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Key Publications

Propane and butane are the main constituents of liquefied petroleum gas and are used extensively for transport and domestic use. They are clean burning fuels, suitable for the development of low carbon footprint fuel and energy policies. Here, we present blueprints for the production of bio-alkane gas (propane and butane) through the conversion of waste volatile fatty acids by bacterial culture. We show that bio-propane and bio-butane can be produced photo-catalytically by bioengineered strains of E. coli and Halomonas (in non-sterile seawater) using fatty acids derived from biomass or industrial waste, and by Synechocystis (using carbon dioxide as feedstock).

The chemical industry must decarbonize to align with UN Sustainable Development Goals. A shift toward circular economies makes CO2 an attractive feedstock for producing chemicals, provided renewable H2 is available through technologies such as supercritical water (scH2O) gasification. Furthermore, high carbon and energy efficiency is paramount to favorable techno-economics, which poses a challenge to chemo-catalysis. This study demonstrates continuous gas fermentation of CO2 and H2 by the cell factory, Cupriavidus necator, to (R,R)-2,3-butanediol and isopropanol as case studies. Although a high carbon efficiency of 0.75 [(C-mol product)/(C-mol CO2)] is exemplified, the poor energy efficiency of biological CO2 fixation requires ∼8 [(mol H2)/(mol CO2)], which is techno-economically infeasible for producing commodity chemicals. Heat integration between exothermic gas fermentation and endothermic scH2O gasification overcomes this energy inefficiency. This study unlocks the promise of sustainable manufacturing using renewable feedstocks by combining the carbon efficiency of bio-catalysis with energy efficiency enforced through process engineering.

Enzymes are increasingly combined into multienzyme systems for cost and productivity benefits. Further advantages can be gained through the use of immobilized enzymes, allowing continuous biotransformations in flow. However, the optimization of such multienzyme systems is challenging, particularly where immobilized enzymes are used. Here, we meet this challenge using both mechanistic and empirical modeling to optimize a reaction involving a reductive aminase and a glucose dehydrogenase for continuous biocatalytic reductive amination in flow. Crucially, the construction of the mechanistic model was achieved quickly, with only a few important parameters determined experimentally, and ensemble modeling used to facilitate the use of estimates or literature values.

Conjugated alkenes such as dienes and polyenes have a range of applications as pharmaceutical agents and valuable building blocks in the polymer industry. Development of a renewable route to these compounds provides an alternative to fossil fuel derived production. The enzyme family of the UbiD decarboxylases offers substantial scope for alkene production, readily converting poly unsaturated acids. However, biochemical pathways producing the required substrates are poorly characterized, and UbiD-application has hitherto been limited to biological styrene production. Herein, we present a proof-of-principle study for microbial production of polyenes using a bioinspired strategy employing a polyketide synthase (PKS) in combination with a UbiD-enzyme. Deconstructing a bacterial iterative type II PKS enabled repurposing the broad-spectrum antibiotic andrimid biosynthesis pathway to access the metabolic intermediate 2,4,6-octatrienoic acid, a valuable chemical for material and pharmaceutical industry. Combination with the fungal ferulic acid decarboxylase (Fdc1) led to a biocatalytic cascade-type reaction for the production of hepta-1,3,5-triene in vivo. Our approach provides a novel route to generate unsaturated hydrocarbons and related chemicals and provides a blue-print for future development and application.

To satisfy the growing demand for limonene, novel pathways for microbial production of limonene have been sought. A techno-economic analysis is carried out for one such process producing limonene from sugar at an industrial plant scale to assess potential economic viability. A conceptual design of the process is developed, in which a gas stripping-solvent scrubbing method is chosen for recovering limonene from bioreactors based on consideration of payback time and process operability. Minimum limonene selling prices are estimated over a range of fermentation productivity based on the calculation of net present value using discounted cash flow method. Under 45% of the maximum theoretical yield, the selling price reaches $19.9/kg, which could be competitive with established production processes when fermentation productivity is above 0.7 kg/(m3·h). Reduction of cost could be realised through improvement of microbial strains, utilisation of cheaper feedstocks, reduction in capital investment and strategic business planning.

Biocatalysis has emerged as one of the most promising technologies to enable green synthesis of important chemicals, due to the ambient conditions generally applied for these reactions. Nonetheless, a general uptake of enzymatic transformations has been hindered by the perceived high cost of recombinant proteins. Recent interest in continuous flow from the synthetic chemistry community has now begun to spread to biotransformations, with protein immobilization playing a key part. As a consequence, continuous biotransformations using immobilized enzymes are becoming more accessible to nonexperts. This review will discuss several recent examples of continuous biotransformations that use immobilization, with a focus on examples involving fine chemical synthesis.

2021 Highlight Publications

  • Cardoso Marques MP, Lorente-Arevalo A, Bolivar JM. (2021) Biocatalysis in Continuous-Flow Microfluidic Reactors. In: . Advances in Biochemical Engineering/Biotechnology. Springer, Berlin, Heidelberg. pp1 – 36.
  • Halliwell T, Fisher K, Payne KAP, Rigby SEJ, Leys D. (2021). Heterologous expression of cobalamin dependent class-III enzymes.  Protein Expression and Purification, 177.
  • Hedison TM, Breslmayr E, Shanmugam M, Karnpakdee K, Heyes DJ, Green AP, Ludwig R, Scrutton NS, Kracher D. (2021). Insights into the H2O2‐driven catalytic mechanism of fungal lytic polysaccharide monooxygenases. The FEBS Journal.
  • Messiha HL, Payne KAP, Scrutton NS, Leys D.  (2021). A Biological Route to Conjugated Alkenes: Microbial Production of Hepta-1,3,5-triene. ACS Synth. Biol., 10:228-235.
  • Rodgers S, Conradie A, King R, Poulston S, Hayes M, Reddy Bommareddy R, McKechnie J. (2021). Reconciling the sustainable manufacturing of commodity chemicals with feasible technoeconomic outcomes: Assessing the investment case for heat integrated aerobic gas fermentation. Johnson Matthey Technology Review.
  • Rosa SS, Prazeres DMF, Azevedo AM, Marques MPC. (2021). mRNA vaccines manufacturing: Challenges and bottlenecks.  Vaccine, 39:2190-2200.
  • Payne KAP, Marshall SA, Fisher K, Rigby SEJ, Cliff MJ, Spiess R, Cannas DM, Larrosa I, Hay S, Leys D.  (2021).  Structure and Mechanism of Pseudomonas aeruginosa PA0254/HudA, a prFMN-Dependent Pyrrole-2-carboxylic Acid Decarboxylase Linked to Virulence. ACS Catalysis , 11: 2865–2878.

2020 Highlight Publications

  • Amer M, Hoeven R, Kelly P, Faulkner M, Smith MH, Toogood HS, Scrutton NS.  (2020). Renewable and tuneable bio-LPG blends derived from amino acids. Biotechnology for Biofuels, 13.
  • Amer M, Toogood H, Scrutton NS. (2020). Engineering nature for gaseous hydrocarbon production. Microbial Cell Factories, 19.
  • Amer M, Wojcik E, Sun C, Hoeven R, Hughes J, Faulkner M, Yunus IS, Tait S, Johannissen L, Hardman S, Heyes D, Chen G-Q, Smith MH, Jones PR, Toogood H, Scrutton N. (2020). Low Carbon Strategies for Sustainable Bio-alkane Gas Production and Renewable Energy. Energy Environ. Sci., 13, 1818-1831.
  • Bajić M, Oberlintner A, Kõrge K, Likozar B, Novak U. (2020).  Formulation of active food packaging by design: Linking composition of the film-forming solution to properties of the chitosan-based film by response surface methodology (RSM) modelling.  International Journal of Biological Macromolecules, 160: 971-978
  • Bagnall J, Rowe W, Alachkar N, Roberts J, England H, Clark C, Platt M, Jackson DA, Muldoon M, Paszek P. (2020).  Gene-Specific Linear Trends Constrain Transcriptional Variability of the Toll-like Receptor Signaling. Cell Systems, 11: 300-314.
  • Berepiki, A., Kent, R., Machado, L. F. M., Dixon N. (2020). Development of high-performance whole cell biosensors aided by statistical modelling. ACS Synth. Biol., 9: 576-89.
  • Bommareddy RR, Wang Y, Pearcy N, Hayes M, Lester E, Minton NP, Conradie AV. (2020). A Sustainable Chemicals Manufacturing Paradigm Using CO2 and Renewable H2. iScience, 23.
  • Breslmayr E, Laurent C V.F.P, Scheiblbrandner S, Jerkovic A, Heyes D, Oostenbrink C, Ludwig R, Hedison TM, Scrutton NS, Kracher D. (2020). Protein Conformational Change is Essential For Reductive Activation of Lytic Polysaccharide Monooxygenase by Cellobiose Dehydrogenase. ACS Catal., 10: 4842-53.
  • Carbonell P, Le Feuvre R, Takano E, Scrutton NS. (2020). In Silico Design And Automated Learning To Boost Next-Generation Smart Biomanufacturing. Synth Biol., 5: ysaa020
  • Cosgrove SC, Thompson MP, Ahmed ST, Parmeggiani F, Turner NJ. (2020). One-Pot Synthesis of Chiral N-Arylamines by Combining Biocatalytic Aminations with Buchwald. Hartwig N-Arylation Angewandte Chemie – International Edition., 59: 18156-18160.
  • Finnigan W, Citoler J, Cosgrove SC, Turner NJ. (2020). Rapid model-based optimization of a two-enzyme system for continuous reductive amination in flow. Org. Process Res. Dev., 24: 1969-1977.
  • Finnigan W, Roberts AD, Ligorio C, Scrutton NS, Breitling R, Blaker JJ, Takano E. (2020). The effect of terminal globular domains on the response of recombinant mini-spidroins to fiber spinning triggers. Scientific Reports, 10.
  • Halliwell T, Fisher K, Payne KAP, Rigby SEJ, Leys D. (2020).  Catabolic reductive dehalogenase substrate complex structures underpin rational repurposing of substrate scope. Microorganisms, 8: 1-16.
  • Hedison TM, Shanmugam M, Heyes DJ, Edge R, Scrutton N. (2020). Active Intermediates in Copper Nitrite Reductase Reactions Probed by a Cryotrapping‐Electron Paramagnetic Resonance Approach. Angew. Chem. Int. Ed., 132: 14040 – 14044.
  • Heyes DJ, Lakavath B, Hardman SJO, Sakuma M, Hedison TM, Scrutton NS. (2020). On the photochemical mechanism of light-driven fatty acid photodecarboxylase. ACS Catalysis, 10: 6691-6696.
  • Kõrge K, Bajić M, Likozar B, Novak U. (2020). Active chitosan–chestnut extract films used for packaging and storage of fresh pasta. Int J Food Sci Technol., 55: 3043-3052.
  • Lakavath B, Hedison TM, Heyes DJ, Shanmugam M, Sakuma M, Hoeven R, Tilakaratna V, Scrutton NS. (2020). Radical-based photoinactivation of fatty acid photodecarboxylases. Anal. Biochem., 600: 113749.
  • Leferink NGH, Ranaghan KE, Battye J, Johannissen LO, Hay S, van der Kamp MW, Mulholland AJ, Scrutton NS. (2020). Taming the reactivity of monoterpene synthases to guide regioselective product hydroxylation. ChemBioChem, 21: 985-990.
  • Long M, Ní Cheallaigh A, Reihill M, Oscarson S, Lahmann M. (2020).  Synthesis of type 1 Lewis b hexasaccharide antigen structures featuring flexible incorporation of l-[U-13C6]-fucose for NMR binding studies.  Organic and Biomolecular Chemistry, 18: 4452-4458.
  • Mattey AP, Sangster JJ, Ramsden JI, Baldwin C, Birmingham WR, Heath RS, Angelastro A, Turner NJ, Cosgrove SC, Flitsch SL. (2020). Natural heterogeneous catalysis with immobilised oxidase biocatalysts. RSC Advances, 10: 19501-05.
  • Mangas-Sanchez J, Sharma M, Cosgrove SC, Ramsden JI, Marshall JR, Thorpe, TW, Palmer RB, Grogan G, Turner NJ. (2020). Asymmetric synthesis of primary amines catalyzed by thermotolerant fungal reductive aminases. Chemical Science, 11: 5052-5057.
  • Ní Cheallaigh A, Guimond SE, Oscarson S, Miller GJ. (2020). Chemical synthesis of a sulfated D-glucosamine library and evaluation of cell proliferation capabilities.  Carbohydrate Research, 495.
  • Novak U, Bajić M, Kõrge K, Oberlintner A, Murn J, Lokar K, Triler KV, Likozar B. (2020). From waste/residual marine biomass to active biopolymer-based packaging film materials for food industry applications- A review. Physical Sciences Reviews, 5.
  • Reddy GK, Leferink NGH, Umemura M, Ahmed ST, Breitling R, Scrutton NS, Takano E. (2020).   Exploring novel bacterial terpene synthases.  PLoS ONE, 15.
  • Roberts A, Kelly P, Bain J, Morrison J, Wimpenny I, Barrow M, Woodward RT, Gresil M, Blanford CF, Hay S, Blaker J, Yeates S, Scrutton N. (2019). Graphene–aramid nanocomposite fibres via superacid co-processing Chem. Commun., 55: 11703-06.
  • Roberts AD, Finnigan W, Kelly PP, Faulkner M, Breitling R, Takano E, Scrutton NS, Blaker JJ, Hay S. (2020). Non-covalent protein-based adhesives for transparent substrates—bovine serum albumin vs. recombinant spider silk.  Materials Today Bio, 7.
  • Roberts A, Lee J, Magaz A, Smith M, Dennis M, Scrutton N, Blaker J. (2020). Hierarchically Porous Silk/Activated-Carbon Composite Fibres for Adsorption and Repellence of Volatile Organic Compounds. Molecules, 25: 1207-13.
  • Scrutton N, Malone K. (2020). Biomanufacturing; a path to sustainable economic recovery. New Statesman Biotechnology Special Edition. (
  • Sun C, Theodoropoulos C, Scrutton N. (2020). Techno-economic assessment of microbial limonene production. Bioresour. Technol., 300: 122666-73.
  • Sun C, Pérez-Rivero C, Webb C, Theodoropoulos C. (2020). Dynamic metabolic analysis of Cupriavidus necator DSM545 producing poly (3-hydroxybutyric acid) from glycerol.  Processes, 8.

2019 Highlight Publications

  • Ahmed S, Leferink N, Scrutton N. (2019). Chemo-enzymatic Routes Towards the Synthesis of Bio-based Monomers and Polymers. Molecular Catalysis, 467: 95-110.
  • Bailey S, Payne K, Saaret A, Marshall S, Gostimskaya I, Kosov I, Fisher K, Hay S, Leys D. (2019). Enzymatic control of cycloadduct conformation ensures reversible 1,3 dipolar cycloaddition in a prFMN dependent decarboxylase. Nat. Chem., 11: 1049-57.
  • Chen FF, Cosgrove SC, Birmingham WR, Mangas-Sanchez J, Citoler J, Thompson MP, Zheng GW, Xu JH, Turner NJ. (2019). Enantioselective Synthesis of Chrial Vicinal Amino Alcohols Using Amine Dehydrogenases. ACS Cat. 9: 11813-18.
  • Cosgrove SC, Mattey AP, Riese M, Chapman MR, Birmingham WR, Blacker AJ, Kapur N, Turner NJ, Flitsch SL. (2019). Biocatalytic Oxidation in Continuous Flow for the Generation of Carbohydrate Dialdehydes. ACS Catalysis, 9: 11658-62.
  • Hedison T, Heyes, D, Shanmugam, M, Iorgu, AI, Scrutton N. (2019). Solvent-slaved protein motions accompany proton coupled electron transfer reactions catalysed by copper nitrite reductase. Chem. Commun., 55: 2863-66.
  • Hedison T, Shenoy R, Iorgu AI, Heyes D, Fisher K, Wright G, Hay S, Eady RR, Antonyuk S, Hasnain SS, Scrutton NS. (2019). Unexpected Roles of a Tether Harboring a Tyrosine Gatekeeper Residue in Modular Nitrite Reductase Catalysis. ACS Catal., 9: 6087-99.
  • Hedison TM, Scrutton NS. (2019). Tripping the light fantastic in membrane redox biology: Linking dynamic structures to function in ER electron transfer chains. FEBS J., 286: 2004-17.
  • Iorgu AI, Hedison T, Hay S, Scrutton N. (2019). Selectivity through discriminatory induced fit enables switching of NAD(P)H coenzyme specificity in Old Yellow Enzyme ene-reductases. FEBS J., 286: 3117-3128.
  • Leferink N, Dunstan M, Hollywood K, Swainston N, Currin A, Jervis A, Takano E, Scrutton N. (2019). An automated pipeline for the screening of diverse monoterpene synthase libraries. Sci Rep., 9: 11936-47.
  • Marshall SA, Payne KAP, Fisher K, Gahloth D, Bailey SS, Balaikaite A, Saaret A, Gostimskaya I, Aleku G, Huang H, Rigby SEJ, Procter D, Leys D. (2019). Heterologous production, reconstitution and EPR spectroscopic analysis of prFMN dependent enzymes. Methods Enzymol, 620: 489-508.
  • Marshall SA, Payne KAP, Fisher K, White MD, Ní Cheallaigh A, Balaikaite A, Rigby SEJ, Leys D. (2019). The UbiX flavin prenyltransferase reaction mechanism resembles class I terpene cyclase chemistry. Nat Commun., 10: 2357-66.
  • Novak U, Bajić M, Kõrge K, Oberlintner A, Murn J, Lokar K, Triler K, Likozar B. (2019). From waste/residual marine biomass to active biopolymer-based packaging film materials for food industry applications – a review. Physical Sciences Reviews, 5: 20190099.
  • Payne KAP, Marshall S, Fisher K, Cliff MJ, Cannas D, Yan C, Heyes DJ, Parker D, Larrosa I, Leys D. (2019). Enzymatic Carboxylation of 2-Furoic Acid Yields 2,5-Furandicarboxylic Acid (FDCA). ACS Catal., 9: 2854-65.
  • Roberts A, Finnigan W, Wolde-Michael E, Kelly P, Blaker J, Hay S, Breitling R, Takano E, Scrutton N. (2019). Synthetic biology for fibres, adhesives and active camouflage materials in protection and aerospace. MRS Commun., 9: 486-504.
  • Roberts A, Kelly P, Bain J, Morrison J, Wimpenny I, Barrow M, Woodward RT, Gresil M, Blanford CF, Hay S, Blaker J, Yeates S, Scrutton N. (2019). Graphene–aramid nanocomposite fibres via superacid co-processing Chem. Commun., 55: 11703-06.
  • Theodoropoulos C, Sun C. (2019). Bioreactor Models and Modeling Approaches. in M Butler (ed.), Comprehensive Biotechnology. 3rd edition edn, 2.45, Comprehensive Biotechnology, vol. 3, Elsevier BV, pp. 663-80.
  • Thompson MP, Peñafiel I, Cosgrove SC, Turner NJ. (2019). Biocatalysis Using Immobilized Enzymes in Continuous Flow for the Synthesis of Fine Chemicals. Organic Process Research & Development., 23: 9-18.