Skip to main content
Have a personal or library account? Click to login
Shared Pathways to Peptides in Biochemistry and Prebiotic Chemistry through Ester Amide Exchange Chemistry Cover

Shared Pathways to Peptides in Biochemistry and Prebiotic Chemistry through Ester Amide Exchange Chemistry

Open Access
|Apr 2026

References

  1. Airapetian VS, Glocer A, Gronoff G, Hébrard E, Danchi W. Prebiotic chemistry and atmospheric warming of early Earth by an active young Sun. Nature Geoscience. 2016;9(6): 452–455. doi: 10.1038/ngeo2719
  2. Bada JL. New insights into prebiotic chemistry from Stanley Miller’s spark discharge experiments. Chemical Society Reviews. 2013;42(5): 2186. doi: 10.1039/c3cs35433d
  3. Cleaves H. Prebiotic chemistry: geochemical context and reaction screening. Life. 2013;3(2): 331–345. doi: 10.3390/life3020331
  4. Islam S, Powner MW. Prebiotic systems chemistry: complexity overcoming clutter. Chem. 2017;2(4): 470–501. doi: 10.1016/j.chempr.2017.03.001
  5. Azevedo HS, Perry SL, Korevaar PA, Das D. Complexity emerges from chemistry. Nature Chemistry. 2020;12(9): 793–794. doi: 10.1038/s41557-020-0537-x
  6. Singh A, Parvin P, Saha B, Das D. Non-equilibrium self-assembly for living matter-like properties. Nature Reviews Chemistry. 2024;8(10): 723–740. doi: 10.1038/s41570-024-00640-z
  7. Ianeselli A, Salditt A, Mast C, Ercolano B, Kufner CL, Scheu B, et al. Physical non-equilibria for prebiotic nucleic acid chemistry. Nature Reviews Physics. 2023;5(3): 185–195. doi: 10.1038/s42254-022-00550-3
  8. Schwintek P, Eren E, Mast CB, Braun D. Prebiotic gas flow environment enables isothermal nucleic acid replication. eLife. 2025;13: RP100152. doi: 10.7554/eLife.100152
  9. Damer B, Deamer D. The hot spring hypothesis for an origin of life. Astrobiology. 2020;20(4): 429–452. doi: 10.1089/ast.2019.2045
  10. Danger G, Plasson R, Pascal R. Pathways for the formation and evolution of peptides in prebiotic environments. Chemical Society Reviews. 2012;41(16): 5416–5429. doi: 10.1039/c2cs35064e
  11. Dondi D, Merli D, Zeffiro A. Photochemistry of the prebiotic atmosphere. Royal Society of Chemistry; 2013; p.342–359.
  12. Ross D, Deamer D. Dry/Wet cycling and the thermodynamics and kinetics of prebiotic polymer synthesis. Life. 2016;6(3): 28. doi: 10.3390/life6030028
  13. Mamajanov I, Macdonald PJ, Ying J, Duncanson DM, Dowdy GR, Walker CA, et al. Ester formation and hydrolysis during wet-dry cycles: generation of far-from-equilibrium polymers in a model prebiotic reaction. Macromolecules. 2014;47(4): 1334–1343. doi: 10.1021/ma402256d
  14. Frenkel-Pinter M, Samanta M, Ashkenasy G, Leman LJ. Prebiotic peptides: molecular hubs in the origin of life. Chemical Reviews. 2020;120(11): 4707–4765. doi: 10.1021/acs.chemrev.9b00664
  15. Edri R, Joshi MP, Frenkel-Pinter M, Hud NV, Keating CD, Leman LJ. From polymerization-enabled folding and assembly to chemical evolution: key processes for emergence of functional polymers in the origin of life. Astrobiology. 2025; 15311074251365943. doi: 10.1177/15311074251365943
  16. Frenkel-Pinter M, Smith KH, Rivera-Santana VF, Sargon AB, Jacobson KC, et al. Water-based dynamic depsipeptide chemistry: building block recycling and oligomer distribution control using hydration–dehydration cycles. JACS Au. 2022;2(6): 1395–1404. doi: 10.1021/jacsau.2c00087
  17. Forsythe JG, Yu SS, Mamajanov I, Grover MA, Krishnamurthy R, Fernández FM, et al. Ester-mediated amide bond formation driven by wet-dry cycles: a possible path to polypeptides on the prebiotic earth. Angewandte Chemie. 2015;127(34): 10009–10013. doi: 10.1002/ange.201503792
  18. Joshi MP, Sawant AA, Rajamani S. Spontaneous emergence of membrane-forming protoamphiphiles from a lipid–amino acid mixture under wet–dry cycles. Chemical Science. 2021;12(8): 2970–2978. doi: 10.1039/D0SC05650B
  19. Ruiz-Mirazo K, Briones C, De La Escosura A. Prebiotic systems chemistry: new perspectives for the origins of life. Chemical Reviews. 2014;114(1): 285–366. doi: 10.1021/cr2004844
  20. Yadav M, Kumar R, Krishnamurthy R. Chemistry of abiotic nucleotide synthesis. Chemical Reviews. 2020;120(11): 4766–4805. doi: 10.1021/acs.chemrev.9b00546
  21. Capera-Aragones P, Matange K, Rajaei V, Pinter Y, Petrov AS, Williams LD, et al. Stringent selection on kinetics of condensation reactions: early steps in chemical evolution. Physical Chemistry Chemical Physics. 2026; 28: 7292–7303. doi: 10.1039/D5CP03057A
  22. Rode BM. Peptides and the origin of life1. Peptides. 1999;20(6): 773–786. doi: 10.1016/S0196-9781(99)00062-5
  23. Fox SW, Harada K. Thermal copolymerization of amino acids to a product resembling protein. Science. 1958;128(3333): 1214. doi: 10.1126/science.128.3333.1214
  24. Whitaker D, Powner MW. On the aqueous origins of the condensation polymers of life. Nature Reviews Chemistry. 2024;8(11): 817–832. doi: 10.1038/s41570-024-00648-5
  25. Bowman JC, Petrov AS, Frenkel-Pinter M, Penev PI, Williams LD. Root of the tree: the significance, evolution, and origins of the ribosome. Chemical Reviews. 2020;120(11): 4848–4878. doi: 10.1021/acs.chemrev.9b00742
  26. Davidovich C, Belousoff M, Wekselman I, Shapira T, Krupkin M, Zimmerman E, et al. The proto-ribosome: an ancient nano-machine for peptide bond formation. Israel Journal of Chemistry. 2010;50(1): 29–35. doi: 10.1002/ijch.201000012
  27. Bashan A, Agmon I, Zarivach R, Schluenzen F, Harms J, Berisio R, et al. Structural basis of the ribosomal machinery for peptide bond formation, translocation, and nascent chain progression. Molecular Cell. 2003;11(1): 91–102. doi: 10.1016/S1097-2765(03)00009-1
  28. Bose T, Fridkin G, Davidovich C, Krupkin M, Dinger N, Falkovich AH, et al. Origin of life: protoribosome forms peptide bonds and links RNA and protein dominated worlds. Nucleic Acids Research. 2022;50(4): 1815–1828. doi: 10.1093/nar/gkac052
  29. Agmon I, Bashan A, Zarivach R, Yonath A. Symmetry at the active site of the ribosome: structural and functional implications. Biological Chemistry. 2005;386(9): 833–844. doi: 10.1515/BC.2005.098
  30. Schluenzen F, Tocilj A, Zarivach R, Harms J, Gluehmann M, Janell D, et al. Structure of functionally activated small ribosomal subunit at 3.3 Å resolution. Cell. 2000;102(5): 615–623. doi: 10.1016/S0092-8674(00)00084-2
  31. Trobro S, Åqvist J. Mechanism of peptide bond synthesis on the ribosome. Proceedings of the National Academy of Sciences. 2005;102(35): 12395–12400. doi: 10.1073/pnas.0504043102
  32. Petrov AS, Gulen B, Norris AM, Kovacs NA, Bernier CR, Lanier KA, et al. History of the ribosome and the origin of translation. Proceedings of the National Academy of Sciences. 2015;112(50): 15396–15401. doi: 10.1073/pnas.1509761112
  33. Hsiao C, Mohan S, Kalahar BK, Williams LD. Peeling the onion: ribosomes are ancient molecular fossils. Molecular Biology and Evolution. 2009;26(11): 2415–2425. doi: 10.1093/molbev/msp163
  34. Ditzler MA, Petrov AS, Rothschild-Mancinelli B, et al. Co-evolution of RNase P and the ribosome. Proceedings of the National Academy of Sciences. 2026.
  35. Petrov, AS, Alvarez-Carreño C, Dean Williams L, Ditzler MA. Coevolution of RNase P and the ribosome. Proceedings of the National Academy of Sciences. (2026); 123(10): e2518495123. doi: 10.1073/pnas.2518495123
  36. Chandru K, Mamajanov I, Cleaves HJ, Jia TZ. Polyesters as a model system for building primitive biologies from non-biological prebiotic chemistry. Life. 2020;10(1): 6. doi: 10.3390/life10010006
  37. Jia TZ, Chandru K, Hongo Y, Afrin R, Usui T, Myojo K, et al. Membraneless polyester microdroplets as primordial compartments at the origins of life. Proceedings of the National academy of Sciences of the United States of America. 2019;116(32): 15830–15835. doi: 10.1073/pnas.1902336116
  38. Mamajanov I, Callahan MP, Dworkin JP, Cody GD. Prebiotic alternatives to proteins: structure and function of hyper-branched polyesters. Origins of Life and Evolution of Biospheres. 2015;45(1–2): 123–137. doi: 10.1007/s11084-015-9430-9
  39. Campbell TD, Febrian R, McCarthy JT, Kleinschmidt HE, Forsythe JG, Bracher PJ. Prebiotic condensation through wet–dry cycling regulated by deliquescence. Nature Communications. 2019;10(1): 4508. doi: 10.1038/s41467-019-11834-1
  40. Doran D, Abul-Haija YM, Cronin L. Emergence of function and selection from recursively programmed polymerisation reactions in mineral environments. Angewandte Chemie. 2019;58(33): 11253–11256. doi: 10.1002/anie.201902287
  41. Edri R, Fisher S, Menor-Salvan C, Williams LD, Frenkel-Pinter M. Assembly-driven protection from hydrolysis as key selective force during chemical evolution. FEBS Letters. 2023;597(23): 2879–2896. doi: 10.1002/1873-3468.14766
  42. Ezerzer Y, Frenkel-Pinter M, Kolodny R, Ben-Tal N. A building blocks perspective on protein emergence and evolution. Current Opinion in Structural Biology. 2025;91: 102996. doi: 10.1016/j.sbi.2025.102996
  43. Forsythe JG, Petrov AS, Millar WC, Yu SS, Krishnamurthy R, Grover MA, et al. Surveying the sequence diversity of model prebiotic peptides by mass spectrometry. Proceedings of the National Academy of Sciences. 2017;114(37): E7652–E9. doi: 10.1073/pnas.1711631114
  44. Frenkel-Pinter M, Haynes JW, C M, Petrov AS, Burcar BT, Krishnamurthy R, et al. Selective incorporation of proteinaceous over nonproteinaceous cationic amino acids in model prebiotic oligomerization reactions. Proceedings of the National academy of Sciences of the United States of America. 2019;116(33): 16338–16346. doi: 10.1073/pnas.1904849116
  45. Frenkel-Pinter M, Jacobson KC, Eskew-Martin J, Forsythe JG, Grover MA, Williams LD, et al. Differential oligomerization of alpha versus beta amino acids and hydroxy acids in abiotic proto-peptide synthesis reactions. Life. 2022;12(2): 265. doi: 10.3390/life12020265
  46. Frenkel-Pinter M, Sargon AB, Glass JB, Hud NV, Williams LD. Transition metals enhance prebiotic depsipeptide oligomerization reactions involving histidine. RSC Advances. 2021;11(6): 3534–3538. doi: 10.1039/D0RA07965K
  47. Yu S-S, Krishnamurthy R, Fernández FM, Hud NV, Schork FJ, Grover MA. Kinetics of prebiotic depsipeptide formation from the ester–amide exchange reaction. Physical Chemistry Chemical Physics. 2016;18(41): 28441–28450. doi: 10.1039/C6CP05527C
  48. Zhang L, Ying J. Amino acid analogues provide multiple plausible pathways to prebiotic peptides. Journal of the Royal Society Interface: Royal Society Publishing. 2024;21(214): 20240014. doi: 10.1098/rsif.2024.0014
  49. Edri R, Williams LD, Frenkel-Pinter M. From catalysis of evolution to evolution of catalysis. Accounts of Chemical Research. 2024;57(21): 3081–3092. doi: 10.1021/acs.accounts.4c00196
  50. John R. Cronin, Carleton B. Moore. Amino Acid Analyses of the Murchison, Murray, and Allende Carbonaceous Chondrites. Science. 1971;172: 1327–1329. doi: 10.1126/science.172.3990.1327.
  51. Aponte JC, Elsila JE, Hein JE, Dworkin JP, Glavin DP, McLain HL, et al. Analysis of amino acids, hydroxy acids, and amines in CR chondrites. Meteoritics and Planetary Science. 2020;55(11): 2422–2439. doi: 10.1111/maps.13586
  52. Chyba C, Sagan C. Endogenous production, exogenous delivery and impact-shock synthesis of organic molecules: an inventory for the origins of life. Nature. 1992;355(6356): 125–132. doi: 10.1038/355125a0
  53. Zaia DAM, Zaia CTBV, De Santana H. Which amino acids should be used in prebiotic chemistry studies? Origins of Life and Evolution of Biospheres. 2008;38(6): 469–488. doi: 10.1007/s11084-008-9150-5
  54. Muchowska KB, Varma SJ, Moran J. Nonenzymatic metabolic reactions and life’s origins. Chemical Reviews. (2020);120(15): 7708–7744. doi: 10.1021/acs.chemrev.0c00191.
  55. Cleaves HJ II. The origin of the biologically coded amino acids. Journal of Theoretical Biology. 2010;263(4): 490–498. doi: 10.1016/j.jtbi.2009.12.014
  56. Newton MS, Morrone DJ, Lee KH, Seelig B. Genetic code evolution investigated through the synthesis and characterisation of proteins from reduced-alphabet libraries. Chembiochem: A European Journal of Chemical Biology. 2019;20(6): 846–856. doi: 10.1002/cbic.201800668
  57. Makarov M, Sanchez Rocha AC, Krystufek R, Cherepashuk I, Dzmitruk V, Charnavets T, et al. Early selection of the amino acid alphabet was adaptively shaped by biophysical constraints of foldability. Journal of the American Chemical Society. 2023;145(9): 5320–5329. doi: 10.1021/jacs.2c12987
  58. Trifonov EN. Consensus temporal order of amino acids and evolution of the triplet code. Gene. 2000;261(1): 139–151. doi: 10.1016/S0378-1119(00)00476-5
  59. Ilardo M, Meringer M, Freeland S, Rasulev B, Cleaves HJ II. Extraordinarily adaptive properties of the genetically encoded amino acids. Scientific Reports. 2015;5(1): 9414. doi: 10.1038/srep09414
  60. Hartman H. Speculations on the evolution of the genetic code. Origins of Life. 1975;6(3): 423–427. doi: 10.1007/BF01130344
  61. Harrison SA, Palmeira RN, Halpern A, Lane N. A biophysical basis for the emergence of the genetic code in protocells. Biochimica et Biophysica Acta - Bioenergetics. 2022;1863(8): 148597. doi: 10.1016/j.bbabio.2022.148597
  62. Halpern A, Bartsch LR, Ibrahim K, Harrison SA, Ahn M, Christodoulou J, et al. Biophysical interactions underpin the emergence of information in the genetic code. Life. 2023;13(5): 1129. doi: 10.3390/life13051129
  63. Fisher S, Ezerzer Y, Edri R, Akulenko D, Marland E, Frenkel-Pinter M. Protopeptide backbone affects assembly in aqueous solutions. Proceedings of the National Academy of Sciences. 2025;122(40): e2500503122. doi: 10.1073/pnas.2500503122
  64. Fialho DM, Karunakaran SC, Greeson KW, Martínez I, Schuster GB, Krishnamurthy R, et al. Depsipeptide nucleic acids: pre-biotic formation, oligomerization, and self-assembly of a new proto-nucleic acid candidate. Journal of the American Chemical Society. 2021;143(34): 13525–13537. doi: 10.1021/jacs.1c02287
  65. Marland E, Lipson G, Edri R, Cohen O, Guzman-Martinez A, Shalev O, et al. Robust synthesis of prebiotic precursors in drying reactions of amino acids and keto acids. ChemSystemsChem. 2025; 8(1): e00018. doi: 10.1002/syst.202500018.
  66. Li Z, Li L, McKenna KR, Schmidt M, Pollet P, Gelbaum L, et al. The oligomerization of glucose under plausible prebiotic conditions. Origins of Life and Evolution of Biospheres. 2019;49(4): 225–240. doi: 10.1007/s11084-019-09588-3
  67. Brunk CF, Marshall CR. ‘Whole organism’, systems biology, and top-down criteria for evaluating scenarios for the origin of life. Life. 2021;11(7): 690. doi: 10.3390/life11070690.
  68. Kocher CD, Dill KA. The prebiotic emergence of biological evolution. Royal Society Open Science. 2024;11(7): 240431. doi: 10.1098/rsos.240431
  69. Kocher C, Dill KA. Origins of life: first came evolutionary dynamics. QRB Discovery. 2023;4: e4. doi: 10.1017/qrd.2023.2
Language: English
Page range: 19 - 24
Published on: Apr 30, 2026
In partnership with: Paradigm Publishing Services

© 2026 Yishi Ezerzer, Disha-Gajanan Hiregange, Anat Bashan, Ada Yonath, Moran Frenkel-Pinter, published by The Israel Biocomplexity Center
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License.