Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Building complex biochemicals from one-carbon compounds

Nature Synthesis volume 4, pages 787–798 (2025)Cite this article

Subjects

Abstract

Life—ranging from cellular processes to the complexities of modern societies—requires a diverse array of chemicals to function. Whereas humans have become adept at synthesizing incredible chemical diversity over the past two centuries, these practices still rely on the use (and breakdown) of fossil resources. However, the challenge of climate change makes it clear that sustainable chemical synthesis requires alternative methods and substrates. The growing abundance of carbonaceous gases in the atmosphere (in particular, carbon dioxide and methane) could serve as feedstocks for such a sustainable synthesis transition, and biological systems are adept at converting one-carbon (C1) compounds into more complex molecules. This Review discusses recent developments and future opportunities for the biosynthesis of chemicals from C1 substrates via cellular and cell-free systems. In addition to the diverse range of products synthesized using natural or designed C1 conversion pathways in vivo or in vitro, we discuss the benefits of spatio-temporal organization and hybrid catalysis to increase the efficiency of enzymatic chemical synthesis from C1 substrates.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Overview of methods to enhance C1 conversion.
Fig. 2: Organization strategies for improving C1 conversion.
Fig. 3: Homeostasis and self-regeneration to prolong in vitro biocatalysis.
Fig. 4: Hybrid catalysis strategies coupling different modes of catalysis.

Similar content being viewed by others

References

  1. Liu, Z., Wang, K., Chen, Y., Tan, T. & Nielsen, J. Third-generation biorefineries as the means to produce fuels and chemicals from CO2. Nat. Catal. 3, 274–288 (2020).

    Article  CAS  Google Scholar 

  2. LeClerc, H. O. et al. The CO2 tree: the potential for carbon dioxide utilization pathways. ACS Sustain. Chem. Eng. 13, 5–29 (2025).

    Article  CAS  Google Scholar 

  3. Vlaeminck, E. et al. Pressure fermentation to boost CO2-based poly(3-hydroxybutyrate) production using Cupriavidus necator. Bioresour. Technol. 408, 131162 (2024).

    Article  CAS  PubMed  Google Scholar 

  4. Liew, F. et al. Gas fermentation—a flexible platform for commercial scale production of low-carbon-fuels and chemicals from waste and renewable feedstocks. Front. Microbiol. 7, 694 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Santos-Merino, M., Singh, A. K. & Ducat, D. C. New applications of synthetic biology tools for cyanobacterial metabolic engineering. Front. Bioeng. Biotechnol. 7, 33 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Chen, F. Y.-H., Jung, H.-W., Tsuei, C.-Y. & Liao, J. C. Converting Escherichia coli to a synthetic methylotroph growing solely on methanol. Cell 182, 933–946.e14 (2020).

    Article  CAS  PubMed  Google Scholar 

  7. Gleizer, S. et al. Conversion of Escherichia coli to generate all biomass carbon from CO2. Cell 179, 1255–1263.e12 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Keller, P. et al. Generation of an Escherichia coli strain growing on methanol via the ribulose monophosphate cycle. Nat. Commun. 13, 5243 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Liew, F. E. et al. Carbon-negative production of acetone and isopropanol by gas fermentation at industrial pilot scale. Nat. Biotechnol. 40, 335–344 (2022).

    Article  CAS  PubMed  Google Scholar 

  10. Nangle, S. N. et al. Valorization of CO2 through lithoautotrophic production of sustainable chemicals in Cupriavidus necator. Metab. Eng. 62, 207–220 (2020).

    Article  CAS  PubMed  Google Scholar 

  11. Schwander, T., Schada von Borzyskowski, L., Burgener, S., Cortina, N. S. & Erb, T. J. A synthetic pathway for the fixation of carbon dioxide in vitro. Science 354, 900–904 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Bogorad, I. W., Lin, T.-S. & Liao, J. C. Synthetic non-oxidative glycolysis enables complete carbon conservation. Nature 502, 693–697 (2013).

    Article  CAS  PubMed  Google Scholar 

  13. Liu, C., Colón, B. C., Ziesack, M., Silver, P. A. & Nocera, D. G. Water splitting–biosynthetic system with CO2 reduction efficiencies exceeding photosynthesis. Science 352, 1210–1213 (2016).

    Article  CAS  PubMed  Google Scholar 

  14. Diehl, C., Gerlinger, P. D., Paczia, N. & Erb, T. J. Synthetic anaplerotic modules for the direct synthesis of complex molecules from CO2. Nat. Chem. Biol. 19, 168–175 (2023).

    Article  CAS  PubMed  Google Scholar 

  15. Cai, T. et al. Cell-free chemoenzymatic starch synthesis from carbon dioxide. Science 373, 1523–1527 (2021).

    Article  CAS  PubMed  Google Scholar 

  16. O’Keeffe, S. et al. Bringing carbon to life via one-carbon metabolism. Trends Biotechnol. 43, 572–585 (2025).

    Article  PubMed  Google Scholar 

  17. Hudson, E. P. The Calvin Benson cycle in bacteria: new insights from systems biology. Semin. Cell Dev. Biol. 155, 71–83 (2024).

    Article  CAS  PubMed  Google Scholar 

  18. Bar-Even, A., Noor, E. & Milo, R. A survey of carbon fixation pathways through a quantitative lens. J. Exp. Bot. 63, 2325–2342 (2012).

    Article  CAS  PubMed  Google Scholar 

  19. Sulis, D. B. et al. Multiplex CRISPR editing of wood for sustainable fiber production. Science 381, 216–221 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Santos-Merino, M., Yun, L. & Ducat, D. C. Cyanobacteria as cell factories for the photosynthetic production of sucrose. Front. Microbiol. 14, 1126032 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Sanford, P. A. & Woolston, B. M. Expanding the genetic engineering toolbox for the metabolically flexible acetogen Eubacterium limosum. J. Ind. Microbiol. Biotechnol. 49, kuac019 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Pham, D. N., Nguyen, A. D. & Lee, E. Y. Outlook on engineering methylotrophs for one-carbon-based industrial biotechnology. Chem. Eng. J. 449, 137769 (2022).

    Article  CAS  Google Scholar 

  23. Bysani, V. R., Alam, A. S., Bar-Even, A. & Machens, F. Engineering and evolution of the complete reductive glycine pathway in Saccharomyces cerevisiae for formate and CO2 assimilation. Metab. Eng. 81, 167–181 (2024).

    Article  CAS  PubMed  Google Scholar 

  24. Kim, S. et al. Growth of E. coli on formate and methanol via the reductive glycine pathway. Nat. Chem. Biol. 16, 538–545 (2020).

    Article  CAS  PubMed  Google Scholar 

  25. Guo, Y. et al. Engineering yeasts to co-utilize methanol or formate coupled with CO2 fixation. Metab. Eng. 84, 1–12 (2024).

    Article  CAS  PubMed  Google Scholar 

  26. Gassler, T. et al. The industrial yeast Pichia pastoris is converted from a heterotroph into an autotroph capable of growth on CO2. Nat. Biotechnol. 38, 210–216 (2020).

    Article  CAS  PubMed  Google Scholar 

  27. Ben Nissan, R. et al. Autotrophic growth of Escherichia coli is achieved by a small number of genetic changes. eLife 12, RP88793 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Gassler, T., Baumschabl, M., Sallaberger, J., Egermeier, M. & Mattanovich, D. Adaptive laboratory evolution and reverse engineering enhances autotrophic growth in Pichia pastoris. Metab. Eng. 69, 112–121 (2022).

    Article  CAS  PubMed  Google Scholar 

  29. Reiter, M. A. et al. A synthetic methylotrophic Escherichia coli as a chassis for bioproduction from methanol. Nat. Catal. 7, 560–573 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Jiang, W. et al. Metabolic engineering strategies to enable microbial utilization of C1 feedstocks. Nat. Chem. Biol. 17, 845–855 (2021).

    Article  CAS  PubMed  Google Scholar 

  31. Schulz-Mirbach, H., Dronsella, B., He, H. & Erb, T. J. Creating new-to-nature carbon fixation: a guide. Metab. Eng. 82, 12–28 (2024).

    Article  CAS  PubMed  Google Scholar 

  32. Erb, T. J., Jones, P. R. & Bar-Even, A. Synthetic metabolism: metabolic engineering meets enzyme design. Curr. Opin. Chem. Biol. 37, 56–62 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bar-Even, A., Noor, E., Lewis, N. E. & Milo, R. Design and analysis of synthetic carbon fixation pathways. Proc. Natl Acad. Sci. USA 107, 8889–8894 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Pandit, A. V., Srinivasan, S. & Mahadevan, R. Redesigning metabolism based on orthogonality principles. Nat. Commun. 8, 15188 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Pandi, A. et al. A versatile active learning workflow for optimization of genetic and metabolic networks. Nat. Commun. 13, 3876 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Luo, S. et al. Construction and modular implementation of the THETA cycle for synthetic CO2 fixation. Nat. Catal. 6, 1228–1240 (2023).

    Article  CAS  Google Scholar 

  37. Wu, C. et al. Acetyl-CoA synthesis through a bicyclic carbon-fixing pathway in gas-fermenting bacteria. Nat. Synth. 1, 615–625 (2022).

    Article  CAS  Google Scholar 

  38. Chou, A., Lee, S. H., Zhu, F., Clomburg, J. M. & Gonzalez, R. An orthogonal metabolic framework for one-carbon utilization. Nat. Metab. 3, 1385–1399 (2021).

    Article  CAS  PubMed  Google Scholar 

  39. Dookeran, Z. A. & Nielsen, D. R. Systematic engineering of Synechococcus elongatus UTEX 2973 for photosynthetic production of L-lysine, cadaverine, and glutarate. ACS Synth. Biol. 10, 3561–3575 (2021).

    Article  CAS  PubMed  Google Scholar 

  40. Mishra, S., Perkovich, P. M., Mitchell, W. P., Venkataraman, M. & Pfleger, B. F. Expanding the synthetic biology toolbox of Cupriavidus necator for establishing fatty acid production. J. Ind. Microbiol. Biotechnol. 51, kuae008 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Xie, H., Kjellström, J. & Lindblad, P. Sustainable production of photosynthetic isobutanol and 3-methyl-1-butanol in the cyanobacterium Synechocystis sp. PCC 6803. Biotechnol. Biofuels Bioprod. 16, 134 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Yunus, I. S. et al. Improved bioproduction of 1-octanol using engineered Synechocystis sp. PCC 6803. ACS Synth. Biol. 10, 1417–1428 (2021).

    Article  CAS  PubMed  Google Scholar 

  43. Vögeli, B. et al. Cell-free prototyping enables implementation of optimized reverse β-oxidation pathways in heterotrophic and autotrophic bacteria. Nat. Commun. 13, 3058 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Ma, Z.-x. et al. Metabolomic analysis improves bioconversion of methanol to isobutanol in Methylorubrum extorquens AM1. Biotechnol. J. 16, 2000413 (2021).

    Article  CAS  Google Scholar 

  45. Sonntag, F. et al. Engineering Methylobacterium extorquens for de novo synthesis of the sesquiterpenoid α-humulene from methanol. Metab. Eng. 32, 82–94 (2015).

    Article  CAS  PubMed  Google Scholar 

  46. Quynh Le, H. T., Anh Mai, D. H., Na, J.-G. & Lee, E. Y. Development of Methylorubrum extorquens AM1 as a promising platform strain for enhanced violacein production from co-utilization of methanol and acetate. Metab. Eng. 72, 150–160 (2022).

    Article  CAS  PubMed  Google Scholar 

  47. Golubova, D., Tansley, C., Su, H. & Patron, N. J. Engineering Nicotiana benthamiana as a platform for natural product biosynthesis. Curr. Opin. Plant Biol. 81, 102611 (2024).

    Article  CAS  PubMed  Google Scholar 

  48. Einhaus, A., Baier, T. & Kruse, O. Molecular design of microalgae as sustainable cell factories. Trends Biotechnol. 42, 728–738 (2024).

    Article  CAS  PubMed  Google Scholar 

  49. Einhaus, A. et al. Engineering a powerful green cell factory for robust photoautotrophic diterpenoid production. Metab. Eng. 73, 82–90 (2022).

    Article  CAS  PubMed  Google Scholar 

  50. Calgaro-Kozina, A. et al. Engineering plant synthetic pathways for the biosynthesis of novel antifungals. ACS Cent. Sci. 6, 1394–1400 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Barnum, C. R. et al. Engineered plants provide a photosynthetic platform for the production of diverse human milk oligosaccharides. Nat. Food 5, 480–490 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Zhang, J. et al. A microbial supply chain for production of the anti-cancer drug vinblastine. Nature 609, 341–347 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Messiha, H. L., Scrutton, N. S. & Leys, D. High-titer bio-styrene production afforded by whole-cell cascade biotransformation. ChemCatChem 15, e202201102 (2023).

    Article  CAS  Google Scholar 

  54. Pyne, M. E. et al. A yeast platform for high-level synthesis of tetrahydroisoquinoline alkaloids. Nat. Commun. 11, 3337 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Sundaram, S. et al. A modular in vitro platform for the production of terpenes and polyketides from CO2. Angew. Chem. Int. Ed. 60, 16420–16425 (2021).

    Article  CAS  Google Scholar 

  56. Flamholz, A. & Shih, P. M. Cell biology of photosynthesis over geologic time. Curr. Biol. 30, R490–R494 (2020).

    Article  CAS  PubMed  Google Scholar 

  57. Abrahamson, C. H., Palmero, B. J., Kennedy, N. W. & Tullman-Ercek, D. Theoretical and practical aspects of multienzyme organization and encapsulation. Annu. Rev. Biophys. 52, 553–572 (2023).

    Article  CAS  PubMed  Google Scholar 

  58. Dueber, J. E. et al. Synthetic protein scaffolds provide modular control over metabolic flux. Nat. Biotechnol. 27, 753–759 (2009).

    Article  CAS  PubMed  Google Scholar 

  59. Fernandez-Lorente, G. et al. Interfacially activated lipases against hydrophobic supports: effect of the support nature on the biocatalytic properties. Process Biochem. 43, 1061–1067 (2008).

    Article  CAS  Google Scholar 

  60. Sánchez-Morán, H., Kaar, J. L. & Schwartz, D. K. Supra-biological performance of immobilized enzymes enabled by chaperone-like specific non-covalent interactions. Nat. Commun. 15, 2299 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Oskoei, V., Mathesh, M. & Yang, W. Enhancing substrate channeling with multi-enzyme architectures in hydrogen-bonded organic frameworks. Chem. Eur. J. 30, e202401256 (2024).

    Article  CAS  PubMed  Google Scholar 

  62. Gao, Y., Roberts, C. C., Toop, A., Chang, C. A. & Wheeldon, I. Mechanisms of enhanced catalysis in enzyme–DNA nanostructures revealed through molecular simulations and experimental analysis. ChemBioChem 17, 1430–1436 (2016).

    Article  CAS  PubMed  Google Scholar 

  63. Satagopan, S., Sun, Y., Parquette, J. R. & Tabita, F. R. Synthetic CO2-fixation enzyme cascades immobilized on self-assembled nanostructures that enhance CO2/O2 selectivity of RubisCO. Biotechnol. Biofuels 10, 175 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Fan, G. et al. Highly efficient carbon dioxide electroreduction via DNA-directed catalyst immobilization. JACS Au 4, 1413–1421 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Zhang, Y. et al. Protein–protein interactions and metabolite channelling in the plant tricarboxylic acid cycle. Nat. Commun. 8, 15212 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Wu, F. & Minteer, S. Krebs cycle metabolon: structural evidence of substrate channeling revealed by cross-linking and mass spectrometry. Angew. Chem. Int. Ed. 54, 1851–1854 (2015).

    Article  CAS  Google Scholar 

  67. Steffens, L. et al. High CO2 levels drive the TCA cycle backwards towards autotrophy. Nature 592, 784–788 (2021).

    Article  CAS  PubMed  Google Scholar 

  68. Eun, C., Kekenes-Huskey, P. M., Metzger, V. T. & McCammon, J. A. A model study of sequential enzyme reactions and electrostatic channeling. J. Chem. Phys. 140, 105101 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Kummer, M. J. et al. Substrate channeling by a rationally designed fusion protein in a biocatalytic cascade. JACS Au 1, 1187–1197 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Yu, S. et al. Light-driven enzymatic nanosystem for highly selective production of formic acid from CO2. Chem. Eng. J. 420, 127649 (2021).

    Article  CAS  Google Scholar 

  71. Breger, J. C. et al. Self assembling nanoparticle enzyme clusters provide access to substrate channeling in multienzymatic cascades. Nat. Commun. 14, 1757 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Kerfeld, C. A., Aussignargues, C., Zarzycki, J., Cai, F. & Sutter, M. Bacterial microcompartments. Nat. Rev. Microbiol. 16, 277–290 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Rae, B. D., Long, B. M., Badger, M. R. & Price, G. D. Functions, compositions, and evolution of the two types of carboxysomes: polyhedral microcompartments that facilitate CO2 fixation in cyanobacteria and some proteobacteria. Microbiol. Mol. Biol. Rev. 77, 357–379 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Dou, Z. et al. CO2 fixation kinetics of Halothiobacillus neapolitanus mutant carboxysomes lacking carbonic anhydrase suggest the shell acts as a diffusional barrier for CO2. J. Biol. Chem. 283, 10377–10384 (2008).

    Article  CAS  PubMed  Google Scholar 

  75. Flamholz, A. I. et al. Functional reconstitution of a bacterial CO2 concentrating mechanism in Escherichia coli. eLife 9, e59882 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Slininger Lee, M. F., Jakobson, C. M. & Tullman-Ercek, D. Evidence for improved encapsulated pathway behavior in a bacterial microcompartment through shell protein engineering. ACS Synth. Biol. 6, 1880–1891 (2017).

    Article  PubMed  Google Scholar 

  77. Lawrence, A. D. et al. Solution structure of a bacterial microcompartment targeting peptide and its application in the construction of an ethanol bioreactor. ACS Synth. Biol. 3, 454–465 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Kirst, H. et al. Toward a glycyl radical enzyme containing synthetic bacterial microcompartment to produce pyruvate from formate and acetate. Proc. Natl Acad. Sci. USA 119, e2116871119 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Küffner, A. M. et al. Acceleration of an enzymatic reaction in liquid phase separated compartments based on intrinsically disordered protein domains. ChemSystemsChem 2, e2000001 (2020).

    Article  Google Scholar 

  80. Freeman Rosenzweig, E. S. et al. The eukaryotic CO2-concentrating organelle is liquid-like and exhibits dynamic reorganization. Cell 171, 148–162.e19 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Küffner, A. M. et al. Bottom-up reconstruction of minimal pyrenoids provides insights into the evolution and mechanisms of carbon concentration by EPYC1 proteins. Preprint at bioRxiv https://doi.org/10.1101/2024.06.28.601168 (2024).

  82. Blikstad, C. et al. Identification of a carbonic anhydrase–Rubisco complex within the alpha-carboxysome. Proc. Natl Acad. Sci. USA 120, e2308600120 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Yu, W. et al. De novo engineering of programmable and multi-functional biomolecular condensates for controlled biosynthesis. Nat. Commun. 15, 7989 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Reifenrath, M., Oreb, M., Boles, E. & Tripp, J. Artificial ER-eerived vesicles as synthetic organelles for in vivo compartmentalization of biochemical pathways. ACS Synth. Biol. 9, 2909–2916 (2020).

    Article  CAS  PubMed  Google Scholar 

  85. Einfalt, T. et al. Biomimetic artificial organelles with in vitro and in vivo activity triggered by reduction in microenvironment. Nat. Commun. 9, 1127 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Mangan, N. M., Flamholz, A., Hood, R. D., Milo, R. & Savage, D. F. pH determines the energetic efficiency of the cyanobacterial CO2 concentrating mechanism. Proc. Natl Acad. Sci. USA 113, E5354–E5362 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Fei, C., Wilson, A. T., Mangan, N. M., Wingreen, N. S. & Jonikas, M. C. Modelling the pyrenoid-based CO2-concentrating mechanism provides insights into its operating principles and a roadmap for its engineering into crops. Nat. Plants 8, 583–595 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Rasor, B. J. et al. Toward sustainable, cell-free biomanufacturing. Curr. Opin. Biotechnol. 69, 136–144 (2021).

    Article  CAS  PubMed  Google Scholar 

  89. Opgenorth, P. H., Korman, T. P. & Bowie, J. U. A synthetic biochemistry module for production of bio-based chemicals from glucose. Nat. Chem. Biol. 12, 393–395 (2016).

    Article  CAS  PubMed  Google Scholar 

  90. Trudeau, D. L. et al. Design and in vitro realization of carbon-conserving photorespiration. Proc. Natl Acad. Sci. USA 115, E11455–E11464 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Opgenorth, P. H., Korman, T. P. & Bowie, J. U. A synthetic biochemistry molecular purge valve module that maintains redox balance. Nat. Commun. 5, 4113 (2014).

    Article  CAS  PubMed  Google Scholar 

  92. Opgenorth, P. H., Korman, T. P., Iancu, L. & Bowie, J. U. A molecular rheostat maintains ATP levels to drive a synthetic biochemistry system. Nat. Chem. Biol. 13, 938–942 (2017).

    Article  CAS  PubMed  Google Scholar 

  93. Yadav, S., Perkins, A. J. P., Liyanagedera, S. B. W., Bougas, A. & Laohakunakorn, N. ATP regeneration from pyruvate in the PURE system. ACS Synth. Biol. 14, 247–256 (2025).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Chowdhury, S. et al. Carbon negative synthesis of amino acids using a cell-free-based biocatalyst. ACS Synth. Biol. 13, 3961–3975 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Aspacio, D. et al. Shifting redox reaction equilibria on demand using an orthogonal redox cofactor. Nat. Chem. Biol. 20, 1535–1546 (2024).

    Article  CAS  PubMed  Google Scholar 

  96. Berhanu, S., Ueda, T. & Kuruma, Y. Artificial photosynthetic cell producing energy for protein synthesis. Nat. Commun. 10, 1325 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Lee, K. Y. et al. Photosynthetic artificial organelles sustain and control ATP-dependent reactions in a protocellular system. Nat. Biotechnol. 36, 530–535 (2018).

    Article  CAS  PubMed  Google Scholar 

  98. Miller, T. E. et al. Light-powered CO2 fixation in a chloroplast mimic with natural and synthetic parts. Science 368, 649–654 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Luo, S. et al. ATP production from electricity with a new-to-nature electrobiological module. Joule 7, 1745–1758 (2023).

    Article  CAS  Google Scholar 

  100. Castañeda-Losada, L. et al. Bioelectrocatalytic cofactor regeneration coupled to CO2 fixation in a redox-active hydrogel for stereoselective C–C bond formation. Angew. Chem. Int. Ed. 60, 21056–21061 (2021).

    Article  Google Scholar 

  101. Lavickova, B., Laohakunakorn, N. & Maerkl, S. J. A partially self-regenerating synthetic cell. Nat. Commun. 11, 6340 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Hagino, K., Masuda, K., Shimizu, Y. & Ichihashi, N. Sustainable regeneration of 20 aminoacyl-tRNA synthetases in a reconstituted system toward self-synthesizing artificial systems. Sci. Adv. 11, eadt6269 (2025).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Schwarz-Schilling, M. et al. Autonomous biogenesis of the entire protein translation machinery excluding ribosomes. Preprint at bioRxiv https://doi.org/10.1101/2024.10.20.619270 (2024).

  104. Ganesh, R. B. & Maerkl, S. J. Towards self-regeneration: exploring the limits of protein synthesis in the protein synthesis using recombinant elements (PURE) cell-free transcription–translation system. ACS Synth. Biol. 13, 2555–2566 (2024).

    Article  CAS  PubMed  Google Scholar 

  105. Giaveri, S. et al. Integrated translation and metabolism in a partially self-synthesizing biochemical network. Science 385, 174–178 (2024).

    Article  CAS  PubMed  Google Scholar 

  106. Nishikawa, S. et al. Amino acid self-regenerating cell-free protein synthesis system that feeds on PLA plastics, CO2, ammonium, and α-ketoglutarate. ACS Catal. 14, 7696–7706 (2024).

    Article  CAS  Google Scholar 

  107. Giaveri, S. et al. Nature-inspired circular-economy recycling for proteins: proof of concept. Adv. Mater. 33, 2104581 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Abil, Z., Giaveri, S., Erb, T. J. & Rothschild, L. J. Integrating metabolism and evolution towards the realization of synthetic life. Nat. Rev. Bioeng. 3, 9–10 (2025).

    Article  CAS  Google Scholar 

  109. Tan, X. & Nielsen, J. The integration of bio-catalysis and electrocatalysis to produce fuels and chemicals from carbon dioxide. Chem. Soc. Rev. 51, 4763–4785 (2022).

    Article  CAS  PubMed  Google Scholar 

  110. Beyazay, T. et al. Ambient temperature CO2 fixation to pyruvate and subsequently to citramalate over iron and nickel nanoparticles. Nat. Commun. 14, 570 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Vornholt, T. et al. Artificial metalloenzymes. Nat. Rev. Methods Primers 4, 78 (2024).

    Article  CAS  Google Scholar 

  112. Jack, J., Fu, H., Leininger, A., Hyster, T. K. & Ren, Z. J. Cell-free CO2 valorization to C6 pharmaceutical precursors via a novel electro-enzymatic process. ACS Sustain. Chem. Eng. 10, 4114–4121 (2022).

    Article  CAS  Google Scholar 

  113. Landwehr, G. M. et al. A synthetic cell-free pathway for biocatalytic upgrading of one-carbon substrates. Preprint at bioRxiv https://doi.org/10.1101/2024.08.08.607227 (2024).

  114. Dinges, I. et al. Coupling of CO2 electrolysis with parallel and semi‐automated biopolymer synthesis – ex‐cell and without downstream processing. ChemSusChem 17, e202301721 (2024).

    Article  CAS  PubMed  Google Scholar 

  115. Gröger, H., Gallou, F. & Lipshutz, B. H. Where chemocatalysis meets biocatalysis: in water. Chem. Rev. 123, 5262–5296 (2023).

    Article  PubMed  Google Scholar 

  116. Hu, G. et al. Light-driven CO2 sequestration in Escherichia coli to achieve theoretical yield of chemicals. Nat. Catal. 4, 395–406 (2021).

    Article  CAS  Google Scholar 

  117. Guan, X. et al. Maximizing light-driven CO2 and N2 fixation efficiency in quantum dot–bacteria hybrids. Nat. Catal. 5, 1019–1029 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Liu, J., Zhang, H., Xu, Y., Meng, H. & Zeng, A.-P. Turn air-captured CO2 with methanol into amino acid and pyruvate in an ATP/NAD(P)H-free chemoenzymatic system. Nat. Commun. 14, 2772 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Waser, V., Mukherjee, M., Tachibana, R., Igareta, N. V. & Ward, T. R. An artificial [Fe4S4]-containing metalloenzyme for the reduction of CO2 to hydrocarbons. J. Am. Chem. Soc. 145, 14823–14830 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Ding, Y. et al. Nanorg microbial factories: light-driven renewable biochemical synthesis using quantum dot–bacteria nanobiohybrids. J. Am. Chem. Soc. 141, 10272–10282 (2019).

    Article  CAS  PubMed  Google Scholar 

  121. Oehlmann, N. N., Schmidt, F. V., Herzog, M., Goldman, A. L. & Rebelein, J. G. The iron nitrogenase reduces carbon dioxide to formate and methane under physiological conditions: a route to feedstock chemicals. Sci. Adv. 10, eado7729 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Guo, Y., Hong, X., Chen, Z. & Lv, Y. Electro-enzyme coupling systems for selective reduction of CO2. J. Energy Chem. 80, 140–162 (2023).

    Article  CAS  Google Scholar 

  123. Jayathilake, B. S., Bhattacharya, S., Vaidehi, N. & Narayanan, S. R. Efficient and Selective electrochemically driven enzyme-catalyzed reduction of carbon dioxide to formate using formate dehydrogenase and an artificial cofactor. Acc. Chem. Res. 52, 676–685 (2019).

    Article  CAS  PubMed  Google Scholar 

  124. Cheng, C. et al. Electricity-enhanced anaerobic, non-photosynthetic mixotrophy by Clostridium carboxidivorans with increased carbon efficiency and alcohol production. Energy Convers. Manag. 252, 115118 (2022).

    Article  CAS  Google Scholar 

  125. Guzman, M. S. et al. Phototrophic extracellular electron uptake is linked to carbon dioxide fixation in the bacterium Rhodopseudomonas palustris. Nat. Commun. 10, 1355 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Ranaivoarisoa, T. O., Singh, R., Rengasamy, K., Guzman, M. S. & Bose, A. Towards sustainable bioplastic production using the photoautotrophic bacterium Rhodopseudomonas palustris TIE-1. J. Ind. Microbiol. Biotechnol. 46, 1401–1417 (2019).

    Article  CAS  PubMed  Google Scholar 

  127. Bird, L. J. et al. Engineering wired life: synthetic biology for electroactive bacteria. ACS Synth. Biol. 10, 2808–2823 (2021).

    Article  CAS  PubMed  Google Scholar 

  128. Baker, J. J. et al. ML-enhanced peroxisome capacity enables compartmentalization of multienzyme pathway. Nat. Chem. Biol. https://doi.org/10.1038/s41589-024-01759-2 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Pandi, A. et al. Cell-free biosynthesis combined with deep learning accelerates de novo-development of antimicrobial peptides. Nat. Commun. 14, 7197 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Landwehr, G. M. et al. Accelerated enzyme engineering by machine-learning guided cell-free expression. Nat. Commun. 16, 865 (2025).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Chainani, Y., Ni, Z., Shebek, K. M., Broadbelt, L. J. & Tyo, K. E. J. DORA-XGB: an improved enzymatic reaction feasibility classifier trained using a novel synthetic data approach. Mol. Syst. Des. Eng. 10, 129–142 (2025).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the Max Planck Society, EMBO Postdoctoral Fellowships to B.J.R. (ALTF 337-2023), S.G. (ALTF 162-2022) and A.M.K. (ALTF 684-2022), and a MSCA Fellowship to A.M.K. (Project 101106795 – ECOFix).

Author information

Author notes

  1. These authors contributed equally: Blake J. Rasor, Simone Giaveri, Andreas M. Küffner.

Authors and Affiliations

  1. Max Planck Institute for Terrestrial Microbiology, Marburg, Germany

    Blake J. Rasor, Simone Giaveri, Andreas M. Küffner & Tobias J. Erb

  2. North Carolina State University, Raleigh, NC, USA

    Blake J. Rasor

  3. Ri.MED Foundation, Palermo, Italy

    Simone Giaveri

  4. Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany

    Andreas M. Küffner

  5. Center for Synthetic Microbiology, Marburg, Germany

    Tobias J. Erb

Authors
  1. Blake J. Rasor
    View author publications

    Search author on:PubMed Google Scholar

  2. Simone Giaveri
    View author publications

    Search author on:PubMed Google Scholar

  3. Andreas M. Küffner
    View author publications

    Search author on:PubMed Google Scholar

  4. Tobias J. Erb
    View author publications

    Search author on:PubMed Google Scholar

Contributions

B.J.R., S.G. and A.M.K. wrote the manuscript and designed the figures. T.J.E. guided ideation and edited the manuscript.

Corresponding author

Correspondence to Tobias J. Erb.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Synthesis thanks Xiulai Chen and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Thomas West, in collaboration with the Nature Synthesis team.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rasor, B.J., Giaveri, S., Küffner, A.M. et al. Building complex biochemicals from one-carbon compounds. Nat. Synth 4, 787–798 (2025). https://doi.org/10.1038/s44160-025-00835-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s44160-025-00835-2

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research