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Natural product biosynthesis in vitro. Cheng et al. (p 557) report the in vitro total synthesis of the bacteriostatic natural product enterocin from Streptomyces maritimus. Balibar et al. (p 584) report the full in vitro reconstitution of the bisindole alkaloid terrequinone A, a fungal cytotoxic metabolite. Both papers highlight the power of assembling biosynthetic pathways outside of the cell (see also News & Views by Fecik, p 531). A picture of Aspergillus nidulans, the source of terrequinone A, is shown. Cover art by Erin Boyle, based on an image provided by Paul D. Straight and Carl J. Balibar.
The mid-nineteenth century saw the development of a radical new direction in chemistry: instead of simply analyzing existing molecules, chemists began to synthesize them—including molecules that did not exist in nature. The combination of this new synthetic approach with more traditional analytical approaches revolutionized chemistry, leading to a deep understanding of the fundamental principles of chemical structure and reactivity and to the emergence of the modern pharmaceutical and chemical industries. The history of synthetic chemistry offers a possible roadmap for the development and impact of synthetic biology, a nascent field in which the goal is to build novel biological systems.
The world's first synthetic biology department at the Lawrence Berkeley National Laboratory is using a bottom-up approach to form a foundation of design rules and models to understand cellular function.
Heterologous production of natural products in non-native bacteria can be used to increase yields of certain bioactive compounds; however, producing small molecules inside bacteria has numerous limitations. Two reports of the in vitro reconstruction of entire biosynthetic pathways highlight the advantages and challenges of this approach for pathway engineering.
The U2 snRNP particle is an essential component of the eukaryotic pre-mRNA splicing apparatus, the spliceosome. Natural and semisynthetic inhibitors that bind the SF3b subunit of the U2 snRNP block splicing and prompt nuclear export of intron-bearing precursors, defining a new mode of action in anticancer drugs.
Bacterial mRNAs begin with a triphosphate on the first transcribed nucleotide, but RNase E, the endonuclease long thought to initiate mRNA decay in Escherichia coli, only works well on RNA with a 5′-monophosphate. Conversion of the 5′-triphosphate to a monophosphate now appears to be the first committed step in mRNA decay in E. coli.
Organomercurial lyase (MerB) catalyzes the difficult cleavage of C-Hg bonds to hydrocarbon and mercuric dithiol products. Model compounds providing two or three thiolate ligands activate organomercurials toward acidic cleavage under mild conditions, which supports a mechanism in which MerB enzymes use two conserved active-site cysteines to activate the substrate.