Editorial: Structural Aspects of Biosynthesis themed issue

The recent advancement in structural biology related to natural product biosynthesis, enzymology and biochemistry has bridged a key knowledge gap, especially in visualizing how Nature creates such a huge array of diverse natural products at the protein structure level. We believe this structural biology themed issue will be of significant interest to both researchers in the natural product community and general readers who are interested in envisioning how complex organic molecules are made.

This themed issue covers the structural biology of enzymes that biosynthesize a diverse array of natural products. The first are structure–function studies of multi-domain “mega-synthases” such as polyketide synthase (PKS) and non-ribosomal peptide synthetase (NRPS). The series starts with a review by Akey et al. (Smith group) (DOI: 10.1039/c2np20016c) on the structural biology of marine PKSs as an intellectual feast that correlates the structures to marine product diversity. This is followed by a comprehensive review of modular type I PKS by Keatinge-Clay (DOI: 10.1039/c2np20019h) that highlights both the structures and future outlook for these mega-synthases. Next, two reviews on NRPSs offer different perspectives: a comprehensive review on the structural biology and enzyme mechanism of individual domains by Hur et al. (Burkart group) (DOI: 10.1039/c2np20025b) followed by an in-depth discussion of multi-domain NRPS structures and non-canonical chemistry associated with NRPSs by Condurso and Bruner (DOI: 10.1039/c2np20023f). Both PKSs and NRPSs utilize a carrier protein for intermediate transportation with precise timing, and Crosby and Crump (DOI: 10.1039/c2np20062g) offer a thought-inspiring review on the structures, functions, interactions and potential applications of these carrier proteins.

In recent years, significant progress has been accomplished in plant natural product biosynthesis. Leading the plant frontier of structural biology, Ravilious and Jez (DOI: 10.1039/c2np20009k) summarize the state of the art knowledge about sulfur assimilation by enzymes from plants. This is followed by Gao et al. (Peters group) (DOI: 10.1039/c2np20059g) with a critical review of enzyme structures related with terpenoid biosynthesis. The series is capped by Panjikar et al. (DOI: 10.1039/c2np20057k), who comprehensively review the current progress of structural biology of alkaloid biosynthesis.

Once the backbone is assembled, natural products often undergo further modifications. Here, Singh et al. (Thorson group) (DOI: 10.1039/c2np20039b) summarize current structural progress of bacterial enzymes involved in the biosynthesis of novel sugar nucleotides. Liscombe et al. (Noel group) (DOI: 10.1039/c2np20029e) then critically review the structural enzymology and evolutionary diversity of S-adenosyl-L-methionine (SAM)-dependent methyltransferases (MTs). The grand-finale of this issue is a comprehensive review by Podust and Sherman (DOI: 10.1039/c2np20020a) on P450 enzymes that modify natural products, and how molecular knowledge about these enzymes can be applied to accelerate metabolic engineering and directed biosynthesis, with the ultimate goal of enhancing the chemical diversity of natural product structures.

Although not included in this issue, the structure–function studies of fungal type I, type II, and type III PKSs were also recently reviewed in this journal (Zhou et al., DOI: 10.1039/B911518H; Hertweck et al., DOI: 10.1039/B507395M; Austin and Noel, DOI: 10.1039/B100917F; Abe and Morita, DOI: 10.1039/B909988N) as well as enzymes associated with enediyne biosynthesis (Liang, DOI: 10.1039/B908165H). Type I fatty acid synthase and polyketide synthase were previously compared by Smith and Tsai (DOI: 10.1039/B603600G). The structural studies of NRPS and ribosomal peptide synthesis were earlier reviewed by Koglin and Walsh (DOI: 10.1039/B904543K) Kopp and Marahiel (DOI: 10.1039/B613652B), and McIntosh et al. (Schmidt group) (DOI: 10.1039/B714132G). The structural biology of plant natural product biosynthesis was formerly covered by Stöckigt and Panjikar (DOI: 10.1039/B711935F), while Kharel and Koyama reviewed the structure and function of cis-prenyltransferase (DOI: 10.1039/B108934J). The readers are directed to these NPR articles for further reading.

It is clear from these combined articles that structural biology of natural product biosynthesis is flourishing, and that the structural knowledge can help correlate the 3-dimensional structures to enzyme sequence, function, protein–protein interactions, and regio-specificity. The molecular knowledge can potentially be applied to redirect biosynthetic enzymes for the expansion of chemical diversity and bioactivities, which may be translated into the clinic in the near future.

Shiou-Chuan (Sheryl) Tsai

Bradley Moore

Sarah O'Connor

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