The ergot alkaloids are a class of natural products known for their pharmacologically privileged molecular structure that are used in the treatment of neurological ailments, such as Parkinsonism and dementia. Their synthesis via chemical and biological routes are therefore of industrial relevance, but suffer from several challenges. Current chemical synthesis methods involve long, multi-step reactions with harsh conditions and are not enantioselective; biological methods utilizing ergot fungi, produce an assortment of products that complicate product recovery, and are susceptible to strain degradation. Reconstituting the ergot alkaloid pathway in a strain strongly amenable for liquid fermentation, could potentially resolve these issues. In this work, we report the production of the main ergoline therapeutic precursor, D-lysergic acid, to a titre of 1.7 mg L−1 in a 1 L bioreactor. Our work demonstrates the proof-of-concept for the biological production of ergoline-derived compounds from sugar in an engineered yeast chassis.
Bacterial microcompartments are proteinaceous shells that encase specialized metabolic processes in bacteria. Recent advances in simplification of these intricate shells have encouraged bioengineering efforts. Here, we construct minimal shells derived from the Halothiobacillus neapolitanus α-carboxysome, which we term Cso-shell. Using cryogenic electron microscopy, the atomic-level structures of two shell forms were obtained, reinforcing notions of evolutionarily conserved features in bacterial microcompartment shell architecture. Encapsulation peptide sequences that facilitate loading of heterologous protein cargo within the shells were identified. We further provide a first demonstration in utilizing minimal bacterial microcompartmentderived shells for hosting heterologous enzymes. Cso-shells were found to stabilize enzymatic activities against heat shock, presence of methanol co-solvent, consecutive freeze−thawing, and alkaline environments. This study yields insights into α-carboxysome assembly and advances the utility of synthetic bacterial microcompartments as nanoreactors capable of stabilizing enzymes with varied properties and reaction chemistries.
Advances and applications of synthetic genetic polymers (xeno-nucleic acids) are reviewed in this article. The types of synthetic genetic polymers are summarized. The basic properties of them are elaborated and their technical applications are presented. Challenges and prospects of synthetic genetic polymers are discussed.
Enzyme engineering is an indispensable tool in the field of synthetic biology, where enzymes are challenged to carry out novel or improved functions. Achieving these goals sometimes goes beyond modifying the primary sequence of the enzyme itself. The use of protein or nucleic acid scaffolds to enhance enzyme properties has been reported for applications such as microbial production of chemicals, biosensor development and bioremediation. Key advantages of using these assemblies include optimizing reaction conditions, improving metabolic flux and increasing enzyme stability. This review summarizes recent trends in utilizing genetically encodable scaffolds, developed in line with synthetic biology methodologies, to complement the purposeful deployment of enzymes. Current molecular tools for constructing these synthetic enzyme-scaffold systems are also highlighted.
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