Editorial: Biosynthetic assembly lines themed issue

This themed issue on biosynthetic assembly lines grew out of the Royal Society of Chemistry's international conference Directing Biosynthesis IV (held at the John Innes Centre from 25 to 27 March 2015), which we co-organised with other members of the UK community. To mark the 25th anniversary of the reports disclosing the discovery of the first modular polyketide synthase (6-deoxyerythronolide synthase – responsible for assembling the aglycone of the antibiotic erythromycin A), a session providing perspectives on thiotemplate assembly line biosynthesis was included in the conference programme. This featured presentations from Profs Peter Leadlay, David Cane, Mohamed Marahiel and Chris Walsh, four highly influential contributors to the discovery and mechanistic understanding of modular polyketide synthases (PKSs) and their close cousins the nonribosomal peptide synthetases (NRPSs). To accompany this, we decided to compile a collection of articles summarising the state-of-the-art in the discovery, investigation and exploitation of biosynthetic assembly lines. This special issue of Natural Product Reports is the result, featuring viewpoints, highlights and reviews from several prominent researchers in the field.

In their viewpoint articles, Chris Walsh and Mohamed Marahiel summarise the state-of-the-art in our understanding of the catalytic mechanisms and structural features of NRPSs. Walsh highlights the key role played by exploitation of phosphopantetheinyl transferase substrate promiscuity in mechanistic studies (DOI: 10.1039/c5np00035a) and Marahiel pieces together the structures of various mono- and multi-domain fragments to propose an overall NRPS structural model (DOI: 10.1039/c5np00082c).

Much of the structural diversity of modular PKS products stems from the range of building blocks selected for chain assembly and the stereochemical outcome of the α- and β-carbon modifying reactions carried out after each cycle of chain extension. Ray and Moore highlight recent progress in understanding the biosynthesis of PKS starter and extender units (DOI: 10.1039/c5np00112a), while Keatinge-Clay illuminates the structural basis for stereocontrol by these fascinating molecular machines (DOI: 10.1039/c5np00092k).

Cyclisation reactions are another significant contributor to the structural diversity of modular PKS and NRPS products, and can occur during chain assembly, at the point of chain release, or as post-assembly line tailoring reactions. Boddy and coworkers review the role played by thioesterase domains in chain release (DOI: 10.1039/c5np00148f), and diverse examples of on- and post-assembly line cyclisations are drawn together by Liu and coworkers (DOI: 10.1039/c5np00095e).

The discovery of the erythromycin assembly line led to the identification of numerous other modular PKSs, mostly in actinobacteria, sharing a similar architecture in which each module contains an acyltransferase domain responsible for selection of the appropriate extender unit. More than two decades later, it was therefore a great surprise when a fundamentally distinct type of modular PKS, in which a standalone acyltransferase supplies the extender unit to each module, was reported. Helfrich and Piel comprehensively review progress over the past six years in the discovery and mechanistic understanding of such trans-AT PKSs (DOI: 10.1039/c5np00125k), which are rare in actinobacteria, but now known to be widely distributed across other bacterial taxa.

The analogous architectures of modular PKSs and NRPSs combined with underlying similarities in their chemical logic have allowed hybrid PKS–NRPS systems to evolve. Such systems are particularly prevalent in cyanobacteria, where they are often associated with unusual on-assembly line modification chemistry. Gerwick, Sherman and colleagues review advances in the understanding of cyanobacterial natural product biosynthesis with a particular focus on hybrid PKS–NRPS assembly lines (DOI: 10.1039/c5np00097a).

Ever since the discovery of the erythromycin PKS, the engineering of modular PKSs and NRPSs to produce novel natural product derivatives or hybrid structures has been an appealing prospect. While this has been more difficult to achieve in practice than initially envisioned, substantial advances have nevertheless been made. Micklefield and coworkers, and Weissman review progress in the engineering of NRPS and PKS assembly lines, respectively (DOI: 10.1039/c5np00099h and DOI: 10.1039/c5np00109a). Expression of engineered modular PKS and NRPS biosynthetic pathways in heterologous hosts is an appealing approach, but has been hampered by the large size of the gene clusters that typically encode such assembly lines. Zhao and coworkers review recent methodological developments aimed at overcoming this problem (DOI: 10.1039/c5np00085h).

It is clear from this collection of articles that research into natural product biosynthetic assembly lines is flourishing. Yet arguably the biggest questions in the field still remain to be fully addressed. One important goal is to develop a detailed understanding of how protein–protein interactions and structural dynamics orchestrate the precise sequence of reactions required to generate a specific product. Such understanding should facilitate the repurposing of these fascinating molecular machines for efficient production of a wide variety of novel and useful molecules.

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