Synthetic Enzymes for Synthetic BIology

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Alexandre Zanghellini

ARZEDA Corp., United States

Like Cro-Magnon architects limited by the rocks and sticks available around their camp, synthetic biologists are currently limited by the catalytic proteins (enzymes) and metabolic pathways available from natural organisms. Civilization only emerged once humanity developed new tools unavailable in our natural environment but well suited to our needs. Likewise, our ability to design cell factories to produce the fuels, chemicals and drugs our industrial world needs will certainly require the “recombination” not only of existing but also designer enzymes into novel pathways. Unfortunately, our ability to rationally engineer synthetic enzymes catalyzing the chemical reactions we care about is nowhere as advanced as our ability to construct synthetic genes! Here we will present the technology developed by our team that enabled for the first time the computational de novo design of synthetic enzymes with entirely new catalytic sites. Using a combination of dedicated high-performance computing and computational structural biology algorithms, around 100 new enzymes were computationally designed and experimentally proven to catalyze a novel retro-aldol reaction, a Kemp elimination reaction and a bimolecular, stereo-selective Diels-Alder reaction. We will also present subsequent case studies of successful applications of this technology to industrial biotechnology challenges. Much more than an incremental improvement over rational protein engineering (which typically involves an expert deciding on a small number of ‘tweaks’ – mutations – to alter an existing enzymatic activity), this new technique allows the automated reconfiguring of existing proteins to impart them with completely novel catalytic activities. We will discuss how this new technology can be integrated with existing synthetic biology tools (such as large-scale DNA synthesis and CAD software) to design novel pathways and cell-factories.