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Cambridge, MA, United States

Yadav V.G.,Massachusetts Institute of Technology | De Mey M.,Massachusetts Institute of Technology | De Mey M.,Ghent University | Giaw Lim C.,Massachusetts Institute of Technology | And 3 more authors.
Metabolic Engineering | Year: 2012

Industrial biotechnology promises to revolutionize conventional chemical manufacturing in the years ahead, largely owing to the excellent progress in our ability to re-engineer cellular metabolism. However, most successes of metabolic engineering have been confined to over-producing natively synthesized metabolites in . E. coli and . S. cerevisiae. A major reason for this development has been the descent of metabolic engineering, particularly secondary metabolic engineering, to a collection of demonstrations rather than a systematic practice with generalizable tools. Synthetic biology, a more recent development, faces similar criticisms. Herein, we attempt to lay down a framework around which bioreaction engineering can systematize itself just like chemical reaction engineering. Central to this undertaking is a new approach to engineering secondary metabolism known as 'multivariate modular metabolic engineering' (MMME), whose novelty lies in its assessment and elimination of regulatory and pathway bottlenecks by re-defining the metabolic network as a collection of distinct modules. After introducing the core principles of MMME, we shall then present a number of recent developments in secondary metabolic engineering that could potentially serve as its facilitators. It is hoped that the ever-declining costs of . de novo gene synthesis; the improved use of bioinformatic tools to mine, sort and analyze biological data; and the increasing sensitivity and sophistication of investigational tools will make the maturation of microbial metabolic engineering an autocatalytic process. Encouraged by these advances, research groups across the world would take up the challenge of secondary metabolite production in simple hosts with renewed vigor, thereby adding to the range of products synthesized using metabolic engineering. © 2012 Elsevier Inc. Source

Martin C.H.,Massachusetts Institute of Technology | Martin C.H.,Dow Chemical Company | Dhamankar H.,Massachusetts Institute of Technology | Tseng H.-C.,Massachusetts Institute of Technology | And 4 more authors.
Nature Communications | Year: 2013

The replacement of petroleum feedstocks with biomass to produce platform chemicals requires the development of appropriate conversion technologies. 3-Hydroxy-γ-butyrolactone has been identified as one such chemical; however, there are no naturally occurring biosynthetic pathways for this molecule or its hydrolyzed form, 3,4-dihydroxybutyric acid. Here we design a novel pathway to produce various chiral 3-hydroxyacids, including 3,4-dihydroxybutyric acid, consisting of enzymes that condense two acyl-CoAs, stereospecifically reduce the resulting β-ketone and hydrolyze the CoA thioester to release the free acid. Acetyl-CoA serves as one substrate for the condensation reaction, whereas the second is produced intracellularly by a pathway enzyme that converts exogenously supplied organic acids. Feeding of butyrate, isobutyrate and glycolate results in the production of 3-hydroxyhexanoate, 3-hydroxy-4-methylvalerate and 3,4-dihydroxybutyric acid+3-hydroxy-γ-butyrolactone, respectively, molecules with potential uses in applications from materials to medicines. We also unexpectedly observe the condensation reaction resulting in the production of the 2,3-dihydroxybutyric acid isomer, a potential value-added monomer. © 2013 Macmillan Publishers Limited. All rights reserved. Source

Santos C.N.S.,Manus Biosynthesis, Inc. | Regitsky D.D.,Calysta Energy Inc. | Yoshikuni Y.,Bio Architecture Laboratory Inc.
Nature Communications | Year: 2013

Evaluating the performance of engineered biological systems with high accuracy and precision is nearly impossible with the use of plasmids due to phenotypic noise generated by genetic instability and natural population dynamics. Minimizing this uncertainty therefore requires a paradigm shift towards engineering at the genomic level. Here, we introduce an advanced design principle for the stable instalment and implementation of complex biological systems through recombinase-assisted genome engineering (RAGE). We apply this concept to the development of a robust strain of Escherichia coli capable of producing ethanol directly from brown macroalgae. RAGE significantly expedites the optimal implementation of a 34 kb heterologous pathway for alginate metabolism based on genetic background, integration locus, copy number and compatibility with two other pathway modules (alginate degradation and ethanol production). The resulting strain achieves a ∼40% higher titre than its plasmid-based counterpart and enables substantial improvements in titre (∼330%) and productivity (∼1,200%) after 50 generations. Source

Agency: NSF | Branch: Standard Grant | Program: | Phase: SMALL BUSINESS PHASE I | Award Amount: 225.00K | Year: 2016

The broader impact/commercial potential of this Small Business Innovation Research (SBIR) project will be to reduce the incidence of Lyme Disease through the biomanufacturing of a novel natural acaricide. New cases of Lyme Disease have grown by nearly 50% over the past decade while the existing synthetic acaricides are dwindling in use due to regulatory and consumer safety concerns. The CDC and USDA have begun to champion a highly effective natural acaricide extracted from grapefruit. This target molecule is a GRAS-approved natural product, which has been used extensively as a food ingredient for decades. It is thought that this compelling safety benefit combined with potent efficacy will spur increased spraying in public areas and private residences. However, the cost of producing this natural acaricide has been prohibitive, and there is an opportunity to develop alternative sustainable production technologies.

This SBIR Phase I project proposes to develop a microbial process for the economical and sustainable production of a highly potent natural acaricide. Increasing wariness of synthetic insecticides combined with the need to prevent tick-borne illnesses creates a tremendous opportunity for natural acaricides. The projects terpene target has long been known as a highly effective acaricide; however, its commercialization has been hampered by a high cost of production. The aim is to develop an alternative fermentation process for biosynthetic production enabling the cost reductions required to effectively penetrate the acaricide market. The main objective for this project is to increase titers by an order of magnitude. This will be accomplished by employing established and novel metabolic and protein engineering approaches. Overall, this project will provide a new sustainable, cost-effective production route, thereby enabling acaricide commercialization.

Philippe R.N.,Manus Biosynthesis, Inc. | De Mey M.,Manus Biosynthesis, Inc. | De Mey M.,Ghent University | Anderson J.,Manus Biosynthesis, Inc. | Ajikumar P.K.,Manus Biosynthesis, Inc.
Current Opinion in Biotechnology | Year: 2014

The increasing public awareness of adverse health impacts from excessive sugar consumption has created increasing interest in plant-derived, natural low-calorie or zero-calorie sweeteners. Two plant species which contain natural sweeteners, Stevia rebaudiana and Siraitia grosvenorii, have been extensively profiled to identify molecules with high intensity sweetening properties. However, sweetening ability does not necessarily make a product viable for commercial applications. Some criteria for product success are proposed to identify which targets are likely to be accepted by consumers. Limitations of plant-based production are discussed, and a case is put forward for the necessity of biotechnological production methods such as plant cell culture or microbial fermentation to meet needs for commercial-scale production of natural sweeteners. © 2014 Elsevier Ltd. Source

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