Biosynthetic Mechanisms of Natural Product Diversity

Natural products exhibit a remarkable breadth of structural and functional diversity, underpinned by modular biosynthetic machinery and versatile enzymatic strategies. Central to this diversity are polyketide synthases and nonribosomal peptide synthetases, whose modular architecture enables the sequential assembly of carbon backbones from simple acyl-CoA or amino acid building blocks. Complementary tailoring enzymes—including oxygenases, methyltransferases, cyclases and glycosyltransferases—further elaborate these scaffolds to yield complex molecules with potent biological activities. Beyond classical assembly lines, pathways exploiting coenzyme A-dependent reactions, radical-mediated rearrangements and atypical extender units expand the chemical lexicon. Evolutionary processes such as gene duplication, horizontal transfer and domain shuffling drive the emergence of new enzymatic functions and biosynthetic gene clusters, fostering continuous innovation in natural product chemistry. These mechanisms underpin the discovery of antibiotics, anticancer agents and agrochemicals, and inspire sustainable biomanufacturing approaches.

Research from Nature Portfolio

Recent studies have uncovered a novel assembly route for alkylmalonyl-CoA extender units in modular polyketide synthases. This pathway operates without the canonical crotonyl-CoA reductase/carboxylase and instead employs direct carboxylation of medium-chain acyl-CoA substrates. High-resolution crystal structures of the acyl-CoA carboxylase β-subunit have revealed molecular determinants of substrate recognition, laying foundations for tailored polyketide assembly. These insights have inspired bioorthogonal tagging strategies enabling the incorporation of azido- and nonynoic acid analogues into polyketide backbones, expanding the chemical repertoire of natural product derivatives.

Biosynthetic Mechanisms of Natural Product Diversity publication trend

The graph below shows the total number of articles in biosynthetic mechanisms of natural product diversity across all publications each year (not limited to Nature Index journals).

Technical terms

Polyketide synthase (PKS): Multi-domain enzymes that assemble polyketide chains by successive condensation of acyl-CoA extender units, often yielding macrolide and antibiotic scaffolds.

Nonribosomal peptide synthetase (NRPS): Modular enzymes that activate and condense amino acid substrates to produce peptide-based natural products independent of the ribosome.

Adenylate-forming enzyme (AFE): Enzymes that catalyse ATP-dependent activation of carboxylic acids to acyl-adenylate intermediates, central to diverse biosynthetic pathways including fatty acid and β-lactone formation.

Crotonyl-CoA reductase/carboxylase (CCR): Bifunctional enzymes that reductively carboxylate α,β-unsaturated acyl-CoA substrates to yield malonate-derived extender units for polyketide biosynthesis.

References

1. A crotonyl-CoA reductase-carboxylase independent pathway for assembly of unusual alkylmalonyl-CoA polyketide synthase extender units. Nature Communications (2016).
2. Global analysis of adenylate-forming enzymes reveals β-lactone biosynthesis pathway in pathogenic Nocardia. Journal of Biological Chemistry (2020).
3. Thiolase: A Versatile Biocatalyst Employing CoA–Thioester Chemistry for Making and Breaking C–C Bonds. Annual Review of Biochemistry (2023).
4. Enzymes of the crotonase superfamily: Diverse assembly and diverse function. Current Opinion in Structural Biology (2023).