Biyofarmasötik Keşif, Geliştirme ve Üretimin Güncel Paradigması Olarak Mikroorganizmaların Metabolik Mühendisliği: Sentetik Biyolojinin Katkıları

Yıl 2022, Cilt: 11 Sayı: 2, 427 - 458, 30.12.2022

Esra Gül , Venhar Çelik

https://doi.org/10.55007/dufed.1187305

Öz

Farmasötik endüstrisinde doğal bileşikler ve türevler önemli bir rol oynar. Ancak bu ürünlerin doğal konaktan izole edilmesindeki veya yeniden kimyasal olarak sentezlenmesindeki zorluklar, genellikle bunların bulunabilirliğini sınırlar, maliyeti yükseltir ve biyofarmasötik üretim sürecini yavaşlatır. Farmasötik metabolik mühendisliği, ilaçların ve ayrıca ilaç öncüllerinin keşif, tasarım ve üretiminde önemli bir rol oynamaktadır. Mikroorganizmaların daha yüksek titreler ve daha az maliyetle büyütülme kolaylığı nedeniyle küçük moleküllü ilaçların heterolog olarak bir mikrobiyal konakta yüksek hızda, düşük maliyet ve yüksek verimle istikrarlı olarak üretilmesi, bitkiler gibi doğal konaklarda üretimine veya kimyasal sentezine göre giderek daha popüler bir alternatif haline gelmektedir. Metabolik mühendisliği, mikroorganizmalar, bitkiler ve hayvanlardaki belirli genetik farklılıkların fizyolojik sonuçlarını inceleyerek ve ayrıca genler ve hücre fonksiyonları arasındaki bağlantıları anlamak için matematiksel ve hesaplamalı yöntemler tasarlayarak yeni mikrobiyal hücre fabrikalarının geliştirilmesine ve mevcut endüstriyel organizmaların iyileştirilmesine olanak tanır. Mikroorganizmalardaki endojenik metabolik yolaklarla çeşitli heterolog biyosentetik yolakların entegre edilerek yeni sentetik yolakların tasarlanması, inşası ve optimizasyonu için sentetik biyoloji metodolojilerini kullanır. Metabolik olarak tasarlanmış organizmaların optimizasyonu, bu endojenik ve heterolog yolak proteinlerinin dengeli düzeylerde üretilmesinin iyi anlaşılmasını gerektirir. Böylece, metabolik mühendisliğinin uygulanması, tüm üretim sürecini hızlandırmayı amaçlayan heterolog mikroorganizmalarda büyük miktarlarda biyofarmasötiklerin verimli bir şekilde üretilmesini sağlayabilir. Bu derleme çalışmasında biyofarmasötiklerin metabolik mühendisliği yaklaşımıyla mikrobiyal hücre fabrikalarında üretiminin tasarlanması, üretimi ve optimizasyon koşulları incelenmiştir.

Anahtar Kelimeler

Metabolik mühendisliği, Sentetik biyoloji, Biyofarmasötik, Mikroorganizma, Heterolog

Destekleyen Kurum

TUBİTAK

Proje Numarası

117M051

Teşekkür

Bu çalışma TUBİTAK 117M051 Nolu 1001 projesi ile desteklenmiştir.

Metabolic Engineering of Microorganisms as the Current Paradigm of Biopharmaceutical Discovery, Development and Production: Contributions of Synthetic Biology

Öz

Natural compounds and derivatives play an important role in the pharmaceutical industry. However, difficulties in isolating or chemically resynthesizing these products from the natural host often limit their availability, increase costs, and slow down the biopharmaceutical production process. Pharmaceutical metabolic engineering plays an important role in the discovery, design and manufacture of drugs as well as drug precursors. Because of the ease with which microorganisms are grown at higher titers and less costly, the stable production of small molecule drugs heterologously in a microbial host at high speed, low cost, and high yield is becoming an increasingly popular alternative to their production or chemical synthesis in natural hosts such as plants. Metabolic engineering allows the development of new microbial cell factories and refinement of existing industrial organisms by examining the physiological consequences of certain genetic differences in microorganisms, plants and animals, as well as designing mathematical and computational methods to understand the links between genes and cell functions. It uses synthetic biology methodologies to design, construct and optimize new synthetic pathways by integrating various heterologous biosynthetic pathways with endogenous metabolic pathways in microorganisms. Optimizing metabolically engineered organisms requires a good understanding of the production of these endogenic and heterologous pathway proteins at balanced levels. Thus, the application of metabolic engineering can enable the efficient production of large quantities of biopharmaceuticals in heterologous microorganisms aimed at speeding up the entire production process. In this review study, the design, production and optimization conditions of the production of biopharmaceuticals in microbial cell factories with the metabolic engineering approach were examined.

Anahtar Kelimeler

Metabolic engineering, Synthetic biology, Biopharmaceutical, Microorganism, Heterologous

Proje Numarası

117M051

Kaynakça

• T. U. Chae, S. Y. Choi, J. W. Kim, Y.-S. Ko, and S. Y. Lee, “Recent advances in systems metabolic engineering tools and strategies,” Current Opinion in Biotechnology, vol. 47, pp. 67–82, 2017.
• A. J. van Maris, D. A. Abbott, E. Bellissimi, J. van den Brink, M. Kuyper, M. A. Luttik, H. W. Wisselink, W. A. Scheffers, J. P. van Dijken, and J. T. Pronk, “Alcoholic fermentation of carbon sources in biomass hydrolysates by saccharomyces cerevisiae: Current status,” Antonie van Leeuwenhoek, vol. 90, no. 4, pp. 391–418, 2006.
• S. Raman, J. K. Rogers, N. D. Taylor, and G. M. Church, “Evolution-guided optimization of biosynthetic pathways,” Proceedings of the National Academy of Sciences, vol. 111, no. 50, pp. 17803–17808, 2014.
• M. Falb, K. Müller, L. Königsmaier, T. Oberwinkler, P. Horn, S. von Gronau, O. Gonzalez, F. Pfeiffer, E. Bornberg-Bauer, and D. Oesterhelt, “Metabolism of halophilic archaea,” Extremophiles, vol. 12, no. 2, pp. 177–196, 2008.
• S. Y. Lee, H. U. Kim, J. H. Park, J. M. Park, and T. Y. Kim, “Metabolic Engineering of Microorganisms: General strategies and drug production,” Drug Discovery Today, vol. 14, no. 1-2, pp. 78–88, 2009.
• J. Nielsen, “Production of biopharmaceutical proteins by yeast,” Bioengineered, vol. 4, no. 4, pp. 207–211, 2013.
• L. B. Pickens, Y. Tang, and Y.-H. Chooi, “Metabolic Engineering for the production of natural products,” Annual Review of Chemical and Biomolecular Engineering, vol. 2, no. 1, pp. 211–236, 2011.
• A. Dasgupta, N. Chowdhury, and R. K. De, “Metabolic pathway engineering: Perspectives and Applications,” Computer Methods and Programs in Biomedicine, vol. 192, pp. 105436, 2020.
• A. Stryjewska, K. Kiepura, T. Librowski, and S. Lochyński, “Biotechnology and genetic engineering in the new drug development. part III. Biocatalysis, Metabolic Engineering and Molecular Modelling,” Pharmacological Reports, vol. 65, no. 5, pp. 1102–1111, 2013.
• K. Deo Pandey, “Metabolic Engineering: New Era in Pharmaceuticals,” Global Journal of Pharmacy & Pharmaceutical Sciences, vol. 2, no. 5, 2017.
• S. Mandal, M. Moudgil, and S. K. Mandal, “Rational drug design,” European Journal of Pharmacology, vol. 625, no. 1-3, pp. 90–100, 2009.
• L. Satish, Y. Seher, K. Rakkammal, P. Muthuramalingam, C. R. Lakshmi, A. Hemasundar, K. Prasanth, S. Shamili, M. K. Swamy, M. S. Dhanarajan, and M. Ramesh, “Metabolic engineering strategies to enhance the production of anticancer drug, Paclitaxel,” Paclitaxel, pp. 229–250, 2022.
• A. M. Redding-Johanson, T. S. Batth, R. Chan, R. Krupa, H. L. Szmidt, P. D. Adams, J. D. Keasling, T. Soon Lee, A. Mukhopadhyay, and C. J. Petzold, “Targeted proteomics for metabolic pathway optimization: Application to terpene production,” Metabolic Engineering, vol. 13, no. 2, pp. 194–203, 2011.
• A. Sarnaik, M. H. Abernathy, X. Han, Y. Ouyang, K. Xia, Y. Chen, B. Cress, F. Zhang, A. Lali, R. Pandit, R. J. Linhardt, Y. J. Tang, and M. A. G. Koffas, “Metabolic Engineering of cyanobacteria for photoautotrophic production of heparosan, a pharmaceutical precursor of heparin,” Algal Research, vol. 37, pp. 57–63, 2019.
• J. Zhu, L. Li, F. Wu, Y. Wu, Z. Wang, X. Chen, J. Li, D. Cai, and S. Chen, “Metabolic Engineering of aspartic acid supply modules for enhanced production of bacitracin in bacillus licheniformis,” ACS Synthetic Biology, vol. 10, no. 9, pp. 2243–2251, 2021.
• J. D. Keasling, “Synthetic Biology and the development of tools for metabolic engineering,” Metabolic Engineering, vol. 14, no. 3, pp. 189–195, 2012.
• V. V. C. Sinatti, C. A. Gonçalves, and A. S. Romão-Dumaresq, “Identification of metabolites identical and similar to drugs as candidates for metabolic engineering,” Journal of Biotechnology, vol. 302, pp. 67–76, 2019.
• J. Nielsen and M. C. Jewett, “Impact of systems biology on metabolic engineering ofsaccharomyces cerevisiae,” FEMS Yeast Research, vol. 8, no. 1, pp. 122–131, 2008.
• I. A. Kurnaz, “A systematic review of Synthetic Biology - a new era in biopharmaceutical drug development,” Biomedical Journal of Scientific & Technical Research, vol. 29, no. 1, 2020.
• A. Nakagawa, H. Minami, J.-S. Kim, T. Koyanagi, T. Katayama, F. Sato, and H. Kumagai, “A bacterial platform for fermentative production of plant alkaloids,”Nature Communications, vol. 2, no. 1, 2011.
• A. Badri, A. Williams, A. Awofiranye, P. Datta, K. Xia, W. He, K. Fraser, J. S. Dordick, R. J. Linhardt, and M. A. Koffas, “Complete biosynthesis of a sulfated chondroitin in escherichia coli,” Nature Communications, vol. 12, no. 1, 2021.
• L. R. Jarboe, X. Zhang, X. Wang, J. C. Moore, K. T. Shanmugam, and L. O. Ingram, “Metabolic Engineering for production of biorenewable fuels and chemicals: Contributions of Synthetic Biology,” Journal of Biomedicine and Biotechnology, vol. 2010, pp. 1–18, 2010.
• F. David, A. M. Davis, M. Gossing, M. A. Hayes, E. Romero, L. H. Scott, and M. J. Wigglesworth, “A perspective on synthetic biology in drug discovery and development—current impact and future opportunities,” SLAS Discovery, vol. 26, no. 5, pp. 581–603, 2021.
• T. Selas Castiñeiras, S. G. Williams, A. G. Hitchcock, and D. C. Smith, “E. coli strain engineering for the production of advanced biopharmaceutical products,” FEMS Microbiology Letters, vol. 365, no. 15, 2018.
• S. Liu, J.-Z. Xu, and W.-G. Zhang, “Advances and prospects in metabolic engineering of escherichia coli for L-tryptophan production,” World Journal of Microbiology and Biotechnology, vol. 38, no. 2, 2022.
• H. B. Bang, I. H. Choi, J. H. Jang, and K. J. Jeong, “Engineering of escherichia coli for the economic production L-phenylalanine in large-scale bioreactor,” Biotechnology and Bioprocess Engineering, vol. 26, no. 3, pp. 468–475, 2021.
• Z. Liu, X. Zhang, D. Lei, B. Qiao, and G.-R. Zhao, “Metabolic engineering of escherichia coli for de novo production of 3-phenylpropanol via retrobiosynthesis approach,” Microbial Cell Factories, vol. 20, no. 1, 2021.
• H. Fang, D. Li, J. Kang, P. Jiang, J. Sun, and D. Zhang, “Metabolic engineering of escherichia coli for de novo biosynthesis of vitamin B12,” Nature Communications, vol. 9, no. 1, 2018.
• M. Zhang, C. Liu, D. Xi, H. Bi, Z. Cui, Y. Zhuang, H. Yin, and T. Liu, “Metabolic engineering of escherichia coli for high-level production of salicin,” ACS Omega, vol. 7, no. 37, pp. 33147–33155, 2022.
• J. T. Ku, A. Y. Chen, and E. I. Lan, “Metabolic engineering of escherichia coli for efficient biosynthesis of butyl acetate,” Microbial Cell Factories, vol. 21, no. 1, 2022.
• E. Rahmat and Y. Kang, “Yeast metabolic engineering for the production of pharmaceutically important secondary metabolites,” Applied Microbiology and Biotechnology, vol. 104, no. 11, pp. 4659–4674, 2020.
• I. Carqueijeiro, C. Langley, D. Grzech, K. Koudounas, N. Papon, S. E. O’Connor, and V. Courdavault, “Beyond the semi-synthetic artemisinin: Metabolic Engineering of Plant-derived anti-cancer drugs,” Current Opinion in Biotechnology, vol. 65, pp. 17–24, 2020.
• L. Xu, D. Wang, J. Chen, B. Li, Q. Li, P. Liu, Y. Qin, Z. Dai, F. Fan, and X. Zhang, “Metabolic engineering of saccharomyces cerevisiae for gram-scale diosgenin production,” Metabolic Engineering, vol. 70, pp. 115–128, 2022.
• Y. Meng, X. Liu, L. Zhang, and G.-R. Zhao, “Modular engineering of saccharomyces cerevisiae for de novo biosynthesis of genistein,” Microorganisms, vol. 10, no. 7, pp. 1402, 2022.
• F. Xiao, J. Lian, S. Tu, L. Xie, J. Li, F. Zhang, R. J. Linhardt, H. Huang, and W. Zhong, “Metabolic engineering of saccharomyces cerevisiae for high-level production of chlorogenic acid from glucose,” ACS Synthetic Biology, vol. 11, no. 2, pp. 800–811, 2022.
• R. Bisquert, A. Planells‐Cárcel, E. Valera‐García, J. M. Guillamón, and S. Muñiz‐Calvo, “Metabolic engineering ofsaccharomyces cerevisiaefor hydroxytyrosol overproduction directly from glucose,” Microbial Biotechnology, vol. 15, no. 5, pp. 1499–1510, 2021.
• H.-Y. Gao, H. Zhao, T.-Y. Hu, Z.-Q. Jiang, M. Xia, Y.-F. Zhang, Y. Lu, Y. Liu, Y. Yin, X.-C. Chen, Y.-F. Luo, J.-W. Zhou, J.-D. Wang, J. Gao, W. Gao, and L.-Q. Huang, “Metabolic engineering of saccharomyces cerevisiae for high-level Friedelin via genetic manipulation,” Frontiers in Bioengineering and Biotechnology, vol. 10, 2022.
• G. Wang, M. Huang, and J. Nielsen, “Exploring the potential of saccharomyces cerevisiae for biopharmaceutical protein production,” Current Opinion in Biotechnology, vol. 48, pp. 77–84, 2017.
• H. Huttanus, J. Sheng, and X. Feng, “Metabolic Engineering for production of Small Molecule Drugs: Challenges and Solutions,” Fermentation, vol. 2, no. 1, pp. 4, 2016.
• D. Na, T. Y. Kim, and S. Y. Lee, “Construction and optimization of synthetic pathways in Metabolic Engineering,” Current Opinion in Microbiology, vol. 13, no. 3, pp. 363–370, 2010.
• D. Morrone, L. Lowry, M. K. Determan, D. M. Hershey, M. Xu, and R. J. Peters, “Increasing diterpene yield with a modular metabolic engineering system in E. coli: Comparison of MeV and MEP isoprenoid precursor pathway engineering,” Applied Microbiology and Biotechnology, vol. 85, no. 6, pp. 1893–1906, 2009.
• A. Das, S.-H. Yoon, S.-H. Lee, J.-Y. Kim, D.-K. Oh, and S.-W. Kim, “An update on microbial carotenoid production: Application of recent Metabolic Engineering Tools,” Applied Microbiology and Biotechnology, vol. 77, no. 3, pp. 505–512, 2007.
• J. D. Keasling, “Manufacturing molecules through metabolic engineering,” Science, vol. 330, no. 6009, pp. 1355–1358, 2010.
• Y. Li, Z. Lin, C. Huang, Y. Zhang, Z. Wang, Y.-jie Tang, T. Chen, and X. Zhao, “Metabolic engineering of escherichia coli using CRISPR–cas9 meditated genome editing,” Metabolic Engineering, vol. 31, pp. 13–21, 2015.
• M. Chartrain, P. M. Salmon, D. K. Robinson, and B. C. Buckland, “Metabolic Engineering and directed evolution for the production of pharmaceuticals,” Current Opinion in Biotechnology, vol. 11, no. 2, pp. 209–214, 2000.
• K. T. Shanmugam and L. O. Ingram, “Principles and practice of designing microbial biocatalysts for fuel and Chemical production,” Journal of Industrial Microbiology and Biotechnology, vol. 49, no. 2, 2021.
• D. Yi, T. Bayer, C. P. Badenhorst, S. Wu, M. Doerr, M. Höhne, and U. T. Bornscheuer, “Recent trends in biocatalysis,” Chemical Society Reviews, vol. 50, no. 14, pp. 8003–8049, 2021.
• A. Illanes, A. Cauerhff, L. Wilson, and G. R. Castro, “Recent trends in Biocatalysis Engineering,” Bioresource Technology, vol. 115, pp. 48–57, 2012.
• A. Madhavan, R. Sindhu, P. Binod, R. K. Sukumaran, and A. Pandey, “Strategies for design of improved biocatalysts for industrial applications,” Bioresource Technology, vol. 245, pp. 1304–1313, 2017.
• J. A. Jones and M. A. G. Koffas, “Optimizing metabolic pathways for the improved production of natural products,” Methods in Enzymology, pp. 179–193, 2016.
• Q. Qi, J. Li, and J. Cheng, “Reconstruction of metabolic pathways by combining probabilistic graphical model-based and knowledge-based methods,” BMC Proceedings, vol. 8, no. S6, 2014.
• A. Perl, H. Dalton, Y. J. Yoo, and M. A. Koffas, “Methods for the development of recombinant microorganisms for the production of natural products,” Plant Metabolic Engineering, pp. 1–17, 2021.
• J. Montaño López, L. Duran, and J. L. Avalos, “Physiological limitations and opportunities in microbial metabolic engineering,” Nature Reviews Microbiology, vol. 20, no. 1, pp. 35–48, 2021.
• Y. Mori and T. Shirai, “Designing artificial metabolic pathways, construction of target enzymes, and analysis of their function,” Current Opinion in Biotechnology, vol. 54, pp. 41–44, 2018.
• S.-U. Park, M. Yu, and P. J. Facchini, “Antisense RNA-mediated suppression of benzophenanthridine alkaloid biosynthesis in transgenic cell cultures of California Poppy,” Plant Physiology, vol. 128, no. 2, pp. 696–706, 2002.
• E. Öz, “Zeaksantin Öncül Maddesini Kullanarak Safran Apokarotenoidlerinin Heterolog Mikrobiyal Biyosentezi,” Yüksek Lisans Tezi, Fen Bilimleri Enstitüsü Biyomühendislik AnaBilim Dalı, Fırat Üniversitesi, Elazığ, 2019.
• J. Du, Y. Yuan, T. Si, J. Lian, and H. Zhao, “Customized optimization of metabolic pathways by combinatorial transcriptional engineering,” Nucleic Acids Research, vol. 40, no. 18, 2012.
• B. W. Biggs, B. De Paepe, C. N. Santos, M. De Mey, and P. Kumaran Ajikumar, “Multivariate modular metabolic engineering for pathway and strain optimization,” Current Opinion in Biotechnology, vol. 29, pp. 156–162, 2014.
• F. He, E. Murabito, and H. V. Westerhoff, “Synthetic Biology and Regulatory Networks: Where Metabolic Systems Biology Meets Control Engineering,” Journal of The Royal Society Interface, vol. 13, no. 117, pp. 20151046, 2016.
• O. D. Kim, M. Rocha, and P. Maia, “A review of dynamic modeling approaches and their application in computational strain optimization for Metabolic Engineering,” Frontiers in Microbiology, vol. 9, 2018.
• R. Mahr and J. Frunzke, “Transcription factor-based biosensors in Biotechnology: Current State and future prospects,” Applied Microbiology and Biotechnology, vol. 100, no. 1, pp. 79–90, 2015.
• M.-K. Kang and J. Nielsen, “Biobased production of alkanes and alkenes through metabolic engineering of Microorganisms,” Journal of Industrial Microbiology and Biotechnology, vol. 44, no. 4-5, pp. 613–622, 2017.
• L. Carrilero, A. Kottara, D. Guymer, E. Harrison, J. P. Hall, and M. A. Brockhurst, “Positive selection inhibits plasmid coexistence in bacterial genomes,” mBio, vol. 12, no. 3, 2021.
• A. Kan, I. Gelfat, S. Emani, P. Praveschotinunt, and N. S. Joshi, “Plasmid vectors for in vivo selection-free use with the probiotic E. coli nissle 1917,” ACS Synthetic Biology, vol. 10, no. 1, pp. 94–106, 2020.
• G. A. Gonçalves, D. M. Bower, D. M. Prazeres, G. A. Monteiro, and K. L. Prather, “Rational engineering of escherichia coli strains for plasmid biopharmaceutical manufacturing,” Biotechnology Journal, vol. 7, no. 2, pp. 251–261, 2011.
• T. Wein, N. F. Hülter, I. Mizrahi, and T. Dagan, “Emergence of plasmid stability under non-selective conditions maintains antibiotic resistance,” Nature Communications, vol. 10, no. 1, 2019.
• C.-W. Jang and T. Magnuson, “A novel selection marker for efficient DNA cloning and recombineering in E. coli,” PLoS ONE, vol. 8, no. 2, 2013.
• J. H. Malone, “Balancing copy number in ribosomal DNA,” Proceedings of the National Academy of Sciences, vol. 112, no. 9, pp. 2635–2636, 2015.
• O. Pös, J. Radvanszky, G. Buglyó, Z. Pös, D. Rusnakova, B. Nagy, and T. Szemes, “DNA copy number variation: Main characteristics, evolutionary significance, and pathological aspects,” Biomedical Journal, vol. 44, no. 5, pp. 548–559, 2021.
• F. Nadler, F. Bracharz, and J. Kabisch, “Copyswitch—in vivo optimization of gene copy numbers for heterologous gene expression in bacillus subtilis,” Frontiers in Bioengineering and Biotechnology, vol. 6, 2019.
• M. M. Watve, N. Dahanukar, and M. G. Watve, “Sociobiological control of plasmid copy number in bacteria,” PLoS ONE, vol. 5, no. 2, 2010.
• T. Schmidt, K. Friehs, and E. Flaschel, “Rapid determination of plasmid copy number,” Journal of Biotechnology, vol. 49, no. 1-3, pp. 219–229, 1996.
• M. Jahn, C. Vorpahl, T. Hübschmann, H. Harms, and S. Müller, “Copy number variability of expression plasmids determined by cell sorting and droplet digital PCR,” Microbial Cell Factories, vol. 15, no. 1, 2016.
• E. J. Nestler and S. E. Hyman, “Regulation of gene expression, ”Neuropsychopharmacology: the fifth generation of progress, pp. 217-228, 2002.
• P. Cramer, “Organization and regulation of Gene Transcription,” Nature, vol. 573, no. 7772, pp. 45–54, 2019.
• T. I. Lee and R. A. Young, “Transcriptional regulation and its misregulation in disease,” Cell, vol. 152, no. 6, pp. 1237–1251, 2013.
• J. A. Jones, V. R. Vernacchio, D. M. Lachance, M. Lebovich, L. Fu, A. N. Shirke, V. L. Schultz, B. Cress, R. J. Linhardt, and M. A. Koffas, “EPathOptimize: A combinatorial approach for transcriptional balancing of metabolic pathways,” Scientific Reports, vol. 5, no. 1, 2015.
• G. Tkačik, C. G. Callan, and W. Bialek, “Information flow and optimization in transcriptional regulation,” Proceedings of the National Academy of Sciences, vol. 105, no. 34, pp. 12265–12270, 2008.
• F. Jacob and J. Monod, “Genetic regulatory mechanisms in the synthesis of proteins,” Journal of Molecular Biology, vol. 3, no. 3, pp. 318–356, 1961.
• J. W. B. Hershey, N. Sonenberg, and M. B. Mathews, “Principles of Translational Control,” Cold Spring Harbor Perspectives in Biology, vol. 11, no. 9, 2018.
• V. Reinke, “Transcriptional regulation of gene expression in C. elegans,” WormBook, pp. 1–31, 2013.
• A. Wegner, J. Meiser, D. Weindl, and K. Hiller, “How metabolites modulate metabolic flux,” Current Opinion in Biotechnology, vol. 34, pp. 16–22, 2015.
• V. Stojković and D. G. Fujimori, “Radical SAM-mediated methylation of ribosomal RNA,” Methods in Enzymology, pp. 355–376, 2015.
• V. N. Uversky, “Posttranslational modification,” Brenner's Encyclopedia of Genetics, pp. 425–430, 2013.
• K. Kochanowski, U. Sauer, and E. Noor, “Posttranslational regulation of Microbial Metabolism,” Current Opinion in Microbiology, vol. 27, pp. 10–17, 2015.
• P. E. MacDonald, “A post-translational balancing act: The good and the bad of sumoylation in pancreatic islets,” Diabetologia, vol. 61, no. 4, pp. 775–779, 2018.
• Z. Abil, X. Xiong, and H. Zhao, “Synthetic Biology for Therapeutic Applications,” Molecular Pharmaceutics, vol. 12, no. 2, pp. 322–331, 2014.
• R. Breitling and E. Takano, “Synthetic Biology advances for pharmaceutical production,” Current Opinion in Biotechnology, vol. 35, pp. 46–51, 2015.
• Y. Xie, Y. Yang, Y. He, X. Wang, P. Zhang, H. Li, and S. Liang, “Synthetic biology speeds up drug target discovery,” Frontiers in Pharmacology, vol. 11, 2020.
• J.-Y. Trosset and P. Carbonell, “Synthetic Biology for Pharmaceutical Drug Discovery,” Drug Design, Development and Therapy, pp. 6285, 2015.