Volume 11 Issue 9, September 2015

As the identification of previously undetected microbial biosynthetic pathways burgeons, there arises the question of how much new chemistry is yet to be found. This, in turn, devolves to: what kinds of biosynthetic enzymatic transformations are yet to be characterized?

A wide variety of enzymatic pathways that produce specialized metabolites in bacteria, fungi and plants are known to be encoded in biosynthetic gene clusters. Information about these clusters, pathways and metabolites is currently dispersed throughout the literature, making it difficult to exploit. To facilitate consistent and systematic deposition and retrieval of data on biosynthetic gene clusters, we propose the Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard.

PROTACs are heterobifunctional small molecules that simultaneously bind a target protein and a ubiquitin ligase, enabling ubiquitination and degradation of the target. Major progress in developing potent and specific PROTACs has recently been reported, invigorating prospects for novel PROTAC-based therapies.

The complex flavonoid montbretin A (MbA) is a powerful inhibitor of human pancreatic amylase (HPA) and a potential tool in the treatment of type 2 diabetes. The X-ray structure of the MbA–HPA complex now shows that a hydrophobic collapse of two phenol fragments in the structure of MbA is key to its activity.

There are many techniques that can be employed to control gene expression at the post-translational level. However, a novel system called SMASh (small molecule–assisted shutoff), which allows for chemically-induced degradation of target proteins, presents some distinct advantages.

The metal binding domains of P_1B-ATPases regulate transport activity via mostly unknown mechanisms. Structural, biochemical and cellular data now describe one such domain that binds two metals using unusual motifs and with different functional consequences.

A bioinformatic and phylogenetic search identifies five enzymes involved in the conversion of DCA to isoDCA in the bacterial bile acid biosynthetic pathway. An investigation of the biological roles of bile acids defines a mutualism between the producer R. gnavus and the nonproducer Bacteroides.

Montbretin A is a potent inhibitor of amylase, an enzyme critical in starch digestion and thus of relevance for diabetes and obesity. Structural and biochemical analyses now show that a minimal core of the glycoside π-stacks on itself to fit into the active site.

Structural and biochemical studies of scavenger decapping enzyme identify conformational changes induced by substrate binding to a second binding site that occur faster than catalytic turnover, such that high substrate concentrations inhibit enzyme activity.

Investigations into the biosynthetic pathways of three families of actin-targeting macrolides lead to insights into their convergent or combinatorial evolution, along with the identification of the first free-living bacterial source of macroalga-derived luminaolides.

SMASh is a strategy for regulating protein stability, in which treatment with a small molecule targets a protein tagged with a self-removing degron that includes an HCV protease sequence. SMASh was used to target measles virus phosphoprotein P, for which no inhibitors exist.

Cyclodipeptide synthases use amino acid–loaded tRNAs as substrates to form cyclic peptide dimers. Biochemical and bioinformatic analyses now show that these enzymes are distributed into two phylogenetically distinct major subfamilies and use a broad range of substrates that can be predicted with newly defined sequence motifs.

A fusion protein containing P450 and aldo-keto reductase domains is shown to catalyze reticuline isomerization, the critical branch point between the noscapine and morphine biosynthetic pathways. This discovery completes the enzymatic route to morphine and related compounds.

An antibiotic biosynthesis monooxygenase (Abm) has been identified in the rice blast fungus Magnaporthe oryzae that converts jasmonic acid into hydroxylated JA, which contributes to pathogenicity through the evasion of host immune response.

This special issue features Commentaries, Reviews and Perspectives highlighting advances in our understanding of natural product biosynthesis at the chemical, structural, informatic and ecological level, along with new opportunities to create natural product analogues for a variety of applications.