrrole moiety is derived from a type II NRPS. Pyoluteorin biosynthesis begins with the activation of L-

proline Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the prot ...

to prolyl-AMP by the

adenylation Adenylylation, more commonly known as AMPylation, is a process in which an adenosine monophosphate (AMP) molecule is covalently attached to the amino acid side chain of a protein. This covalent addition of AMP to a hydroxyl side chain of the prote ...

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. Next, the dehydrogenase PltE desaturates the prolyl moiety on PltL to create pyrrolyl-PltL. The

halogenation In chemistry, halogenation is a chemical reaction that entails the introduction of one or more halogens into a compound. Halide-containing compounds are pervasive, making this type of transformation important, e.g. in the production of polymers, ...

domain PltA then dichlorinates the pyrrole moiety first at position 5 and then at position 4 in a FADH2 dependent manner. 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 copy

References

{{reflist, 32em Antibiotics Biosynthesis Halogen-containing natural products Pyrroles