Biosynthesis & Natural Products

PKS-NRPS Hybrid Systems

Summary

PKS-NRPS hybrid systems combine polyketide synthase and non-ribosomal peptide synthetase modules to produce structurally complex natural products containing both polyketide and peptide moieties.

Key Points

  • 1PKS-NRPS hybrids combine polyketide and peptide biosynthetic logic in single assembly lines
  • 2Interface domains (KS-like, C-like) enable chain transfer between the two systems
  • 3Products include cytochalasins, tetramic acids, and complex polycyclic structures
  • 4Tailoring enzymes add further complexity through cyclization and oxidation
  • 5Engineering these systems is challenging due to complex inter-domain communication

# PKS-NRPS Hybrid Systems

Polyketide synthase-nonribosomal peptide synthetase (PKS-NRPS) hybrid systems represent sophisticated biosynthetic assembly lines that integrate the chemical logic of both polyketide and peptide biosynthesis. These systems produce compounds of remarkable structural complexity and pharmacological importance.

Modular Architecture

PKS Modules

Polyketide synthases extend carbon chains through iterative Claisen condensations:

- Acyltransferase (AT): Selects and loads acyl-CoA extender units

- Ketosynthase (KS): Catalyzes decarboxylative condensation

- Acyl Carrier Protein (ACP): Tethers growing chain via phosphopantetheine

NRPS Modules

Non-ribosomal peptide synthetases incorporate amino acids:

- Adenylation (A): Activates and selects amino acid substrates

- Peptidyl Carrier Protein (PCP): Tethers amino acid/peptide intermediates

- Condensation (C): Forms peptide bonds between modules

Hybrid Interface Domains

Critical for communication between PKS and NRPS modules:

- Ketosynthase-like (KS°): Decarboxylative condensation at interface

- Condensation-like: Amide bond formation joining polyketide to amino acid

Biosynthetic Programming

Chain Transfer Mechanisms

Three main strategies for PKS→NRPS handoff:

1. Direct condensation: KS domain accepts aminoacyl-PCP

2. Aminotransferase insertion: Converts ketone to amine for amide formation

3. Reductive domain: Generates aldehyde for subsequent reactions

Tailoring and Release

- Dieckmann cyclases: Form tetramic acid rings

- Reductase (R) domains: Release as aldehydes or alcohols

- Thioesterase (TE) domains: Macrocyclization or hydrolysis

Representative Natural Products

Cytochalasins

  • Fungal metabolites with actin-binding activity
  • PKS-NRPS + Diels-Alderase for complex polycycle
  • Example: Cytochalasin E (anti-angiogenic)

    • Pseurotin A

  • Aspergillus fumigatus metabolite
  • Spirocyclic structure from hybrid assembly line
  • Immunosuppressive and antimicrobial properties

    • Fusarin C

  • Fusarium mycotoxin
  • Linear PKS-NRPS with extensive tailoring
  • Mutagenic pyrrolidone structure

    • Equisetin

  • Tetramic acid-containing fungal metabolite
  • Demonstrates PKS chain transfer to NRPS
  • HIV integrase inhibitor

    • Myceliothermophin E

  • Thermophilic fungal metabolite
  • Complex decalin-tetramic acid architecture

    • Engineering Opportunities

    Domain Swapping

  • Exchange of A domains to alter amino acid selection
  • AT domain substitution for different extender units
  • Challenges: maintaining inter-domain communication

    • Truncation and Fusion

  • Creating minimal hybrid systems
  • Fusing heterologous PKS and NRPS modules
  • Requires compatible docking domains

    • Biosynthetic Gene Cluster Refactoring

  • Heterologous expression in engineered hosts
  • Promoter engineering for balanced expression
  • Pathway debugging using metabolomics
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