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Zanghellini A.,ARZEDA Corp.
Current Opinion in Biotechnology | Year: 2014

Recent advances in systems and synthetic biology as well as metabolic engineering are poised to transform industrial biotechnology by allowing us to design cell factories for the sustainable production of valuable fuels and chemicals. To deliver on their promises, such cell factories, as much as their brick-and-mortar counterparts, will require appropriate catalysts, especially for classes of reactions that are not known to be catalyzed by enzymes in natural organisms. A recently developed methodology, de novo computational enzyme design can be used to create enzymes catalyzing novel reactions. Here we review the different classes of chemical reactions for which active protein catalysts have been designed as well as the results of detailed biochemical and structural characterization studies. We also discuss how combining de novo computational enzyme design with more traditional protein engineering techniques can alleviate the shortcomings of state-of-the-art computational design techniques and create novel enzymes with catalytic proficiencies on par with natural enzymes. © 2014 Elsevier Ltd.


Patent
ARZEDA Corp. and DuPont Pioneer | Date: 2014-03-14

Compositions and methods comprising polynucleotides and polypeptides having dicamba decarboxylase activity are provided. Further provided are nucleic acid constructs, host cells, plants, plant cells, explants, seeds and grain having the dicamba decarboxylase sequences. Various methods of employing the dicamba decarboxylase sequences are provided. Such methods include, for example, methods for decarboxylating an auxin-analog, method for producing an auxin-analog tolerant plant, plant cell, explant or seed and methods of controlling weeds in a field containing a crop employing the plants and/or seeds disclosed herein. Methods are also provided to identify additional dicamba decarboxylase variants.


Patent
DuPont Pioneer and ARZEDA Corp. | Date: 2014-03-14

Compositions and methods comprising polynucleotides and polypeptides having dicamba decarboxylase activity are provided. Further provided are nucleic acid constructs, host cells, plants, plant cells, explants, seeds and grain having the dicamba decarboxylase sequences. Various methods of employing the dicamba decarboxylase sequences are provided. Such methods include, for example, methods for decarboxylating an auxin-analog, method for producing an auxin-analog tolerant plant, plant cell, explant or seed and methods of controlling weeds in a field containing a crop employing the plants and/or seeds disclosed herein. Methods are also provided to identify additional dicamba decarboxylase variants.


Grant
Agency: National Science Foundation | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 500.00K | Year: 2013

This Small Business Innovation Research Phase II project focuses on the development of a high-yield fermentation route for the production of levulinic acid (LA). LA is one of the best-suited C5 building blocks for bio-refinery production due to higher value, broad applications, and likely quick adoption by the chemical industry. During Phase I, this project has designed and experimentally validated the concept of a novel fermentation pathway for the production of LA. The focus of this Phase II work will be to transition from this technical proof-of-concept to the development of a lab-scale fermentation process. The limiting enzymatic steps in the designed pathway will first be optimized to reach levels of activity consistent with the flux/yield required for economical production. Variants of the designed pathway incorporating the original and optimized enzymes will subsequently be cloned into suitable fermentation organism(s). Using computational and experimental metabolic engineering tools, knock-out and knock-down mutations will be performed to further optimize flux/yield in the pathway while optimizing for host cell growth. This work represents the first commercial application of enzyme design to rationally engineer novel metabolic pathway that do not have any natural counterpart, bringing us closer to the dream of designer cell factories. The broader impact/commercial potential of this project is the advancement of a U.S. green chemistry industry and to allow America to take the lead in the commercial production of a new renewable chemical building block. The lack of a high-yield alternative to costly thermo-chemical processes has been preventing widespread adoption of levulinic acid (LA). Because LA can be converted, chemically or biochemically, to synthetic rubber (through isoprene and butenes), bio-fuels (such as kerosene and HMF), polymers (for instance, nylons) and polymer additives (for changing polymer characteristics), the addressable market is in excess of $20B annually. When considered as the end product, LA trades at a considerable higher price than ethanol, the current product of most commercial bio-refineries, and thus can help diversify their product offering and considerably increase their margins.


Grant
Agency: National Science Foundation | Branch: | Program: STTR | Phase: Phase I | Award Amount: 225.00K | Year: 2013

This Small Business Technology Transfer (STTR) Phase I project brings together computational enzyme design with systems biology to create a fully integrated platform for novel pathway designs. The approach chosen will combine specific databases and a novel pathway synthesis tool. This computational tool will use the information present in the databases to automatically discover, or "design", novel pathways for fermenting natural renewable feedstock to virtually any chemical of human interest. In the Phase II Experimental Plan, the goal is to further advance the concept by developing a high-performance pathway prioritization module to estimate each designed pathway yield and impact on organism metabolism, and experimentally test the performance of the system. To our knowledge, the proposed research is the first attempt of combining computational enzyme design with computational pathway prospecting and modeling. The broader impact/commercial potential of this project, if successful, will be to engineer biosystems and cell factories for industrial applications, especially in the field of bio-based chemicals and biofuels. Most successes to date in the field of synthetic biology have involved recombining natural enzyme building blocks into novel pathways. However, recent developments in computational enzyme design make it possible to have designer enzymes to enhance nature's catalytic repertoire. Being able to have an automated, computer-aided design tool that leverages new capabilities to create novel metabolic pathways employing synthetic enzymes will bring us closer to truly synthetic biology.


Grant
Agency: National Science Foundation | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 744.81K | Year: 2015

The broader impact/commercial potential of this Small Business Innovation Research (SBIR) Phase II project is to develop a platform to rapidly design synthetic organisms to produce biochemicals, which will replace environmentally harmful, ecologically inefficient industrial chemical processes. The technology developed in this proposal will provide a competitive edge in the rapid engineering of synthetic organisms to produce biochemicals by fermentation that are currently produced from oil (reducing our CO2 emissions) or extracted from natural species (reducing our taxing load on existing ecosystems). This technology also has the potential to be used for the manufacture of drugs, and to engineer novel organisms to improve crop production and therefore help address the mounting challenges of providing food to a growing world population without tapping too much in Earth's resources. Commercially, the chemicals that will be enabled by application of the technology developed during the Phase I program open up billion dollar markets that are currently inaccessible to the chemical industry. This SBIR Phase II project proposes to develop a platform that combines computational enzyme design with systems biology to create a fully integrated system for the design and testing of novel cell factories for the production of bulk and fine chemicals. During the Phase I project, the company, in collaboration with the University of Washington, has successfully developed a high-performance software code to rapidly design novel metabolic pathways to produce any target chemical from central metabolism. In Phase II, the company will further advance the concept by (1) developing a high-performance pathway prioritization module to estimate each designed pathway yield and impact on organism metabolism in the context of whole-genome models and (2) use the software platform to design libraries of pathways for the production of a variety of specialty chemical targets that are commercially valuable and not known to be produced by fermentation at scale. Then, (3) using an experimental screening setup, the DNA for all the proposed pathways will be assembled screened at high-throughput for detectable production of the target chemicals.


Grant
Agency: Department of Energy | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 224.95K | Year: 2015

Statement of Problem: In order to be able to develop in a robust manner, high-yield bioprocesses, especially for molecules that dont exist in nature, on a faster timescale and significant lower expenses then the current industry standard a multiplex, high-throughput screening platform for prospecting large pathway libraries is required. Technical Approach: Synthetic transcription factors, a technology developed at JBEI, has the potential to provide a general approach to this limitation and thereby enable the access of a wide variety of next generation biofuels. To demonstrate the general applicability of this technology to bio-based chemicals and fuels not found in nature and its integration into Arzedas core computational pathway and enzyme design technology stack, we will develop a high-throughput screen for levulinic acid, a promising novel building block for biorefineries, based on synthetic transcription factors. Phase I Work: We first establish the licensed technology from JBEI at Arzeda. We use this framework to construct synthetic transcription factors for levulinic acid. These synthetic transcription factors are then used to develop a multiplex, high-throughput pathway library platform that enables to rapid optimization of a high-yield levulinic acid producing bioprocess. Commercial Applications and Other Benefits: Levulinic acid is regarded to be one of the most attractive C5 building block as it can be converted to fuels, fuel additives, polymers and solvents. Arzedas high-yield fermentation route can produce levulinic acid at $0.75/lb and down to $0.5/lb, depending on the plant scale, enabling many of the above markets. On a societal level, this innovation will lead to a faster access to next generation biofuels and thereby help the nation reduce its dependence on foreign oil. Reports from the U.S. Office of Industrial Technologies estimate that levulinic acid at 200400M lb/yr scale could save 75.6 trillion Btu per year of energy by 2020. Finally, by providing a platform building block that can be produced economically with a fermentation process extremely similar to that of ethanol, the innovation could dramatically improve the economics of US-based biorefineries. Arzedas fermentation process to produce LA at low cost, high yield and large scale could ultimately help to protect US jobs, to decrease reliance on foreign oil and to secure the US lead in biotechnology Key Words: Synthetic biology, designer cell factory, next generation biofuel, levulinic acid, synthetic transcription factor, multiplex high-throughput screening of metabolic pathway libraries, computational pathway design, computational enzyme design Summary for Members of Congress: Currently, the development of high-yield bioprocesses for fuels is a time- and cost-intensive endeavor. Combining JBEIs and Arzedas technology we can enable the rapid optimization of economical, high-yield fermentation routes to next generation biofuels.


Grant
Agency: NSF | Branch: Standard Grant | Program: | Phase: | Award Amount: 225.00K | Year: 2013

This Small Business Technology Transfer (STTR) Phase I project brings together computational enzyme design with systems biology to create a fully integrated platform for novel pathway designs. The approach chosen will combine specific databases and a novel pathway synthesis tool. This computational tool will use the information present in the databases to automatically discover, or design, novel pathways for fermenting natural renewable feedstock to virtually any chemical of human interest. In the Phase II Experimental Plan, the goal is to further advance the concept by developing a high-performance pathway prioritization module to estimate each designed pathway yield and impact on organism metabolism, and experimentally test the performance of the system. To our knowledge, the proposed research is the first attempt of combining computational enzyme design with computational pathway prospecting and modeling.

The broader impact/commercial potential of this project, if successful, will be to engineer biosystems and cell factories for industrial applications, especially in the field of bio-based chemicals and biofuels. Most successes to date in the field of synthetic biology have involved recombining natural enzyme building blocks into novel pathways. However, recent developments in computational enzyme design make it possible to have designer enzymes to enhance natures catalytic repertoire. Being able to have an automated, computer-aided design tool that leverages new capabilities to create novel metabolic pathways employing synthetic enzymes will bring us closer to truly synthetic biology.


Grant
Agency: NSF | Branch: Standard Grant | Program: | Phase: SMALL BUSINESS PHASE II | Award Amount: 760.81K | Year: 2015

The broader impact/commercial potential of this Small Business Innovation Research (SBIR) Phase II project is to develop a platform to rapidly design synthetic organisms to produce biochemicals, which will replace environmentally harmful, ecologically inefficient industrial chemical processes. The technology developed in this proposal will provide a competitive edge in the rapid engineering of synthetic organisms to produce biochemicals by fermentation that are currently produced from oil (reducing our CO2 emissions) or extracted from natural species (reducing our taxing load on existing ecosystems). This technology also has the potential to be used for the manufacture of drugs, and to engineer novel organisms to improve crop production and therefore help address the mounting challenges of providing food to a growing world population without tapping too much in Earths resources. Commercially, the chemicals that will be enabled by application of the technology developed during the Phase I program open up billion dollar markets that are currently inaccessible to the chemical industry.

This SBIR Phase II project proposes to develop a platform that combines computational enzyme design with systems biology to create a fully integrated system for the design and testing of novel cell factories for the production of bulk and fine chemicals. During the Phase I project, the company, in collaboration with the University of Washington, has successfully developed a high-performance software code to rapidly design novel metabolic pathways to produce any target chemical from central metabolism. In Phase II, the company will further advance the concept by (1) developing a high-performance pathway prioritization module to estimate each designed pathway yield and impact on organism metabolism in the context of whole-genome models and (2) use the software platform to design libraries of pathways for the production of a variety of specialty chemical targets that are commercially valuable and not known to be produced by fermentation at scale. Then, (3) using an experimental screening setup, the DNA for all the proposed pathways will be assembled screened at high-throughput for detectable production of the target chemicals.


Grant
Agency: NSF | Branch: Standard Grant | Program: | Phase: | Award Amount: 613.01K | Year: 2013

This Small Business Innovation Research Phase II project focuses on the development of a high-yield fermentation route for the production of levulinic acid (LA). LA is one of the best-suited C5 building blocks for bio-refinery production due to higher value, broad applications, and likely quick adoption by the chemical industry. During Phase I, this project has designed and experimentally validated the concept of a novel fermentation pathway for the production of LA. The focus of this Phase II work will be to transition from this technical proof-of-concept to the development of a lab-scale fermentation process. The limiting enzymatic steps in the designed pathway will first be optimized to reach levels of activity consistent with the flux/yield required for economical production. Variants of the designed pathway incorporating the original and optimized enzymes will subsequently be cloned into suitable fermentation organism(s). Using computational and experimental metabolic engineering tools, knock-out and knock-down mutations will be performed to further optimize flux/yield in the pathway while optimizing for host cell growth. This work represents the first commercial application of enzyme design to rationally engineer novel metabolic pathway that do not have any natural counterpart, bringing us closer to the dream of designer cell factories.

The broader impact/commercial potential of this project is the advancement of a U.S. green chemistry industry and to allow America to take the lead in the commercial production of a new renewable chemical building block. The lack of a high-yield alternative to costly thermo-chemical processes has been preventing widespread adoption of levulinic acid (LA). Because LA can be converted, chemically or biochemically, to synthetic rubber (through isoprene and butenes), bio-fuels (such as kerosene and HMF), polymers (for instance, nylons) and polymer additives (for changing polymer characteristics), the addressable market is in excess of $20B annually. When considered as the end product, LA trades at a considerable higher price than ethanol, the current product of most commercial bio-refineries, and thus can help diversify their product offering and considerably increase their margins.

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