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Abstract (short):
In living organisms, translation of genetic information by the ribosome transforms the information embedded in DNA into actuating components, namely proteins. Though life itself is incredibly diverse at the macroscopic level, at the molecular level, all of life uses the same set of machinery for translation - 20 standard amino acid building blocks (with minor exceptions), transfer RNAs (tRNA), and ribosomes. The convergence and association of these interdependent biomolecules is neatly captured in a table known as the ‘standard genetic code’. Even after billions of years of genetic drift, the ‘standard genetic code’ has been largely refractory to change. In this talk, I will be discussing strategies and methods for building organisms that can make and use non-standard building blocks, such as amino acids, to make proteins with enhanced or expanded function.
First, I will cover the recent discovery and characterization of a biosynthetic gene cluster for making amino acids with terminal-alkyne side chains. Repurposing this gene cluster from its native host, a soil bacterium, and installing it in an industrial host, such as E. coli, offers the potential to genetically encode the de novo production of halo-, alkene-, and alkyne-labeled proteins and peptides. These non-standard amino acids are ultimately derived from primary carbon sources such as glucose and provide a path to scalable production of biomacromolecules with expanded chemistry.
I will then describe an approach for in vivo, ribosomal translation of proteins composed of up to 32 non-standard building blocks. The key is genetic engineering of a host capable of harboring an orthogonal set of translational machinery (i.e. an orthogonal ribosome-tRNA pair). For this parallel translation system to work as envisioned, we will also need to develop new tools and analytical methods. For example, engineered tRNA biosensors that can report if a tRNA species of interest is aminoacylated inside a cell. As an exciting application, the industrial organisms of the future may one day be able to produce ‘mirror-image’ proteins composed entirely of D-amino. Beyond the bench, metabolic and genetic code expansion is a source of innovation in areas such as biotechnology, biocatalysts, biomaterials, and biocontainment.