Jeffrey D. Rudolf

Within the natural products field there is an increasing emphasis on the study of compounds from microbial sources. This has been fuelled by interest in the central role that microorganisms play in mediating both interspecies interactions and host-microbe relationships. To support the study of natural products chemistry produced by microorganisms we released the Natural Products Atlas, a database of known microbial natural products structures, in 2019. This paper reports the release of a new version of the database which includes a full RESTful application programming interface (API), a new website framework, and an expanded database that includes 8128 new compounds, bringing the total to 32 552. In addition to these structural and content changes we have added full taxonomic descriptions for all microbial taxa and have added chemical ontology terms from both NP Classifier and ClassyFire. We have also performed manual curation to review all entries with incomplete configurational assignments and have integrated data from external resources, including CyanoMetDB. Finally, we have improved the user experience by updating the Overview dashboard and creating a dashboard for taxonomic origin. The database can be accessed via the new interactive website at https://www.npatlas.org.

Covering: up to January 2017Cytochrome P450 enzymes (P450s) are some of the most exquisite and versatile biocatalysts found in nature. In addition to their well-known roles in steroid biosynthesis and drug metabolism in humans, P450s are key players in natural product biosynthetic pathways. Natural products, the most chemically and structurally diverse small molecules known, require an extensive collection of P450s to accept and functionalize their unique scaffolds. In this review, we survey the current catalytic landscape of P450s within the Streptomyces genus, one of the most prolific producers of natural products, and comprehensively summarize the functionally characterized P450s from Streptomyces. A sequence similarity network of >8500 P450s revealed insights into the sequence-function relationships of these oxygen-dependent metalloenzymes. Although only ∼2.4% and <0.4% of streptomycete P450s have been functionally and structurally characterized, respectively, the study of streptomycete P450s involved in the biosynthesis of natural products has revealed their diverse roles in nature, expanded their catalytic repertoire, created structural and mechanistic paradigms, and exposed their potential for biomedical and biotechnological applications. Continued study of these remarkable enzymes will undoubtedly expose their true complement of chemical and biological capabilities.

Covering: up to July 2019 Terpene synthases (TSs) are responsible for generating much of the structural diversity found in the superfamily of terpenoid natural products. These elegant enzymes mediate complex carbocation-based cyclization and rearrangement cascades with a variety of electron-rich linear and cyclic substrates. For decades, two main classes of TSs, divided by how they generate the reaction-triggering initial carbocation, have dominated the field of terpene enzymology. Recently, several novel and unconventional TSs that perform TS-like reactions but do not resemble canonical TSs in sequence or structure have been discovered. In this review, we identify 12 families of non-canonical TSs and examine their sequences, structures, functions, and proposed mechanisms. Nature provides a wide diversity of enzymes, including prenyltransferases, methyltransferases, P450s, and NAD+-dependent dehydrogenases, as well as completely new enzymes, that utilize distinctive reaction mechanisms for TS chemistry. These unique non-canonical TSs provide immense opportunities to understand how nature evolved different tools for terpene biosynthesis by structural and mechanistic characterization while affording new probes for the discovery of novel terpenoid natural products and gene clusters via genome mining. With every new discovery, the dualistic paradigm of TSs is contradicted and the field of terpene chemistry and enzymology continues to expand.

Covering: up to mid-2020 Terpenoids, also called isoprenoids, are the largest and most structurally diverse family of natural products. Found in all domains of life, there are over 80 000 known compounds. The majority of characterized terpenoids, which include some of the most well known, pharmaceutically relevant, and commercially valuable natural products, are produced by plants and fungi. Comparatively, terpenoids of bacterial origin are rare. This is counter-intuitive to the fact that recent microbial genomics revealed that almost all bacteria have the biosynthetic potential to create the C5 building blocks necessary for terpenoid biosynthesis. In this review, we catalogue terpenoids produced by bacteria. We collected 1062 natural products, consisting of both primary and secondary metabolites, and classified them into two major families and 55 distinct subfamilies. To highlight the structural and chemical space of bacterial terpenoids, we discuss their structures, biosynthesis, and biological activities. Although the bacterial terpenome is relatively small, it presents a fascinating dichotomy for future research. Similarities between bacterial and non-bacterial terpenoids and their biosynthetic pathways provides alternative model systems for detailed characterization while the abundance of novel skeletons, biosynthetic pathways, and bioactivies presents new opportunities for drug discovery, genome mining, and enzymology.

Trio of enzymes power divergent synthesis Diterpene natural products are built from a 20-carbon building block, with a huge range of possible structures and modifications. Chemical synthesis of specific molecules, some of which have valuable biological activities, is tricky because of the need for selective oxidations and rearrangements when starting from widely available scaffolds. Zhang et al. characterized selectivities for three oxidative enzymes that each attack different positions on a common scaffold. They then seamlessly combined chemical transformations with the enzymatic oxidations to produce nine distinct compounds across three families of diterpenes. These results highlight the potential of hybrid organic-biocatalytic synthetic schemes for divergent synthesis. Science , this issue p. 799