A biosynthetic platform for rapid enzyme discovery

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Fong Tian Wong, Shawn Hoon, Ying Swan Ho and Yin Nah Teo

Molecular Engineering Lab, Singapore

Over the past decade, both academia and industry have increasingly turned to the use of microbes for the synthesis of value-added chemicals. Microbial biosynthesis is advantageous for it affords green, complex chemical reactions at a lower cost. Successful examples include the production of plant-derived malaria drug, artemisinin, in yeast, production scale biosynthesis of cholesterol-lowering drug, Zocor, and synthesis of several biofuels through modified enzyme pathways. Biosynthetic engineering of metabolic pathways have provided new and effective methods for the synthesis of value-added chemicals, drug compounds and biofuels. One of the few major chain-elongation enzymatic families is the polyketide synthases (PKSs), which produces stereochemically and structurally complex drug compounds, such as lovastatin, erythromycin and rifamycin. PKSs are often utilized in biosynthetic applications as they use simple carbon building blocks as feedstock, have a modular assembly-line design and can perform a rich repertoire of chemical reactions. Characterization of novel PKS biosynthetic pathways is a promising line of research for it could lead to the development of new chemical scaffolds for drug development and the discovery of new reaction domains for biotechnological applications.However, many difficulties still exist in manipulation of these gene families. For example, these genes are often very large, making genetic engineering a challenging task even with current technologies. As a result, the journey from PKS discovery to production and then to manipulation is a long process. To overcome this, we will develop a common scaffold on which novel enzymatic domains can be rapidly evaluated for activity. This platform will allow for rapid search and verification of novel enzymatic domains for applications in metabolic engineering and to discover new active biosynthetic clusters.