Modelling and response curve engineering of β-alanine-responsive biosensors

Vincent Crabbe
Persbericht

Biosensors: een cruciaal ingrediënt voor de bio-economie

Onze afhankelijkheid van fossiele brandstoffen is brandend actueel, en hun impact op het klimaat is een van de grootste uitdagingen van deze eeuw. Daarom gebeurt veel onderzoek naar de productie van brandstof en plastics door micro-organismen, microscopisch kleine wezentjes zoals bacteriën en gisten, op basis van hernieuwbare grondstoffen. Ondanks enkele successen staat de transitie van onze petrochemische industrie naar een meer duurzame bio-economie op een laag pitje. Een belangrijke oorzaak hiervoor is dat deze micro-organismen drastisch gewijzigd moeten worden, waardoor hun metabolisme uit balans kan raken. Een mogelijke oplossing steunt op biosensors, die de concentratie van een specifieke molecule bínnenin de cel kunnen meten en zo over deze balans kunnen waken.

Hoewel sommige microben ons ziek kunnen maken, hebben bepaalde micro-organismen een enorm economisch potentieel: ze kunnen ingezet worden voor de productie van biobrandstoffen en chemicaliën. Gisten kunnen bijvoorbeeld de suikers uit biologische grondstoffen – zoals mais – fermenteren tot het waardevolle product ethanol. Dit proces wordt al duizenden jaren toegepast voor de productie van alcoholhoudende dranken, maar tegenwoordig wordt het merendeel van de geproduceerde ethanol gebruikt als brandstof. Zulke biobrandstoffen zijn namelijk beter voor het klimaat en verlagen onze afhankelijkheid van fossiele brandstoffen – en van de soms obscure regimes die ons hiervan bevoorraden.

Voorts wordt 12% van de aardolie die we wereldwijd oppompen gebruikt in de petrochemische industrie, onder andere voor de productie van plastics. Ook hier vormen micro-organismen een belangrijk alternatief. Zo produceren bepaalde micro-organismen biodegradeerbare plastics op basis van hernieuwbare grondstoffen. Er is echter nog veel werk aan de winkel om alle producten uit ons dagelijks leven te vervangen door een biologisch alternatief.

In deze context hechten biotechnologen bijvoorbeeld veel belang aan 3-HP (3-HydroxyPropionzuur). Deze molecule kan op basis van verscheidene hernieuwbare grondstoffen geproduceerd worden en kan makkelijk omgezet worden in een reeks chemicaliën met diverse toepassingen, goed voor een totale marktomvang van meer dan 30 miljard dollar.

Meten is weten

Eén probleem: micro-organismen produceren van nature niet voldoende 3-HP om een economisch interessant proces te ontwikkelen. En dus proberen bio-ingenieurs van over de hele wereld deze micro-organismen te verbeteren. Hierbij moeten heel wat wijzigingen aan het micro-organisme worden aangebracht. Deze ingrepen kunnen echter de balans in het metabolisme ontwrichten.

Veel wetenschappers, onder wie mijn promotors Eveline Peeters en Sophie de Buyl en ikzelf, trachten dit probleem aan te pakken aan de hand van biosensors. Zulke sensors laten toe om de concentratie van bepaalde moleculen binnenin de microbiële cel in realtime te meten.

Want meten is weten. Stel je bijvoorbeeld voor: je probeert een cake te maken … zonder weegschaal. Zo wordt het moeilijk om alle ingrediënten in de juiste verhouding toe te voegen. En als je ook tussendoor niet mag proeven van het beslag, heb je al helemaal geen idee waar je mee bezig bent.

Dat is precies de troef van biosensors: ze laten je toe om de juiste verhouding van de “ingrediënten” van het waardevolle molecule 3-HP (“de cake”) in te stellen binnenin de cel die dit produceert. Of door de concentratie van intermediaire producten op te volgen met zo’n biosensor (in “het beslag”), kan de ingenieur het proces in realtime fijnregelen, en zo de balans herstellen.

Biosensors zijn moeilijk af te regelen

Niettegenstaande hun potentieel al meermaals bewezen is in experimentele opstellingen, hebben biosensors nog niet hun weg naar de industrie gevonden. Het blijft namelijk een uitdaging om biosensors af te regelen voor een concrete toepassing. Want zoals dikwijls in de biologie, zijn ook biosensors behoorlijk complex en kan een bepaalde modificatie naast het beoogde effect ook ongewenste of zelfs averechtse effecten uitlokken. Daarom rekenen wetenschappers voor hun ontwikkeling vaak op proefondervindelijke methoden, die veel tijd en geld kosten en – ironisch genoeg – in veel plastic afval van gebruiksvoorwerpen uit het laboratorium resulteren.

Om tijd en middelen te sparen, gebruikte ik voor een groot deel van mijn masterproef een wiskundig model uit de wetenschappelijke literatuur. Dit model voorspelt het outputsignaal van de biosensor in functie van de concentratie van het doelwitmolecule – het molecule dat de biosensor waarneemt. Achter de computer bracht ik dan modificaties aan bij een fictieve biosensor en evalueerde vervolgens het voorspelde effect op de output. Zo kon ik een heleboel experimenten simuleren die in realiteit jaren in beslag zouden nemen.

Toch kwamen niet alle simulaties overeen met eerdere experimenten uit de wetenschappelijke literatuur. Dit suggereert dat het model een belangrijk biologisch aspect over het hoofd ziet. Dat lijkt jammer, maar toch blijft dit model aantrekkelijk door zijn eenvoud. Mijn scriptie legde de basis om in te toekomst de grenzen aan de toepasbaarheid van dit model vast te leggen.

In het tweede deel van mijn masterproef bestudeerde ik biosensors die de concentratie van β-alanine, een intermediaire molecule voor de productie van 3-HP, meten in het laboratorium. Of je zou kunnen zeggen dat je met deze biosensors “van het beslag kan proeven”. De ontwikkelde biosensors werden uitgebreid gekarakteriseerd en kunnen in de toekomst geselecteerd worden voor diverse toepassingen.

Conclusie

Onze tweeledige aanpak – wiskundig modelleren in combinatie met praktisch werk in het laboratorium – is redelijk zeldzaam maar zeer nuttig. Het modelleren laat toe om efficiënt biosensor-ontwerpen te testen en de meest interessante parameters uit te kiezen. Deze theorie moet uiteraard omgezet worden in praktijk, en daarom ontwikkelde ik verschillende biosensors in de context van een belangrijke toepassing: de productie van het waardevolle molecule 3-HP. Maar de vertaling van deze biosensors naar de industrie zal nog jaren duren, want dat is geen piece of cake

Bibliografie

Ajikumar, P. K., Xiao, W.-H., Tyo, K. E. J., Wang, Y., Simeon, F., Leonard, E., Mucha,
O., Phon, T. H., Pfeifer, B. and Stephanopoulos, G. (2010). Isoprenoid pathway optimization
for taxol precursor overproduction in Escherichia coli. Science 330, 70–74.
Alberts, A. and Vagelos, P. R. (1966). Acyl carrier protein: Studies of acyl carrier protein
and coenzyme A in Escherichia coli pantothenate or β-alanine auxotrophs. Journal
of Biological Chemistry 241, 5201–5204.
Alcántara-Díaz, D., Breña-Valle, M. and Serment-Guerrero, J. (2004). Divergent adaptation
of Escherichia coli to cyclic ultraviolet light exposures. Mutagenesis 19, 349–
354.
Altuvia, S., Kornitzer, D., Teff, D. and Oppenheim, A. B. (1989). Alternative mRNA
structures of the cIII gene of bacteriophage determine the rate of its translation
initiation. Journal of Molecular Biology 210(2), 265–280.
Amidani, D., Tramonti, A., Canosa, A. V., Campanini, B., Maggi, S., Milano, T.,
di Salvo, M. L., Pascarella, S., Contestabile, R., Bettati, S. and Rivetti, C. (2017).
Study of DNA binding and bending by Bacillus subtilis GabR, a PLP-dependent transcription
factor. Biochimica et Biophysica Acta - General Subjects 1861, 3474–3489.
Anashkin, V. A., Aksenova, V. A., Salminen, A., Lahti, R. and Baykov, A. A. (2019).
Cooperativity in catalysis by canonical family II pyrophosphatases. Biochemical and
Biophysical Research Communications 517, 266–271.
Anderson, J. J., Quay, S. C. and Oxender, D. L. (1976). Mapping of two loci affecting the
regulation of branched-chain amino acid transport in Escherichia coli K-12. Journal
of Bacteriology 126, 80–90.
Andrews, S. S. and Bray, D. (2004). Stochastic simulation of chemical reactions with
spatial resolution and single molecule detail. Physical Biology 1, 137.
Anthony, J. R., Anthony, L. C., Nowroozi, F., Kwon, G., Newman, J. D. and Keasling,
J. D. (2009). Optimization of the mevalonate-based isoprenoid biosynthetic pathway in Escherichia coli for production of the anti-malarial drug precursor amorpha-4,11-
diene. Metabolic Engineering 11, 13–19.
Ashyraliyev, M., Fomekong-Nanfack, Y., Kaandorp, J. A. and Blom, J. G. (2009).
Systems biology: parameter estimation for biochemical models. The FEBS Journal
276, 886–902.
Belitsky, B. R. and Sonenshein, A. L. (2002). GabR, a member of a novel protein family,
regulates the utilization of -aminobutyrate in Bacillus subtilis. Molecular Microbiology
45, 569–583.
Bernauw, A. J., De Kock, V. and Bervoets, I. (2022). In vivo screening method for the
identification and characterization of prokaryotic, metabolite-responsive transcription
factors. In: Prokaryotic Gene Regulation (E. Peeters and I. Bervoets, eds). Humana
Press. New York, NY, USA. pp. 113–141.
Bervoets, I. and Charlier, D. (2019). Diversity, versatility and complexity of bacterial gene regulation mechanisms: opportunities and drawbacks for applications in synthetic
biology. FEMS Microbiology Reviews 43, 304–339.
Bhagwat, S. P., Rice, M. R., Matthews, R. G. and Blumenthal, R. M. (1997). Use of an inducible regulatory protein to identify members of a regulon: application to the
regulon controlled by the leucine-responsive regulatory protein (Lrp) in Escherichia
coli. Journal of Bacteriology 179, 6254–6263.
Binder, R., Horowitz, J. A., Basilion, J. P., Koeller, D. M., Klausner, R. D. and Harford,
J. B. (1994). Evidence that the pathway of transferrin receptor mRNA degradation
involves an endonucleolytic cleavage within the 3′ UTR and does not involve poly(A)
tail shortening. The EMBO Journal 13, 1969–1980.
Binder, S., Schendzielorz, G., Stäbler, N., Krumbach, K., Hoffmann, K., Bott, M. and
Eggeling, L. (2012). A high-throughput approach to identify genomic variants of bacterial
metabolite producers at the single-cell level. Genome Biology 13, R40.
Boada, Y., Vignoni, A., Picó, J. and Carbonell, P. (2020). Extended metabolic biosensor
design for dynamic pathway regulation of cell factories. iScience 23, 101305.
Borodina, I., Kildegaard, K. R., Jensen, N. B., Blicher, T. H., Maury, J., Sherstyk, S.,
Schneider, K., Lamosa, P., Herrgård, M. J., Rosenstand, I., Öberg, F., Forster, J.
and Nielsen, J. (2015). Establishing a synthetic pathway for high-level production of
3-hydroxypropionic acid in Saccharomyces cerevisiae via β-alanine. Metabolic Engineering
27, 57–64.
Breaker, R. R. (2011). Prospects for riboswitch discovery and analysis. Molecular Cell
43, 867–879.
Briegel, A., Ortega, D. R., Tocheva, E. I., Wuichet, K., Li, Z., Chen, S., Müller, A.,
Iancu, C. V., Murphy, G. E., Dobro, M. J., Zhulin, I. B. and Jensen, G. J. (2009).
Universal architecture of bacterial chemoreceptor arrays. Proceedings of the National
Academy of Sciences of the United States of America 106, 17181–17186.
Brown, B. D., Zipkin, I. D. and Harland, R. M. (1993). Sequence-specific endonucleolytic
cleavage and protection of mRNA in Xenopus and Drosophila. Genes & Development
7, 1620–1631.
Burgard, A. P., Pharkya, P. and Maranas, C. D. (2003). Optknock: a bilevel programming
framework for identifying gene knockout strategies for microbial strain optimization.
Biotechnology and Bioengineering 84, 647–657.
Çakar, Z. P., Seker, U. O., Tamerler, C., Sonderegger, M. and Sauer, U. (2005). Evolutionary
engineering of multiple-stress resistant Saccharomyces cerevisiae. FEMS
Yeast Research 5, 569–578.
Calvo, J. M. and Matthews, R. G. (1994). The leucine-responsive regulatory protein, a
global regulator of metabolism in Escherichia coli. Microbiological Reviews 58, 466–
490.
Campbell, L. L. (1960). Reductive degradation of pyrimidines: enzymatic conversion
of N-carbamyl-β-alanine to β-alanine, carbon dioxide, and ammonia. Journal of Biological
Chemistry 235, 2375–2378.
Carmany, D. O., Hollingsworth, K. and McCleary, W. R. (2003). Genetic and biochemical
studies of phosphatase activity of PhoR. Journal of Bacteriology 185, 1112–1115.
Carpenter, A. C., Paulsen, I. T. and Williams, T. C. (2018). Blueprints for biosensors:
design, limitations, and applications. Genes 9, 375.
Castaño-Cerezo, S., Fournié, M., Urban, P., Faulon, J.-L. and Truan, G. (2020). Development
of a biosensor for detection of benzoic acid derivatives in Saccharomyces
cerevisiae. Frontiers in Bioengineering and Biotechnology 7, 372.
Ceres, P., Trausch, J. J. and Batey, R. T. (2013). Engineering modular ‘ON’ RNA
switches using biological components. Nucleic Acids Research 41(22), 10449–10461.
Charlier, D., Roovers, M., Gigot, D., Huysveld, N., Piérard, A. and Glansdorff, N.
(1993). Integration Host Factor (IHF) modulates the expression of the pyrimidinespecific
promoter of the carAB operons of Escherichia coli K12 and Salmonella typhimurium
LT2. Molecular and General Genetics 237, 273–286.
Chaurasia, A., Mohammed, N., Feki Tounsi, M. and Trabelsi, H. (2020). Microbial indicators
and biosensors for bioremediation. In: Bioremediation of Pollutants (V. C.
Pandey and V. Singh, eds). Elsevier. Amsterdam, The Netherlands. pp. 313–331.
Chen, S., Rosner, M. H. and Calvo, J. M. (2001). Leucine-regulated self-association of
leucine-responsive regulatory protein (Lrp) from Escherichia coli. Journal of Molecular
Biology 312, 625–635.
Chen, X., Yang, X., Shen, Y., Hou, J. and Bao, X. (2018). Screening phosphorylation
site mutations in yeast acetyl-CoA carboxylase using malonyl-CoA sensor to improve
malonyl-CoA-derived product. Frontiers in Microbiology 9, 47.
Cordone, A., Mauriello, E. M. F., Pickard, D. J., Dougan, G., De Felice, M. and Ricca,
E. (2005). The lrp gene and its role in type I fimbriation in Citrobacter rodentium.
Journal of Bacteriology 187, 7009–7017.
Cordova, L. T., Lu, J., Cipolla, R. M., Sandoval, N. R., Long, C. P. and Antoniewicz,
M. R. (2016). Co-utilization of glucose and xylose by evolved Thermus thermophilus
LC113 strain elucidated by 13C metabolic flux analysis and whole genome sequencing.
Metabolic Engineering 37, 63–71.
Cox III, R. S., Surette, M. G. and Elowitz, M. B. (2007). Programming gene expression
with combinatorial promoters. Molecular Systems Biology 3, 145.
Crasnier, M., Dumay, V. and Danchin, A. (1994). The catalytic domain of Escherichia
coli K-12 adenylate cyclase as revealed by deletion analysis of the cya gene. Molecular
and General Genetics 243, 409–416.
Cronan Jr, J. E. (1980). β-Alanine synthesis in Escherichia coli. Journal of Bacteriology
141, 1291–1297.
Crooks, G. E., Hon, G., Chandonia, J. M. and Brenner, S. E. (2004). WebLogo: a sequence
logo generator. Genome Research 14, 1188–1190.
Cumming, G., Fidler, F. and Vaux, D. L. (2007). Error bars in experimental biology.
Journal of Cell Biology 177, 7–11.
Curran, K. A., Leavitt, J. M., Karim, A. S. and Alper, H. S. (2013). Metabolic engineering
of muconic acid production in Saccharomyces cerevisiae. Metabolic Engineering
15, 55–66.
Daley, D. O., Rapp, M., Granseth, E., Melén, K., Drew, D. and Von Heijne, G. (2005).
Global topology analysis of the Escherichia coli inner membrane proteome. Science
308, 1321–1323.
Dalwadi, M. P. and King, J. R. (2020). An asymptotic analysis of the malonyl-CoA route
to 3-hydroxypropionic acid in genetically engineered microbes. Bulletin of Mathematical
Biology 82, 36.
David, F., Nielsen, J. and Siewers, V. (2016). Flux control at the malonyl-CoA node
through hierarchical dynamic pathway regulation in Saccharomyces cerevisiae. ACS
Synthetic Biology 5, 224–233.
de los Rios, S. and Perona, J. J. (2007). Structure of the Escherichia coli Leucineresponsive
Regulatory Protein Lrp reveals a novel octameric assembly. Journal of
Molecular Biology 366, 1589–1602.
De Paepe, B., Maertens, J., Vanholme, B. and De Mey, M. (2018). Modularization and
response curve engineering of a naringenin-responsive transcriptional biosensor. ACS
Synthetic Biology 7, 1303–1314.
De Paepe, B., Peters, G., Coussement, P., Maertens, J. and De Mey, M. (2017). Tailormade
transcriptional biosensors for optimizing microbial cell factories. Journal of
Industrial Microbiology and Biotechnology 44, 623–645.
Delvigne, F., Zune, Q., Lara, A. R., Al-Soud, W. and Sørensen, S. J. (2014). Metabolic
variability in bioprocessing: implications of microbial phenotypic heterogeneity.
Trends in Biotechnology 32, 608–616.
Dietrich, J. A., McKee, A. E. and Keasling, J. D. (2010). High-throughput metabolic
engineering: advances in small-molecule screening and selection. Annual Review of
Biochemistry 79, 563–590.
Dray, K. E., Muldoon, J. J., Mangan, N. M., Bagheri, N. and Leonard, J. N. (2022).
GAMES: a dynamic model development workflow for rigorous characterization of
synthetic genetic systems. ACS Synthetic Biology 11, 1009–1029.
Edayathumangalam, R., Wu, R., Garcia, R., Wang, Y., Wang, W., Kreinbring, C. A.,
Bach, A., Liao, J., Stone, T. A., Terwilliger, T. C., Hoang, Q. Q., Belitsky, B. R., Petsko,
G. A., Ringe, D. and Liu, D. (2013). Crystal structure of Bacillus subtilis GabR,
an autorepressor and transcriptional activator of gabT. Proceedings of the National
Academy of Sciences of the United States of America 110, 17820–17825.
Edelheit, O., Hanukoglu, A. and Hanukoglu, I. (2009). Simple and efficient site-directed
mutagenesis using two single-primer reactions in parallel to generate mutants for protein
structure-function studies. BMC Biotechnology 9, 61.
Elledge, S. J. and Davis, R. W. (1989). Position and density effects on repression by
stationary and mobile DNA-binding proteins. Genes & Development 3, 185–197.
Elowitz, M. B., Surette, M. G., Wolf, P.-E., Stock, J. B. and Leibler, S. (1999). Protein
mobility in the cytoplasm of Escherichia coli. Journal of Bacteriology 181, 197–203.
Englesberg, E., Squires, C. and Meronk Jr, F. (1969). The l-arabinose operon in Escherichia
coli B/r: a genetic demonstration of two functional states of the product of a
regulator gene. Proceedings of the National Academy of Sciences of the United States
of America 62, 1100–1107.
Ernsting, B. R., Atkinson, M. R., Ninfa, A. J. and Matthews, R. G. (1992). Characterization
of the regulon controlled by the leucine-responsive regulatory protein in
Escherichia coli. Journal of Bacteriology 174(4), 1109–1118.
Ettema, T. J., Brinkman, A. B., Tani, T. H., Rafferty, J. B. and Van Oost, J. D. (2002).
A novel ligand-binding domain involved in regulation of amino acid metabolism in
prokaryotes. Journal of Biological Chemistry 277, 37464–37468.
Etzel, M. and Mörl, M. (2017). Synthetic riboswitches: from plug and pray toward plug
and play. Biochemistry 56, 1181–1198.
Falk, J., Mendler, M. and Kabisch, J. (2022). Pipette Show: an open source web application
to support pipetting into microplates. ACS Synthetic Biology 11, 996–999.
Falson, P., Goffeau, A., Boutry, M. and Jault, J.-M. (2004). Structural insight into the
cooperativity between catalytic and noncatalytic sites of F1-ATPase. Biochimica et
Biophysica Acta - Bioenergetics 1658, 133–140.
Farmer, W. R. and Liao, J. C. (2000). Improving lycopene production in Escherichia coli
by engineering metabolic control. Nature Biotechnology 18, 533–537.
Fernandez-López, R., Ruiz, R., de la Cruz, F. and Moncalián, G. (2015). Transcription
factor-based biosensors enlightened by the analyte. Frontiers in Microbiology 6, 648.
Ferreira, R., Skrekas, C., Hedin, A., Sánchez, B. J., Siewers, V., Nielsen, J. and David,
F. (2019). Model-assisted fine-tuning of central carbon metabolism in yeast through
dCas9-based regulation. ACS Synthetic Biology 8, 2457–2463.
Ferrer, L., Elsaraf, M., Mindt, M. and Wendisch, V. F. (2022). l-Serine biosensorcontrolled
fermentative production of l-tryptophan derivatives by Corynebacterium
glutamicum. Biology 11, 744.
Fic, E., Bonarek, P., Gorecki, A., Kedracka-Krok, S., Mikolajczak, J., Polit, A.,
Tworzydlo, M., Dziedzicka-Wasylewska, M. and Wasylewski, Z. (2009). cAMP receptor
protein from Escherichia coli as a model of signal transduction in proteins – a
review. Microbial Physiology 17, 1–11.
Findeiß, S., Etzel, M., Will, S., Mörl, M. and Stadler, P. F. (2017). Design of artificial
riboswitches as biosensors. Sensors 17, 1990.
Fisher, S. L., Jiang, W., Wanner, B. L. and Walsh, C. T. (1995). Cross-talk between the
histidine protein kinase VanS and the response regulator PhoB: characterization and
identification of a VanS domain that inhibits activation of PhoB. Journal of Biological
Chemistry 270, 23143–23149.
Flachbart, L. K., Sokolowsky, S. and Marienhagen, J. (2019). Displaced by deceivers:
prevention of biosensor cross-talk is pivotal for successful biosensor-based highthroughput
screening campaigns. ACS Synthetic Biology 8, 1847–1857.
Fong, S. S., Burgard, A. P., Herring, C. D., Knight, E. M., Blattner, F. R., Maranas, C. D.
and Palsson, B. O. (2005). In silico design and adaptive evolution of Escherichia coli
for production of lactic acid. Biotechnology and Bioengineering 91, 643–648.
Fowler, C. C., Brown, E. D. and Li, Y. (2008). A FACS-based approach to engineering
artificial riboswitches. ChemBioChem 9, 1906–1911.
Frank, S. A. (2013). Input-output relations in biological systems: measurement, information
and the Hill equation. Biology Direct 8, 31.
Gadkar, K. G., Doyle III, F. J., Edwards, J. S. and Mahadevan, R. (2005). Estimating
optimal profiles of genetic alterations using constraint-based models. Biotechnology
and Bioengineering 89, 243–251.
Galperin, M. Y. (2006). Structural classification of bacterial response regulators: diversity
of output domains and domain combinations. Journal of Bacteriology 188, 4169–
4182.
Gardner, S. G., Johns, K. D., Tanner, R. and McCleary, W. R. (2014). The PhoU protein
from Escherichia coli interacts with PhoR, PstB, and metals to form a phosphatesignaling
complex at the membrane. Journal of Bacteriology 196, 1741–1752.
Georgi, C., Buerger, J., Hillen, W. and Berens, C. (2012). Promoter strength driving TetR
determines the regulatory properties of Tet-controlled expression systems. PLOS ONE
7(7), e41620.
Gilbert, W. and Müller-Hill, B. (1966). Isolation of the lac repressor. Proceedings of the
National Academy of Sciences of the United States of America 56, 1891–1898.
Glick, B. R. (1995). Metabolic load and heterologous gene expression. Biotechnology
Advances 13, 247–261.
Gottesman, S. (1984). Bacterial regulation: global regulatory networks. Annual Review
of Genetics 18, 415–441.
Grundy, F. J. and Henkin, T. M. (1993). tRNA as a positive regulator of transcription
antitermination in B. subtilis. Cell 74, 475–482.
Guo, K.-H., Chen, P.-H., Lin, C., Chen, C.-F., Lee, I.-R. and Yeh, Y.-C. (2018). Determination
of gold ions in human urine using genetically engineered microorganisms
on a paper device. ACS Sensors 3, 744–748.
Hallberg, Z. F., Su, Y., Kitto, R. Z. and Hammond, M. C. (2017). Engineering and in
vivo applications of riboswitches. Annual Review of Biochemistry 86, 515–539.
Halling, P. J. (1989). Do the laws of chemistry apply to living cells?. Trends in Biochemical
Sciences 14, 317–318.
Han, Y. and Zhang, F. (2020). Control strategies to manage trade-offs during microbial
production. Current Opinion in Biotechnology 66, 158–164.
Hanko, E. K., Minton, N. P. and Malys, N. (2017). Characterisation of a 3-
hydroxypropionic acid-inducible system from Pseudomonas putida for orthogonal
gene expression control in Escherichia coli and Cupriavidus necator. Scientific Reports
7, 1724.
Hanko, E. K., Paiva, A. C., Jonczyk, M., Abbott, M., Minton, N. P. and Malys, N. (2020).
A genome-wide approach for identification and characterisation of metaboliteinducible
systems. Nature Communications 11, 1213.
Hao, T., Li, G., Zhou, S. and Deng, Y. (2021). Engineering the reductive TCA pathway to
dynamically regulate the biosynthesis of adipic acid in Escherichia coli. ACS Synthetic
Biology 10, 632–639.
Hartline, C. J., Schmitz, A. C., Han, Y. and Zhang, F. (2021). Dynamic control
in metabolic engineering: theories, tools, and applications. Metabolic Engineering
63, 126–140.
Haßlacher, M., Ivessa, A. S., Paltauf, F. and Kohlwein, S. D. (1993). Acetyl-CoA carboxylase
from yeast is an essential enzyme and is regulated by factors that control
phospholipid metabolism. Journal of Biological Chemistry 268, 10946–10952.
Hayaishi, O., Nishizuka, Y., Tatibana, M., Takeshita, M. and Kuno, S. (1961). Enzymatic
studies on the metabolism of β-alanine. Journal of Biological Chemistry 236, 781–
790.
Haydon, D. J. and Guest, J. R. (1991). A new family of bacterial regulatory proteins.
FEMS Microbiology Letters 79, 291–296.
Henry, M. F. and Cronan Jr, J. E. (1991). Escherichia coli transcription factor that both
activates fatty acid synthesis and represses fatty acid degradation. Journal of Molecular
Biology 222, 843–849.
Herman, J. and Usher, W. (2017). SALib: an open-source Python library for sensitivity
analysis. Journal of Open Source Software 2(9), 97.
Hess, J. F., Oosawa, K., Kaplan, N. and Simon, M. I. (1988). Phosphorylation of three
proteins in the signaling pathway of bacterial chemotaxis. Cell 53, 79–87.
Hicks, M., Bachmann, T. T. and Wang, B. (2020). Synthetic biology enables programmable
cell-based biosensors. ChemPhysChem 21, 132–144.
Hill, A. V. (1910). The possible effects of the aggregation of the molecules of hæmoglobin
on its dissociation curves. The Journal of Physiology 40(suppl), 4–7.
Hong, K.-K., Vongsangnak, W., Vemuri, G. N. and Nielsen, J. (2011). Unravelling evolutionary
strategies of yeast for improving galactose utilization through integrated systems
level analysis. Proceedings of the National Academy of Sciences of the United
States of America 108, 12179–12184.
Hossain, G. S., Saini, M., Miyake, R., Ling, H. and Chang, M. W. (2020). Genetic
biosensor design for natural product biosynthesis in microorganisms. Trends in
Biotechnology 38, 797–810.
Huber, P. J. (1981). Robust Statistics. John Wiley & Sons. New York, NY, USA.
Ingalls, B. (2018). Mathematical Modelling in Systems Biology: An Introduction. The
Massachusetts Institute of Technology Press. Cambridge, MA, USA.
Jansen, M. L. A., Diderich, J. A., Mashego, M., Hassane, A., de Winde, J. H., Daran-
Lapujade, P. and Pronk, J. T. (2005). Prolonged selection in aerobic, glucose-limited
chemostat cultures of Saccharomyces cerevisiae causes a partial loss of glycolytic
capacity. Microbiology 151, 1657–1669.
Jantama, K., Haupt, M. J., Svoronos, S. A., Zhang, X., Moore, J. C., Shanmugam, K. T.
and Ingram, L. O. (2008). Combining metabolic engineering and metabolic evolution
to develop nonrecombinant strains of Escherichia coli C that produce succinate and
malate. Biotechnology and Bioengineering 99, 1140–1153.
Jiang, T., Li, C., Teng, Y., Zhang, R. and Yan, Y. (2020). Recent advances in improving
metabolic robustness of microbial cell factories. Current Opinion in Biotechnology
66, 69–77.
Jiang, X., Meng, X. and Xian, M. (2009). Biosynthetic pathways for 3-hydroxypropionic
acid production. Applied Microbiology and Biotechnology 82, 995–1003.
Jung, K., Fried, L., Behr, S. and Heermann, R. (2012). Histidine kinases and response
regulators in networks. Current Opinion in Microbiology 15, 118–124.
Kim, S.-K., Wilmes-Riesenberg, M. R. and Wanner, B. L. (1996). Involvement of the
sensor kinase EnvZ in the in vivo activation of the response-regulator PhoB by acetyl
phosphate. Molecular Microbiology 22, 135–147.
Klein, J., Henrich, B. and Plapp, R. (1986). Cloning and expression of the pepD gene of
Escherichia coli. Journal of General Microbiology 132, 2337–2343.
Koch, M., Pandi, A., Borkowski, O., Batista, A. C. and Faulon, J.-L. (2019). Custommade
transcriptional biosensors for metabolic engineering. Current Opinion in
Biotechnology 59, 78–84.
Kofoid, E. C. and Parkinson, J. S. (1988). Transmitter and receiver modules in bacterial
signaling proteins. Proceedings of the National Academy of Sciences of the United
States of America 85, 4981–4985.
Kölling, R. and Lother, H. (1985). AsnC: an autogenously regulated activator of asparagine
synthetase A transcription in Escherichia coli. Journal of Bacteriology
164, 310–315.
Kreutz, C. (2019). Guidelines for benchmarking of optimization-based approaches for
fitting mathematical models. Genome Biology 20, 281.
Kruger, K., Grabowski, P. J., Zaug, A. J., Sands, J., Gottschling, D. E. and Cech, T. R.
(1982). Self-splicing RNA: autoexcision and autocyclization of the ribosomal RNA
intervening sequence of tetrahymena. Cell 31, 147–157.
Kumarevel, T., Nakano, N., Ponnuraj, K., Gopinath, S. C. B., Sakamoto, K., Shinkai,
A., Kumar, P. K. R. and Yokoyama, S. (2008). Crystal structure of glutamine receptor
protein from Sulfolobus tokodaii strain 7 in complex with its effector l-glutamine:
implications of effector binding in molecular association and DNA binding. Nucleic
Acids Research 36, 4808–4820.
Kuthan, H. (2001). Self-organisation and orderly processes by individual protein complexes
in the bacterial cell. Progress in Biophysics and Molecular Biology 75, 1–17.
LaCroix, R. A., Sandberg, T. E., O’Brien, E. J., Utrilla, J., Ebrahim, A., Guzman,
G. I., Szubin, R., Palsson, B. O. and Feist, A. M. (2015). Use of adaptive laboratory
evolution to discover key mutations enabling rapid growth of Escherichia coli
K-12 MG1655 on glucose minimal medium. Applied and Environmental Microbiology
81, 17–30.
Lai, N., Luo, Y., Fei, P., Hu, P. and Wu, H. (2021). One stone two birds: biosynthesis
of 3-hydroxypropionic acid from CO2 and syngas-derived acetic acid in Escherichia
coli. Synthetic and Systems Biotechnology 6, 144–152.
Lamarche, M. G., Wanner, B. L., Crépin, S. and Harel, J. (2008). The phosphate regulon
and bacterial virulence: a regulatory network connecting phosphate homeostasis and
pathogenesis. FEMS Microbiology Reviews 32, 461–473.
Landgraf, D. (2012). Quantifying Localizations and Dynamics in Single Bacterial Cells.
Harvard University. Cambridge, MA, USA.
Landry, B. P., Palanki, R., Dyulgyarov, N., Hartsough, L. A. and Tabor, J. J. (2018).
Phosphatase activity tunes two-component system sensor detection threshold. Nature
Communications 9, 1433.
Lanzer, M. and Bujard, H. (1988). Promoters largely determine the efficiency of repressor
action. Proceedings of the National Academy of Sciences of the United States of
America 85, 8973–8977.
Latif, H., Sahin, M., Tarasova, J., Tarasova, Y., Portnoy, V. A., Nogales, J. and Zengler,
K. (2015). Adaptive evolution of Thermotoga maritima reveals plasticity of the ABC
transporter network. Applied and Environmental Microbiology 81, 5477–5485.
Lee, D. H. and Palsson, B. O. (2010). Adaptive evolution of Escherichia coli K-12
MG1655 during growth on a nonnative carbon source, L-1,2-propanediol. Applied
and Environmental Microbiology 76, 4158–4168.
Lee, M. E., Aswani, A., Han, A. S., Tomlin, C. J. and Dueber, J. E. (2013). Expressionlevel
optimization of a multi-enzyme pathway in the absence of a high-throughput
assay. Nucleic Acids Research 41, 10668–10678.
Levenberg, K. (1944). A method for the solution of certain non-linear problems in least
squares. Quarterly of Applied Mathematics 2, 164–168.
Li, S., Si, T., Wang, M. and Zhao, H. (2015). Development of a synthetic malonyl-
CoA sensor in Saccharomyces cerevisiae for intracellular metabolite monitoring and
genetic screening. ACS Synthetic Biology 4, 1308–1315.
Li, X., Guo, D., Cheng, Y., Zhu, F., Deng, Z. and Liu, T. (2014). Overproduction of
fatty acids in engineered Saccharomyces cerevisiae. Biotechnology and Bioengineering
111, 1841–1852.
Liang, C., Zhang, X., Wu, J., Mu, S., Wu, Z., Jin, J. M. and Tang, S. Y. (2020). Dynamic
control of toxic natural product biosynthesis by an artificial regulatory circuit.
Metabolic Engineering 57, 239–246.
Liberman, J. A. and Wedekind, J. E. (2012). Riboswitch structure in the ligand-free state.
Wiley Interdisciplinary Reviews: RNA 3, 369–384.
Lillacci, G. and Khammash, M. (2010). Parameter estimation and model selection in
computational biology. PLOS Computational Biology 6, e1000696.
Lin, R., D’Ari, R. and Newman, E. B. (1992). Lambda placMu insertions in genes of the
leucine regulon: extension of the regulon to genes not regulated by leucine. Journal
of Bacteriology 174, 1948–1955.
Liu, B., Kearns, D. B. and Bechhofer, D. H. (2016). Expression of multiple Bacillus
subtilis genes is controlled by decay of slrA mRNA from Rho-dependent 3′ ends.
Nucleic Acids Research 44, 3364–3372.
Liu, D., Evans, T. and Zhang, F. (2015). Applications and advances of metabolite biosensors
for metabolic engineering. Metabolic Engineering 31, 35–43.
Liu, D., Mannan, A. A., Han, Y., Oyarzún, D. A. and Zhang, F. (2018). Dynamic
metabolic control: towards precision engineering of metabolism. Journal of Industrial
Microbiology and Biotechnology 45, 535–543.
Liu, D. and Zhang, F. (2018). Metabolic Feedback Circuits Provide Rapid Control of
Metabolite Dynamics. ACS Synthetic Biology 7, 347–356.
Liu, H., Orell, A., Maes, D., van Wolferen, M., Lindås, A.-C., Bernander, R., Albers,
S.-V., Charlier, D. and Peeters, E. (2014). BarR, an Lrp-type transcription factor in
Sulfolobus acidocaldarius, regulates an aminotransferase gene in a β-alanine responsive
manner. Molecular Microbiology 92, 625–639.
Liu, X., Silverman, A. D., Alam, K. K., Iverson, E., Lucks, J. B., Jewett, M. C. and
Raman, S. (2020). Design of a transcriptional biosensor for the portable, on-demand
detection of cyanuric acid. ACS Synthetic Biology 9, 84–94.
López-Garrido, J., Puerta-Fernández, E. and Casadesús, J. (2014). A eukaryotic-like
3′ untranslated region in Salmonella enterica hilD mRNA. Nucleic Acids Research
42, 5894–5906.
Lotz, T. S. and Suess, B. (2018). Small-Molecule-Binding Riboswitches. Microbiology
Spectrum 6(4), 26.
Lu, Z., Zhang, X., Dai, J., Wang, Y. and He, W. (2019). Engineering of leucineresponsive
regulatory protein improves spiramycin and bitespiramycin biosynthesis.
Microbial Cell Factories 18, 1–12.
Lv, Y., Gu, Y., Xu, J., Zhou, J. and Xu, P. (2020). Coupling metabolic addiction with
negative autoregulation to improve strain stability and pathway yield. Metabolic Engineering
61, 79–88.
Maas, W. K. (1952). Pantothenate studies: description of the extracted pantothenatesynthesizing
enzyme of Escherichia coli. Journal of Biological Chemistry 198, 23–
32.
Maeda, T. and Wachi, M. (2012). 3’ Untranslated region-dependent degradation of the
aceA mRNA, encoding the glyoxylate cycle enzyme isocitrate lyase, by RNase E/G
in Corynebacterium glutamicum. Applied and Environmental Microbiology 78, 8753–
8761.
Magnus, W. (2021). Genetically Encoded Biosensors for the Improvement of 3-
Hydroxypropionic Acid Production in Escherichia coli. Vrije Universiteit Brussel.
Brussels, Belgium.
Mahr, R. and Frunzke, J. (2016). Transcription factor-based biosensors in biotechnology:
current state and future prospects. Applied Microbiology and Biotechnology 100, 79–
90.
Maiwald, T., Hass, H., Steiert, B., Vanlier, J., Engesser, R., Raue, A., Kipkeew, F., Bock,
H. H., Kaschek, D., Kreutz, C. and Timmer, J. (2016). Driving the model to its limit:
profile likelihood based model reduction. PLOS ONE 11(9), e0162366.
Makino, K., Shinagawa, H., Amemura, M., Kawamoto, T., Yamada, M. and Nakata,
A. (1989). Signal transduction in the phosphate regulon of Escherichia coli involves
phosphotransfer between PhoR and PhoB proteins. Journal of Molecular Biology
210, 551–559.
Makino, K., Shinagawa, H., Amemura, M. and Nakata, A. (1986). Nucleotide sequence
of the phoB gene, the positive regulatory gene for the phosphate regulon of Escherichia
coli K-12. Journal of Molecular Biology 190, 37–44.
Mannan, A. A. and Bates, D. G. (2021). Designing an irreversible metabolic switch for
scalable induction of microbial chemical production. Nature Communications 12, 1–
11.
Mannan, A. A., Liu, D., Zhang, F. and Oyarzún, D. A. (2017). Fundamental design
principles for transcription-factor-based metabolite biosensors. ACS Synthetic Biology
6, 1851–1859.
Marquardt, D. W. (1963). An algorithm for least-squares estimation of nonlinear parameters.
Journal of the Society for Industrial and Applied Mathematics 11(2), 431–441.
Martin, V. J. J., Pitera, D. J., Withers, S. T., Newman, J. D. and Keasling, J. D. (2003).
Engineering a mevalonate pathway in Escherichia coli for production of terpenoids.
Nature Biotechnology 21, 796–802.
Maury, J., Kannan, S., Jensen, N. B., Öberg, F. K., Kildegaard, K. R., Forster, J., Nielsen,
J., Workman, C. T. and Borodina, I. (2018). Glucose-dependent promoters for dynamic
regulation of metabolic pathways. Frontiers in Bioengineering and Biotechnology
6, 63.
McFarland, K. A. and Dorman, C. J. (2008). Autoregulated expression of the gene coding
for the leucine-responsive protein, Lrp, a global regulator in Salmonella enterica
serovar Typhimurium. Microbiology 154, 2008–2016.
McKay, D. B. and Steitz, T. A. (1981). Structure of catabolite gene activator protein at
2.9 Å resolution suggests binding to left-handed B-DNA. Nature 290, 744–749.
McKay, M. D., Beckman, R. J. and Conover, W. J. (1979). A comparison of three methods
for selecting values of input variables in the analysis of output from a computer
code. Technometrics 21, 239–245.
Mehta, P. K., Hale, T. I. and Christen, P. (1993). Aminotransferases: demonstration of
homology and division into evolutionary subgroups. European Journal of Biochemistry
214, 549–561.
Michaelis, L. and Menten, M. L. (1913). Die Kinetik der Invertinwirkung. Biochemische
Zeitschrift 49, 333–369.
Milano, T., Angelaccio, S., Tramonti, A., Di Salvo, M. L., Contestabile, R. and Pascarella,
S. (2016). A bioinformatics analysis reveals a group of MocR bacterial transcriptional
regulators linked to a family of genes coding for membrane proteins. Biochemistry
Research International 2016, 4360285.
Mizuno, T., Chou, M. Y. and Inouye, M. (1984). A unique mechanism regulating gene
expression: translational inhibition by a complementary RNA transcript (micRNA).
Proceedings of the National Academy of Sciences of the United States of America
81, 1966–1970.
Moré, J. J. (1978). The Levenberg-Marquardt algorithm: implementation and theory. In:
Numerical Analysis (G. A. Watson, ed.). Springer. Berlin, Germany. pp. 105–116.
Moser, F., Borujeni, A. E., Ghodasara, A. N., Cameron, E., Park, Y. and Voigt, C. A.
(2018). Dynamic control of endogenous metabolism with combinatorial logic circuits.
Molecular Systems Biology 14, e8605.
Nahvi, A., Sudarsan, N., Ebert, M. S., Zou, X., Brown, K. L. and Breaker, R. R. (2002).
Genetic control by a metabolite binding mRNA. Chemistry & Biology 9, 1043–1049.
Nakamura, K. and Bernheim, F. (1961). Studies of malonic semialdehyde dehydrogenase
from Pseudomonas aeruginosa. Biochimica et Biophysica Acta 50, 147–152.
Nardella, C., Barile, A., di Salvo, M. L., Milano, T., Pascarella, S., Tramonti, A. and
Contestabile, R. (2020). Interaction of Bacillus subtilis GabR with the gabTD promoter:
role of repeated sequences and effect of GABA in transcriptional activation.
The FEBS Journal 287, 4952–4970.
Newville, M., Stensitzki, T., Allen, D. B., Rawlik, M., Ingargiola, A. and Nelson, A.
(2016). Lmfit: non-linear least-square minimization and curve-fitting for Python.
URL: https://doi.org/10.5281/zenodo.598352
Nguyen-Duc, T., van Oeffelen, L., Song, N., Hassanzadeh-Ghassabeh, G., Muyldermans,
S., Charlier, D. and Peeters, E. (2013). The genome-wide binding profile of the
Sulfolobus solfataricus transcription factor Ss-LrpB shows binding events beyond direct
transcription regulation. BMC Genomics 14, 828.
Nguyen, N. H., Ainala, S. K., Zhou, S. and Park, S. (2019). A novel 3-hydroxypropionic
acid-inducible promoter regulated by the LysR-type transcriptional activator protein
MmsR of Pseudomonas denitrificans. Scientific Reports 9, 5333.
Nguyen, N. H., Kim, J.-R. and Park, S. (2019). Development of biosensor for 3-
hydroxypropionic acid. Biotechnology and Bioprocess Engineering 24, 109–118.
Nguyen-Vo, T. P., Ko, S., Ryu, H., Kim, J. R., Kim, D. and Park, S. (2020). Systems
evaluation reveals novel transporter YohJK renders 3-hydroxypropionate tolerance in
Escherichia coli. Scientific Reports 10, 19064.
Nguyen-Vo, T. P., Liang, Y., Sankaranarayanan, M., Seol, E., Chun, A. Y., Somasundar,
A., Chauhan, A. S., Kim, J. R. and Park, S. (2019). Development of 3-
hydroxypropionic-acid-tolerant strain of Escherichia coli W and role of minor global
regulator yieP. Metabolic Engineering 53, 48–58.
Nguyen-Vo, T. P., Ryu, H., Sauer, M. and Park, S. (2022). Improvement of 3-
hydroxypropionic acid tolerance in Klebsiella pneumoniae by novel transporter
YohJK. Bioresource Technology 346, 126613.
Ni, C., Fox, K. J. and Prather, K. L. (2022). Substrate-activated expression of a biosynthetic
pathway in Escherichia coli. Biotechnology Journal 17, 2000433.
Ni’Bhriain, N. N., Silver, S. and Foster, T. J. (1983). Tn5 insertion mutations in the
mercuric ion resistance genes derived from plasmid R100. Journal of Bacteriology
155, 690–703.
Nielsen, F. C. and Christiansen, J. (1992). Endonucleolysis in the turnover of insulin-like
growth factor II mRNA. Journal of Biological Chemistry 267, 19404–19411.
Ninfa, A. J. and Magasanik, B. (1986). Covalent modification of the glnG product, NRI,
by the glnL product, NRII, regulates the transcription of the glnALG operon in Escherichia
coli. Proceedings of the National Academy of Sciences of the United States
of America 83, 5909–5913.
Nishino, K., Honda, T. and Yamaguchi, A. (2005). Genome-wide analyses of Escherichia
coli gene expression responsive to the BaeSR two-component regulatory
system. Journal of Bacteriology 187, 1763–1772.
Nixon, B. T., Ronson, C. W. and Ausubel, F. M. (1986). Two-component regulatory
systems responsive to environmental stimuli share strongly conserved domains with
the nitrogen assimilation regulatory genes ntrB and ntrC. Proceedings of the National
Academy of Sciences of the United States of America 83, 7850–7854.
Nomura, S., Horiuchi, T., Ōmura, S. and Hata, T. (1972). The action mechanism of cerulenin:
effect of cerulenin on sterol and fatty acid biosyntheses in yeast. The Journal
of Biochemistry 71, 783–796.
Novichkov, P. S., Kazakov, A. E., Ravcheev, D. A., Leyn, S. A., Kovaleva, G. Y., Sutormin,
R. A., Kazanov, M. D., Riehl, W., Arkin, A. P., Dubchak, I. and Rodionov,
D. A. (2013). RegPrecise 3.0 - a resource for genome-scale exploration of transcriptional
regulation in bacteria. BMC Genomics 14, 745.
Nowroozi, F. F., Baidoo, E. E. K., Ermakov, S., Redding-Johanson, A. M., Batth, T. S.,
Petzold, C. J. and Keasling, J. D. (2014). Metabolic pathway optimization using ribosome
binding site variants and combinatorial gene assembly. Applied Microbiology
and Biotechnology 98, 1567–1581.
Okuda, K., Kato, S., Ito, T., Shiraki, S., Kawase, Y., Goto, M., Kawashima, S., Hemmi,
H., Fukada, H. and Yoshimura, T. (2015). Role of the aminotransferase domain in Bacillus subtilis GabR, a pyridoxal 5′-phosphate-dependent transcriptional regulator.
Molecular Microbiology 95, 245–257.
Otero, J. M., Cimini, D., Patil, K. R., Poulsen, S. G., Olsson, L. and Nielsen, J. (2013).
Industrial systems biology of Saccharomyces cerevisiae enables novel succinic acid
cell factory. PLOS ONE 8(1), e54144.
Otero-Muras, I., Mannan, A. A., Banga, J. R. and Oyarzún, D. A. (2019). Multiobjective
optimization of gene circuits for metabolic engineering. IFAC-PapersOnLine 52, 13–
16.
Ozcan, S. and Johnston, M. (1995). Three different regulatory mechanisms enable yeast
hexose transporter (HXT) genes to be induced by different levels of glucose. Molecular
and Cellular Biology 15, 1564–1572.
Palomares, L. A., Estrada-Moncada, S. and Ramírez, O. T. (2004). Production of recombinant
proteins. In: Recombinant Gene Expression: Reviews and Protocols (P. Balbás
and A. Lorence, eds). 2 edn. Humana Press. Totowa, NJ, USA. pp. 15–52.
Pastan, I. and Adhya, S. (1976). Cyclic adenosine 5’-monophosphate in Escherichia coli.
Bacteriological Reviews 40, 527–551.
Pelletier, J. and Sonenberg, N. (1985). Insertion mutagenesis to increase secondary structure
within the 5′ noncoding region of a eukaryotic mRNA reduces translational efficiency.
Cell 40, 515–526.
Pérez-Rueda, E. and Janga, S. C. (2010). Identification and genomic analysis of transcription
factors in Archaeal genomes exemplifies their functional architecture and
evolutionary origin. Molecular Biology and Evolution 27, 1449–1459.
Perutz, M. F. (1980). Review lecture - stereochemical mechanism of oxygen transport
by haemoglobin. Proceedings of the Royal Society of London. Series B. Biological
Sciences 208, 135–162.
Pfeifer, E., Gätgens, C., Polen, T. and Frunzke, J. (2017). Adaptive laboratory evolution
of Corynebacterium glutamicum towards higher growth rates on glucose minimal
medium. Scientific Reports 7, 16780.
Pharkya, P., Burgard, A. P. and Maranas, C. D. (2004). OptStrain: a computational
framework for redesign of microbial production systems. Genome Research 14, 2367–
2376.
Pigou, M. and Morchain, J. (2015). Investigating the interactions between physical and
biological heterogeneities in bioreactors using compartment, population balance and
metabolic models. Chemical Engineering Science 126, 267–282.
Pittard, A. J. and Davidson, B. E. (1991). TyrR protein of Escherichia coli and its role
as repressor and activator. Molecular Microbiology 5, 1585–1592.
Platko, J. V. and Calvo, J. M. (1993). Mutations affecting the ability of Escherichia coli
Lrp to bind DNA, activate transcription, or respond to leucine. Journal of Bacteriology
175, 1110–1117.
Platko, J. V., Willins, D. A. and Calvo, J. M. (1990). The ilvIH operon of Escherichia
coli is positively regulated. Journal of Bacteriology 172, 4563–4570.
Pohlmann, A., Fricke, W. F., Reinecke, F., Kusian, B., Liesegang, H., Cramm,
R., Eitinger, T., Ewering, C., Pötter, M., Schwartz, E., Strittmatter, A., Voß, I.,
Gottschalk, G., Steinbüchel, A., Friedrich, B. and Bowien, B. (2006). Genome sequence
of the bioplastic-producing “Knallgas” bacterium Ralstonia eutropha H16.
Nature Biotechnology 24, 1257–1262.
Qin, L., Dong, S., Yu, J., Ning, X., Xu, K., Zhang, S. J., Xu, L., Li, B. Z., Li, J., Yuan,
Y. J. and Li, C. (2020). Stress-driven dynamic regulation of multiple tolerance genes
improves robustness and productive capacity of Saccharomyces cerevisiae in industrial
lignocellulose fermentation. Metabolic Engineering 61, 160–170.
Qin, L., Liu, X., Xu, K. and Li, C. (2022). Mining and design of biosensors for engineering
microbial cell factory. Current Opinion in Biotechnology 75, 102694.
R Core Team (2022). R: a language and environment for statistical computing.
URL: https://www.r-project.org/
Rajaraman, E., Agarwal, A., Crigler, J., Seipelt-Thiemann, R., Altman, E. and Eiteman,
M. A. (2016). Transcriptional analysis and adaptive evolution of Escherichia
coli strains growing on acetate. Applied Microbiology and Biotechnology 100, 7777–
7785.
Raman, S., Rogers, J. K., Taylor, N. D. and Church, G. M. (2014). Evolution-guided
optimization of biosynthetic pathways. Proceedings of the National Academy of Sciences
of the United States of America 111, 17803–17808.
Rathnasingh, C., Raj, S. M., Lee, Y., Catherine, C., Somasundar, A. and Park, S. (2012).
Production of 3-hydroxypropionic acid via malonyl-CoA pathway using recombinant
Escherichia coli strains. Journal of Biotechnology 157, 633–640.
Raue, A., Becker, V., Klingmüller, U. and Timmer, J. (2010). Identifiability and observability
analysis for experimental design in nonlinear dynamical models. Chaos: An
Interdisciplinary Journal of Nonlinear Science 20, 045105.
Raue, A., Kreutz, C., Maiwald, T., Bachmann, J., Schilling, M., Klingmüller, U.
and Timmer, J. (2009). Structural and practical identifiability analysis of partially
observed dynamical models by exploiting the profile likelihood. Bioinformatics
25, 1923–1929.
Raue, A., Kreutz, C., Maiwald, T., Klingmüller, U. and Timmer, J. (2011). Addressing
parameter identifiability by model-based experimentation. IET Systems Biology
5, 120–130.
Raue, A., Schilling, M., Bachmann, J., Matteson, A., Schelker, M., Kaschek, D., Hug,
S., Kreutz, C., Harms, B. D., Theis, F. J., Klingmüller, U. and Timmer, J. (2013).
Lessons learned from quantitative dynamical modeling in systems biology. PLOS
ONE 8(9), e74335.
Ravikumar, S., Baylon, M. G., Park, S. J. and Choi, J.-i. (2017). Engineered microbial
biosensors based on bacterial two-component systems as synthetic biotechnology
platforms in bioremediation and biorefinery. Microbial Cell Factories 16, 62.
Ravikumar, S., Yoo, I.-k., Lee, S. Y. and Hong, S. H. (2011). A study on the dynamics
of the zraP gene expression profile and its application to the construction of zinc
adsorption bacteria. Bioprocess and Biosystems Engineering 34, 1119.
Razin, S., Bachrach, U. and Gery, I. (1958). Formation of β-alanine from spermine and
spermidine by Pseudomonas aeruginosa. Nature 181, 700–701.
Riehle, M. M., Bennett, A. F., Lenski, R. E. and Long, A. D. (2003). Evolutionary
changes in heat-inducible gene expression in lines of Escherichia coli adapted to high
temperature. Physiological Genomics 14, 47–58.
Rogers, J. K. and Church, G. M. (2016a). Genetically encoded sensors enable real-time
observation of metabolite production. Proceedings of the National Academy of Sciences
of the United States of America 113, 2388–2393.
Rogers, J. K. and Church, G. M. (2016b). Multiplexed engineering in biology. Trends in
Biotechnology 34, 198–206.
Rogers, J. K., Guzman, C. D., Taylor, N. D., Raman, S., Anderson, K. and Church,
G. M. (2015). Synthetic biosensors for precise gene control and real-time monitoring
of metabolites. Nucleic Acids Research 43, 7648–7660.
Rogers, J. K., Taylor, N. D. and Church, G. M. (2016). Biosensor-based engineering of
biosynthetic pathways. Current Opinion in Biotechnology 42, 84–91.
Rossbach, S., Kulpa, D. A., Rossbach, U. and de Bruijn, F. J. (1994). Molecular and
genetic characterization of the rhizopine catabolism (mocABRC) genes of Rhizobium
meliloti L5-30. Molecular and General Genetics 245(1), 11–24.
Sandberg, T. E., Lloyd, C. J., Palsson, B. O. and Feist, A. M. (2017). Laboratory evolution
to alternating substrate environments yields distinct phenotypic and genetic
adaptive strategies. Applied and Environmental Microbiology 83(13), e00410–17.
Sandberg, T. E., Salazar, M. J., Weng, L. L., Palsson, B. O. and Feist, A. M. (2019).
The emergence of adaptive laboratory evolution as an efficient tool for biological
discovery and industrial biotechnology. Metabolic Engineering 56, 1–16.
Santoro, S. W., Wang, L., Herberich, B., King, D. S. and Schultz, P. G. (2002). An
efficient system for the evolution of aminoacyl-tRNA synthetase specificity. Nature
Biotechnology 20, 1044–1048.
Savidor, A., Chalupowicz, L., Teper, D., Gartemann, K. H., Eichenlaub, R., Manulis-
Sasson, S., Barash, I. and Sessa, G. (2014). Clavibacter michiganensis subsp. michiganensis
Vatr1 and Vatr2 transcriptional regulators are Required for virulence in tomato.
Molecular Plant-Microbe Interactions 27, 1035–1047.
Schneider, F., Krämer, R. and Burkovski, A. (2004). Identification and characterization
of the main β-alanine uptake system in Escherichia coli. Applied Microbiology and
Biotechnology 65, 576–582.
Schneider, T. D. and Stephens, R. M. (1990). Sequence logos: a new way to display
consensus sequences. Nucleic Acids Research 18, 6097.
Scholten, M. and Tommassen, J. (1993). Topology of the PhoR protein of Escherichia
coli and functional analysis of internal deletion mutants. Molecular Microbiology
8, 269–275.
Schujman, G. E., Paoletti, L., Grossman, A. D. and de Mendoza, D. (2003). FapR, a
bacterial transcription factor involved in global regulation of membrane lipid biosynthesis.
Developmental Cell 4, 663–672.
Seok, J. Y., Han, Y. H., Yang, J.-S., Yang, J., Lim, H. G., Kim, S. G., Seo, S. W.
and Jung, G. Y. (2021). Synthetic biosensor accelerates evolution by rewiring carbon
metabolism toward a specific metabolite. Cell Reports 36, 109589.
Seok, J. Y., Yang, J., Choi, S. J., Lim, H. G., Choi, U. J., Kim, K. J., Park, S., Yoo, T. H.
and Jung, G. Y. (2018). Directed evolution of the 3-hydroxypropionic acid production
pathway by engineering aldehyde dehydrogenase using a synthetic selection device.
Metabolic Engineering 47, 113–120.
Setny, P. and Wiśniewska, M. D. (2018). Water-mediated conformational preselection
mechanism in substrate binding cooperativity to protein kinase A. Proceedings of the
National Academy of Sciences of the United States of America 115, 3852–3857.
Shrivastava, T., Dey, A. and Ramachandran, R. (2009). Ligand-induced structural
transitions, mutational analysis, and ‘open’ quaternary structure of the M. tuberculosis
Feast/Famine Regulatory Protein (Rv3291c). Journal of Molecular Biology
392, 1007–1019.
Slotnick, I. J. and Weinfeld, H. (1957). Dihydrouracil as a growth factor for mutant
strains of Escherichia coli. Journal of Bacteriology 74, 122–125.
Somasundar, A., Raj, S. M., Rathnasingh, C. and Park, S. (2011). Development
of recombinant Klebsiella pneumoniae dhaT strain for the co-production of 3-
hydroxypropionic acid and 1,3-propanediol from glycerol. Applied Microbiology and
Biotechnology 90, 1253–1265.
Sonderegger, M. and Sauer, U. (2003). Evolutionary engineering of Saccharomyces
cerevisiae for anaerobic growth on xylose. Applied and Environmental Microbiology
69, 1990–1998.
Song, C. W., Kim, J. W., Cho, I. J. and Lee, S. Y. (2016). Metabolic engineering of Escherichia
coli for the production of 3-hydroxypropionic acid and malonic acid through β-alanine route. ACS Synthetic Biology 5, 1256–1263.
Song, N., Nguyen Duc, T., van Oeffelen, L., Muyldermans, S., Peeters, E. and Charlier,
D. (2013). Expanded target and cofactor repertoire for the transcriptional activator
LysM from Sulfolobus. Nucleic Acids Research 41, 2932–2949.
Stock, A. M., Robinson, V. L. and Goudreau, P. N. (2000). Two-component signal transduction.
Annual Review of Biochemistry 69, 183–215.
Stoebel, D. M., Hokamp, K., Last, M. S. and Dorman, C. J. (2009). Compensatory evolution
of gene regulation in response to stress by Escherichia coli lacking RpoS. PLOS
Genetics 5(10), e1000671.
Stoeckle, M. Y. and Hanafusa, H. (1989). Processing of 9E3 mRNA and regulation of its
stability in normal and Rous sarcoma virus-transformed cells. Molecular and Cellular
Biology 9, 4738–4745.
Sullivan, M. J., Curson, A. R., Shearer, N., Todd, J. D., Green, R. T. and Johnston,
A. W. (2011). Unusual regulation of a leaderless operon involved in the catabolism of
dimethylsulfoniopropionate in Rhodobacter sphaeroides. PLOS ONE 6(1), e15972.
Suvorova, I. A. and Rodionov, D. A. (2016). Comparative genomics of pyridoxal 5’-
phosphate-dependent transcription factor regulons in Bacteria. Microbial genomics
2(1).
Sybers, D., Bernauw, A. J., El Masri, D., Maklad, H. R., Charlier, D., De Mey, M.,
Bervoets, I. and Peeters, E. (2022). Engineering transcriptional regulation in Escherichia
coli using an archaeal TetR-family transcription factor. Gene 809, 146010.
Takenaka, T., Ito, T., Miyahara, I., Hemmi, H. and Yoshimura, T. (2015). A new member
of MocR/GabR-type PLP-binding regulator of d-alanyl-d-alanine ligase in Brevibacillus
brevis. The FEBS Journal 282, 4201–4217.
Tanna, T., Ramachanderan, R. and Platt, R. J. (2021). Engineered bacteria to report gut
function: technologies and implementation. Current Opinion in Microbiology 59, 24–
33.
Teo, W. S. and Chang, M. W. (2015). Bacterial XylRs and synthetic promoters function
as genetically encoded xylose biosensors in Saccharomyces cerevisiae. Biotechnology
Journal 10, 315–322.
Teo, W. S., Hee, K. S. and Chang, M. W. (2013). Bacterial FadR and synthetic promoters
function as modular fatty acid sensor-regulators in Saccharomyces cerevisiae.
Engineering in Life Sciences 13, 456–463.
Thi Nguyen, T., Lama, S., Kumar Ainala, S., Sankaranarayanan, M., Singh Chauhan,
A., Rae Kim, J. and Park, S. (2021). Development of Pseudomonas asiatica as a host
for the production of 3-hydroxypropionic acid from glycerol. Bioresource Technology
329, 124867.
Torres-Bacete, J., García, J. L. and Nogales, J. (2021). A portable library of phosphatedepletion
based synthetic promoters for customable and automata control of gene expression
in bacteria. Microbial Biotechnology 14, 2643–2658.
Transtrum, M. K., Machta, B. B. and Sethna, J. P. (2010). Why are nonlinear fits to data
so challenging?. Physical Review Letters 104, 060201.
Transtrum, M. K., Machta, B. B. and Sethna, J. P. (2011). Geometry of nonlinear least
squares with applications to sloppy models and optimization. Physical Review E -
Statistical, Nonlinear, and Soft Matter Physics 83, 036701.
Transtrum, M. K. and Qiu, P. (2012). Optimal experiment selection for parameter estimation
in biological differential equation models. BMC Bioinformatics 13, 181.
Trausch, J. J. and Batey, R. T. (2015). Design of modular “plug-and-play” expression
platforms derived from natural riboswitches for engineering novel genetically encodable
RNA regulatory devices. In: Riboswitches as Targets and Tools (D. H. Burke-
Aguero, ed.). Vol. 550. Academic Press. Cambridge, MA, USA. pp. 41–71.
Tuerk, C. and Gold, L. (1990). Systematic evolution of ligands by exponential enrichment:
RNA ligands to bacteriophage T4 DNA polymerase. Science 249, 505–510.
Ulrich, L. E., Koonin, E. V. and Zhulin, I. B. (2005). One-component systems dominate
signal transduction in prokaryotes. Trends in Microbiology 13, 52–56.
Uluşeker, C., Torres-Bacete, J., García, J. L., Hanczyc, M. M., Nogales, J. and Kahramanoğulları,
O. (2019). Quantifying dynamic mechanisms of auto-regulation in Escherichia
coli with synthetic promoter in response to varying external phosphate levels.
Scientific Reports 9, 2076.
Umeyama, T., Okada, S. and Ito, T. (2013). Synthetic gene circuit-mediated monitoring
of endogenous metabolites: identification of GAL11 as a novel multicopy enhancer
of S-adenosylmethionine level in yeast. ACS Synthetic Biology 2, 425–430.
U.S. EPA (1996). Method 8315A (SW-846): determination of carbonyl compounds by
high performance liquid chromatography (HPLC).
Utrilla, J., Licona-Cassani, C., Marcellin, E., Gosset, G., Nielsen, L. K. and Martinez,
A. (2012). Engineering and adaptive evolution of Escherichia coli for d-lactate fermentation
reveals GatC as a xylose transporter. Metabolic Engineering 14, 469–476.
van Hijum, S. A. F. T., Medema, M. H. and Kuipers, O. P. (2009). Mechanisms and
evolution of control logic in prokaryotic transcriptional regulation. Microbiology and
Molecular Biology Reviews 73, 481–509.
Van Rossum, G. and Drake, F. L. (2009). Python 3 Reference Manual. CreateSpace.
Scotts Valley, CA, USA.
Vandamme, P. and Coenye, T. (2004). Taxonomy of the genus Cupriavidus: a tale of
lost and found. International Journal of Systematic and Evolutionary Microbiology
54, 2285–2289.
Vanden Berghen, F. (2004). Levenberg-Marquardt algorithms vs trust region algorithms.
URL: https://www.applied-mathematics.net/LMvsTR/LMvsTR.pdf
Vassart, A., Van Wolferen, M., Orell, A., Hong, Y., Peeters, E., Albers, S.-V. and
Charlier, D. (2013). Sa-Lrp from Sulfolobus acidocaldarius is a versatile, glutamineresponsive,
and architectural transcriptional regulator. MicrobiologyOpen 2, 75–93.
Verhamme, D. T., Arents, J. C., Postma, P. W., Crielaard, W. and Hellingwerf, K. J.
(2002). Investigation of in vivo cross-talk between key two-component systems of
Escherichia coli. Microbiology 148, 69–78.
Verma, B. K., Mannan, A. A., Zhang, F. and Oyarzún, D. A. (2022). Trade-offs in biosensor
optimization for dynamic pathway engineering. ACS Synthetic Biology 11, 228–
240.
von Kamp, A. and Klamt, S. (2017). Growth-coupled overproduction is feasible for
almost all metabolites in five major production organisms. Nature Communications
8, 15956.
Wachsmuth, M., Domin, G., Lorenz, R., Serfling, R., Findeiß, S., Stadler, P. F. and
Mörl, M. (2015). Design criteria for synthetic riboswitches acting on transcription.
RNA Biology 12, 221–231.
Wachsmuth, M., Findeiß, S., Weissheimer, N., Stadler, P. F. and Mörl, M. (2013). De
novo design of a synthetic riboswitch that regulates transcription termination. Nucleic
Acids Research 41, 2541–2551.
Wang, B., Barahona, M. and Buck, M. (2015). Amplification of small moleculeinducible
gene expression via tuning of intracellular receptor densities. Nucleic Acids
Research 43, 1955–1964.
Wang, C., Liwei, M., Park, J. B., Jeong, S. H., Wei, G., Wang, Y. and Kim, S. W. (2018).
Microbial platform for terpenoid production: Escherichia coli and yeast. Frontiers in
Microbiology 9, 2460.
Wang, K., Sybers, D., Maklad, H. R., Lemmens, L., Lewyllie, C., Zhou, X., Schult,
F., Bräsen, C., Siebers, B., Valegård, K., Lindås, A.-C. and Peeters, E. (2019). A
TetR-family transcription factor regulates fatty acid metabolism in the archaeal model
organism Sulfolobus acidocaldarius. Nature Communications 10, 1542.
Wanner, B. L. (1992). Is cross regulation by phosphorylation of two-component response
regulator proteins important in bacteria?. Journal of Bacteriology 174, 2053–2058.
Wanner, B. L. (1993). Gene regulation by phosphate in enteric bacteria. Journal of Cellular
Biochemistry 51, 47–54.
Wanner, B. L. (1996). Phosphorus assimilation and control of the phosphate regulon. In:
Escherichia coli and Salmonella: Cellular and Molecular Biology (F. C. Neidhardt,
R. Curtiss III, J. L. Ingraham, E. C. C. Lin, K. B. Low, B. Magasanik, W. S. Reznikoff,
M. Riley, M. Schaechter and H. E. Umbarger, eds). 2 edn. American Society for Microbiology.
Washington, DC, USA. pp. 1357–1381.
Wanner, B. L., Wilmes, M. R. and Young, D. C. (1988). Control of bacterial alkaline
phosphatase synthesis and variation in an Escherichia coli K-12 phoR mutant by
adenyl cyclase, the cyclic AMP receptor protein, and the phoM operon. Journal of
Bacteriology 170, 1092–1102.
Wanner, B. L. and Wilmes-Riesenberg, M. R. (1992). Involvement of phosphotransacetylase,
acetate kinase, and acetyl phosphate synthesis in control of the phosphate
regulon in Escherichia coli. Journal of Bacteriology 174, 2124–2130.
Waterfall, J. J., Casey, F. P., Gutenkunst, R. N., Brown, K. S., Myers, C. R., Brouwer,
P. W., Elser, V. and Sethna, J. P. (2006). Sloppy-model universality class and the
Vandermonde matrix. Physical Review Letters 97, 150601.
Werner, F. and Grohmann, D. (2011). Evolution of multisubunit RNA polymerases in
the three domains of life. Nature Reviews Microbiology 9, 85–98.
Wieland, F.-G., Hauber, A. L., Rosenblatt, M., Tönsing, C. and Timmer, J. (2021). On
structural and practical identifiability. Current Opinion in Systems Biology 25, 60–69.
Win, M. N. and Smolke, C. D. (2007). A modular and extensible RNA-based generegulatory
platform for engineering cellular function. Proceedings of the National
Academy of Sciences of the United States of America 104, 14283–14288.
Winkler, W. C., Cohen-Chalamish, S. and Breaker, R. R. (2002). An mRNA structure
that controls gene expression by binding FMN. Proceedings of the National Academy
of Sciences of the United States of America 99, 15908–15913.
Winkler, W. C., Nahvi, A., Roth, A., Collins, J. A. and Breaker, R. R. (2004). Control of
gene expression by a natural metabolite-responsive ribozyme. Nature 428, 281–286.
Woods, A., Munday, M. R., Scott, J., Yang, X., Carlson, M. and Carling, D. (1994). Yeast
SNF1 is functionally related to mammalian AMP-activated protein kinase and regulates
acetyl-CoA carboxylase in vivo. Journal of Biological Chemistry 269, 19509–
19515.
Woolston, B. M., Roth, T., Kohale, I., Liu, D. R. and Stephanopoulos, G. (2018). Development
of a formaldehyde biosensor with application to synthetic methylotrophy.
Biotechnology and Bioengineering 115, 206–215.
Wu, Y., Chen, T., Liu, Y., Tian, R., Lv, X., Li, J., Du, G., Chen, J., Ledesma-Amaro, R.
and Liu, L. (2020). Design of a programmable biosensor-CRISPRi genetic circuits for
dynamic and autonomous dual-control of metabolic flux in Bacillus subtilis. Nucleic
Acids Research 48, 996–1009.
Wu, Y., Du, G., Chen, J. and Liu, L. (2020). Genetically encoded biosensors and their
applications in the development of microbial cell factories. In: Engineering of Microbial
Biosynthetic Pathways (V. Singh, A. K. Singh, P. Bhargava, M. Joshi and C. G.
Joshi, eds). Springer. Singapore, Singapore. pp. 53–73.
Wuichet, K., Cantwell, B. J. and Zhulin, I. B. (2010). Evolution and phyletic distribution
of two-component signal transduction systems. Current Opinion in Microbiology
13(2), 219–225.
Xu, P. (2018). Production of chemicals using dynamic control of metabolic fluxes. Current
Opinion in Biotechnology 53, 12–19.
Xu, X., Li, X., Liu, Y., Zhu, Y., Li, J., Du, G., Chen, J., Ledesma-Amaro, R. and
Liu, L. (2020). Pyruvate-responsive genetic circuits for dynamic control of central
metabolism. Nature Chemical Biology 16, 1261–1268.
Yamada, E. W. and Jakoby, W. B. (1960). Aldehyde oxidation: V. direct conversion
of malonic semialdehyde to acetyl-coenzyme A. Journal of Biological Chemistry
235, 589–594.
Yanofsky, C. (1981). Attenuation in the control of expression of bacterial operons. Nature
289, 751–758.
Yu, S., Zhao, Q., Miao, X. and Shi, J. (2013). Enhancement of lipid production in lowstarch
mutants Chlamydomonas reinhardtii by adaptive laboratory evolution. Bioresource
Technology 147, 499–507.
Zhang, J., Wang, Z., Su, T., Sun, H., Zhu, Y., Qi, Q. and Wang, Q. (2020). Tuning
the binding affinity of heme-responsive biosensor for precise and dynamic pathway
regulation. iScience 23, 101067.
Zhang, Q., Bhattacharya, S. and Andersen, M. E. (2013). Ultrasensitive response motifs:
basic amplifiers in molecular signalling networks. Open Biology 3, 130031.
Zhang, Y., Werling, U. and Edelmann, W. (2012). SLiCE: a novel bacterial cell extractbased
DNA cloning method. Nucleic Acids Research 40, e55.
Zhao, M., Wang, M., Zhang, X., Zhu, Y., Cao, J., She, Y., Cao, Z., Li, G., Wang, J. and
Abd El-Aty, A. M. (2021). Recognition elements based on the molecular biological
techniques for detecting pesticides in food: a review. Critical Reviews in Food Science
and Nutrition .
Zhou, L., Grégori, G., Blackman, J. M., Robinson, J. P. and Wanner, B. L. (2005).
Stochastic activation of the response regulator PhoB by noncognate histidine kinases.
Journal of Integrative Bioinformatics 2(1), 10–22.
Zhou, S., Ainala, S. K., Seol, E., Nguyen, T. T. and Park, S. (2015). Inducible gene
expression system by 3-hydroxypropionic acid. Biotechnology for Biofuels 8, 169.
Zhou, S., Catherine, C., Rathnasingh, C., Somasundar, A. and Park, S. (2013). Production
of 3-hydroxypropionic acid from glycerol by recombinant Pseudomonas denitrificans.
Biotechnology and Bioengineering 110, 3177–3187.
Zhu, H., Mao, X.-J., Guo, X.-P. and Sun, Y.-C. (2016). The hmsT 3′ untranslated region
mediates c-di-GMP metabolism and biofilm formation in Yersinia pestis. Molecular
Microbiology 99, 1167–1178.
Zhu, Y., Li, Y., Xu, Y., Zhang, J., Ma, L., Qi, Q. and Wang, Q. (2021). Development
of bifunctional biosensors for sensing and dynamic control of glycolysis flux
in metabolic engineering. Metabolic Engineering 68, 142–151.
Ziegler, C. A. and Freddolino, P. L. (2021). The leucine-responsive regulatory
proteins/feast-famine regulatory proteins: an ancient and complex class of transcriptional
regulators in bacteria and archaea. Critical Reviews in Biochemistry and Molecular
Biology 56(4), 373–400.
Zobel, S., Benedetti, I., Eisenbach, L., de Lorenzo, V., Wierckx, N. and Blank,
L. M. (2015). Tn7-based device for calibrated heterologous gene expression in Pseudomonas
putida. ACS Synthetic Biology 4, 1341–1351.
Zorraquino-Salvo, V., Quinones-Soto, S., Kim, M., Rai, N. and Tagkopoulos, I. (2014).
Deciphering the genetic and transcriptional basis of cross-stress responses in Escherichia
coli under complex evolutionary scenarios. bioRxiv p. 10595.
Zubay, G., Schwartz, D. and Beckwith, J. (1970). Mechanism of activation of catabolitesensitive
genes: a positive control system. Proceedings of the National Academy of
Sciences of the United States of America 66, 104–110.
Zweigenbaum, J., Heinig, K., Steinborner, S., Wachs, T. and Henion, J. (1999). Highthroughput
bioanalytical LC/MS/MS determination of benzodiazepines in human
urine: 1000 samples per 12 hours. Analytical Chemistry 71, 2294–2300.

Universiteit of Hogeschool
Bio-ingenieurswetenschappen: cel- en genbiotechnologie
Publicatiejaar
2022
Promotor(en)
Prof. Dr. ir. Eveline Peeters, Prof. Dr. Sophie de Buyl
Kernwoorden
Share this on: