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Patent
Zuchem Inc. and University of Illinois at Urbana - Champaign | Date: 2011-07-20

Materials and methods are described to produce xylitol from a mixture of hemicellulosic sugars by several routes. Examples include either as a direct co-product of a biorefinery or ethanol facility, or as a stand-alone product produced from an agricultural or forestry biomass feedstock including using, e.g. ethanol waste streams.


Patent
University of Illinois at Urbana - Champaign and Zuchem Inc. | Date: 2016-12-07

Materials and methods are described to produce xylitol from a mixture of hemicellulosic sugars by several routes. Examples include either as a direct co-product of a biorefinery or ethanol facility, or as a stand-alone product produced from an agricultural or forestry biomass feedstock including using, e.g. ethanol waste streams.


Materials and methods are described to produce xylitol from a mixture of hemicellulosic sugars by several routes. Examples include either as a direct co-product of a biorefinery or ethanol facility, or as a stand-alone product produced from an agricultural or forestry biomass feedstock including using, e.g. ethanol waste streams.


Patent
Zuchem Inc. | Date: 2016-06-03

Kinase and nucleotidyltransferase enzymes for the production of activated sugars have been developed. These enzymes have improved stability for industrial application and relaxed specificity towards a variety of sugars. These enzymes are useful in, for example, the production of diverse NDP-sugars for glycosylation of aglycones of interest, production of oligosaccharides, production of other important glycoylated sugars, and in drug discovery applications.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 152.73K | Year: 2012

DESCRIPTION (provided by applicant): The ultimate goal of the proposal presented herein is to use E. coli as whole cell biocatalysts for the production of a wide variety of TDP-deoxysugars including di- and tri-deoxysugars, amino sugars and branched-chainsugars. These specialized activated hexoses are found as important structural components throughout plant and microbial secondary metabolites often playing a crucial role in conferring activity in bioactive natural products such as antibiotics and anticancer therapeutics. We propose to investigate a novel approach to produce rare TDP-deoxysugars in Escherichia coli through metabolic engineering. By combining genetic mutations which separately lead to increased bioavailability of glucose-6-phosphate (G6P; an intermediate of TKDG) and TDP-4-keto-6-deoxy-D-glucose (TKDG; an intermediate of TDP-deoxysugars) we plan to increase the accumulation of the TKDG precursor beyond previous reports. Additional over-expression of endogenous TKDG biosynthetic proteins mayfurther optimize TKDG production. Finally, exogenous TDP-deoxysugar biosynthetic genes will be introduced into the strain to convert the accumulated TKDG pool into specific TDP-deoxysugars. Specifically, in Phase I we will demonstrate the feasibility of TDP-deoxysugar production in E. coli through by 1) developing analytical methods for the isolation, purification and characterization of TDP-deoxysugars produced by E. coli, 2) metabolically engineering E. coli to accumulate the TKDG and, 3) demonstrating the utility of the resulting TKDG over-producing strain by producing various TDP-deoxysugars. Specifically, biosynthetic genes responsible for the individual production of TDP-D- fucose, TDP-D-fucofuranose and TDP-D-olivose will be placed into inducible E.coli expression vectors and transformed into the engineered strain accumulating TKDG. We propose the resulting strains will be capable of producing at least 50 mg/L of TDP-D-fucose, TDP-D-fucofuranose and/or TDP-D-olivose in the Phase I study. In Phase II, we will scale-up production of TDP-deoxysugars and optimize chromatographic techniques for increased throughput. Furthermore, we will continue to utilize various TDP-deoxysugar biosynthetic genes for the production of amino sugars, branched-chain sugarsand additional deoxysugars. In Phase III we will commercialize the technology developed by offering a wide variety of TDP-sugars for sale, carrying out custom synthesis of TDP-sugars, and carrying out custom glycodiversification projects. PUBLIC HEALTH RELEVANCE: This project is aimed toward developing E. coli as a whole-cell biocatalyst for the production of activated TDP-deoxysugars. These deoxysugars can be used to make derivatives of natural products with new therapeutic properties, for example,antibiotics that are effective against antibiotic-resistant bacteria.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 184.76K | Year: 2013

DESCRIPTION: Fucosylation plays an important role in much cellular process. Fucosylated oligosaccharides in the cell are involved in various types of biochemical recognition processes and in microbial infections, toxin entry, and cancer cells metastasis.These properties make these carbohydrates valuable for pharmaceutical and drug discovery needs but current production methods production is very expensive and impractical. Most notably is the expense and difficulty in producing the activated sugar, GDP-fucose. Current methods described to date for the production of GDP-fucose using chemoenzymatic synthesis, or modified microorganisms such E. coli and S. cerevisiae all either yield too small quantities of material or are overly complicated and can't be scaled. Here we propose to develop an entirely new system based on the use of a yeast system for production GDP-fucose. This system uses a strong inducible promoter for overexpression of the enzyme from a de novo pathway in methylotrophic yeast. These yeast naturally produce a high yield of GDP-mannose which the proposed system will convert to GDP-fucose and utilize nucleotide-sugar transporter for extracellular release. We foresee the advantages of this approach to be high- level expression of protein involved to GDP-fucose synthesis and transport and the possibility to use the desired enzymes for in vivo synthesis. In Phase I we will test the feasibility of developing this system by screening a set of yeast that can produce GDP-mannose in highest yield, overexpress the enzymes necessary to convert GDP-mannose to GDP-fucose, and test the ability to produce GDP-L-fucose. We will then test the ability to transport GDP-L- fucose out of the cell and determine the initial conditios for fermentation. In Phase II wewill further engineer and optimize the production of GDP-fucose and demonstrate its utility by testing the production of several human milk from starting materials that are readily available to us. Finally, Phase III commercialization will involve sellngGDP-fucose, licensing the system for use by a variety of companies, and in using it to produce custom fucosylated oligosaccharides, small molecules, and proteins. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Development of the yeast gene expression system proposed here will allow production of GDP-fucose in vivo at a large scale. This technology will make this sugar nucleotide available in low price for modification of already synthesized or natural sugar, lipids, proteins, antibiotics andvaccines. The proposed research has the potential to open up several multi-billion dollar markets in anti-infective and anticancer therapeutics.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 1.28M | Year: 2015

DESCRIPTION provided by applicant Fucosylation plays an important role in many cellular processes Fucosylated oligosaccharides in the cell are involved in many biochemical recognition processes microbial infections toxin entry and cancer cell metastasis These properties make fucosylated molecules valuable for pharmaceutical and drug discovery needs but current production methods are very expensive and impractical Most notably is the expense and difficulty in producing the activated sugar GDP fucose Our goal is to increase accessibility of GDP fucose and fucosylated molecules such as oligosaccharides so that the research community can better understand the role of these compounds in human health develop novel antimicrobial anti inflammatory and anti cancer agents and develop strains suitable for large scale production of various oligosaccharides and fucosylated molecules Current methods described to date for the production of GDP fucose using either chemoenzymatic synthesis or modified E coli and S cerevisiae strains all yield only small milligram quantities of material or are overly complicated and canandapos t be scaled Here we propose to develop an entirely new yeast based method for production of GDP fucose There are two main advantages to this this yeast based system First it uses an inducible promoter in the presence of glucose to overexpress two enzymes capable of converting a naturally abundant source of GDP mannose to GDP fucose Second it utilizes a nucleotide sugar transporter for the extracellular release of GDP Fucose The system also allows the possibility of using additional enzymes for in vivo synthesis of target molecules In Phase I we demonstrated the feasibility of using this approach by developing a yeast strain that can produce GDP mannose at high yields overexpressing the enzymes necessary to convert GDP mannose to GDP fucose and demonstrating the ability to produce GDP fucose at high yields We have also demonstrated the ability to transport GDP fucose out of the cell and have determined the initial conditions for fermentation In Phase II we will further engineer and optimize the production of GDP fucose and demonstrate its utility by testing the production of several important fucosylated molecules such as human milk oligosaccharides and fucosylated proteins from starting materials that are readily available to us Finally Phase III commercialization will involve selling GDP fucose licensing the system for use in a variety of applications and using the system to produce custom fucosylated oligosaccharides small molecules and proteins PUBLIC HEALTH RELEVANCE We propose to develop a yeast based system for the production of GDP fucose in vivo at large scale This technology will make this sugar nucleotide economically available for modification of natural sugars lipids proteins antibiotics antibodie and vaccines The proposed research has the potential to open up several multi billion dollar markets in anti infective and anticancer therapeutics as well as having application in the production of nutritional oligosaccharides


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 175.81K | Year: 2016

DESCRIPTION provided by applicant The goal of this proposal is to develop a fermentative strategy for the large scale production of L fucose and other rare sugars L fucose deoxy L galactose is an important hexose deoxysugar found in a variety of organisms attached to an array of macromolecules These L fucose containing glycans exhibit a wide range of medicinal properties including supporting infant health L fucose containing human milk oligosaccharides anticoagulant and antithrombotic antivirus antitumor anticancer and immunomodulatory anti inflammatory blood lipids reducing antioxidant activitiy against hepatopathy uropathy and renalpathy gastric protective effects and therapeutic potential in surgery L fucose containing polymers The L fucose monomer has therapeutic properties such as inhibiting virulence factors and is also an invaluable synthetic starting material for a wide range of molecules including human milk oligosaccharides blood group antigens E and P selectin antagonists and functionalized L fucose derivatives In addition to pharmaceutical relevance L fucose also possesses topical properties attractive to the cosmetic industry including anti aging wrinkle reducing and is safe for sensitive skin Despite the impressive range of bioactivity discovered thus far L fucose remains prohibitively expensive and unavailable in the scale needed to support these applications We feel a fermentative approach is needed to meet these large scale requirements and to provide the glycoresearch community with this important building block needed to prepare scarce or unavailable glycans A key aspect of our strategy is the production of an engineered L fuculose phosphate aldolase that no longer requires the phosphorylated donor substrate dihydroxyacetone phosphate Instead the novel L fuculose phosphate aldolase FucA will catalyze the condensation between dihydroxyacetone and L lactaldehyde to form L fuculose thereby bypassing the typical sugar phosphate intermediate Through metabolic engineering we envision an E coli system capable of integrating this engineered L fuculose phosphate for the specific synthesis of L fucose In Phase I we will demonstrate the feasibility of a fermentative L fucose system by identifying and engineering a mutant FucA enzyme capable of condensing dihydroxyacetone and L lactaldehyde to form L fuculose for the ultimate production of L fucose In Phase II we will focus on the genetic and metabolic engineering of E coli for the production and accumulation of the substrates needed for the engineered L fuculose phospahte aldolase We propose a yield of g L production of L fucose after integration of the engineered L fuculose phosphate aldolase and subsequent optimizations In Phase III we will commercialize L fucose as well as other rare sugars produced by the engineered L fuculose phosphate aldolase using various acceptor aldehyde substrates PUBLIC HEALTH RELEVANCE This project is aimed toward developing a fermentative process for the large scale production of L fucose and other rare sugars L fucose is used as a synthetic building block for a wide range of pharmaceutically relevant biomolecules Additional rare sugars produced in this program will include D psicose L tagatose L fructose D ribulose L fuculose and deoxy D psicose which have applications as glucosidase inhibitors used in chemotherapy and serve as building blocks precursors to various therapeutics


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 168.16K | Year: 2014

DESCRIPTION (provided by applicant): UDP-GlcNAc and UDP-GalNAc comprise the core structures of glycans in glycoproteins and glycolipids. Oligosaccharides containing N-acetyl-hexosamines involved in various biological process, including microbial infection,toxin entry, cancer cell metastasis. They are the key building blocks for human milk oligosaccharides, blood antigens, and other important oligosaccharides. Oligosaccharides with core structures containing these sugars are needed for investigating cell signaling processes and metabolic regulation; these oligosaccharides have intensively been investigated as antimicrobial agents and prospective anticancer vaccines. The limiting factor in the development of these applications is the high production cost andlow availability of the UDP-GlcNAc and UDP-GalNAc building blocks. Cost factors include a lack of effective enzymatic systems for making these activated sugars, extensive purification steps, and the cost of nucleoside triphosphates. Here we propose t


Grant
Agency: NSF | Branch: Standard Grant | Program: | Phase: | Award Amount: 615.92K | Year: 2010

This SBIR Phase II project will develop a method to convert the byproduct glycerol to a value-added co-product, xylitol, thereby helping to reduce the costs associated with biodiesel production. The anticipated result is a scalable process capable of converting crude glycerol to xylitol in a single step bioreactor process and a demonstrated method for recovery of the value-added product.

The broader impact/commercial potential of the project will be to further biodiesel as a replacement for petrochemical diesel. Converting the main by-product of biodiesel production, glycerol, to a value-added product would improve the economics of biodiesel, while removing a waste stream and providing a reduction in price of the co-product. Xylitol itself also has beneficial societal impacts including anti-carcinogenic effects as a safe sweetener for diabetics, and it does not promote new cases of diabetes as some sweeteners are suspected of doing.

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