Crystallographic analysis revealed that both this peptide and its Dab-substituted derivative adopted the double-Z β-barrel (DZBB) fold, a likely evolutionary intermediate between extant β-barrel folds, which might have supported the foldability of primitive proteins before the incorporation of lysine and arginine into the genetic code.
A central question in origin-of-life research is how biological macromolecules and cellular structures arose from simple precursors under prebiotic conditions. This review focuses on the chemical evolution model of N-phosphoryl amino acids (NPAAs) and their multifaceted roles in this process. Featuring high-energy P–N bonds, NPAAs enable intramolecular activation via pentacoordinate phosphorus intermediates, facilitating the formation of homochiral peptides and nucleotides under mild aqueous conditions. Moreover, N-amino acid-nucleotide conjugates (N-aa-NMPs) drive peptide formation with chiral selection between amino acids and nucleosides, where the peptide yield for each amino acid is modulated by specific nucleosides, thereby laying a foundation for a proto-genetic code. Additionally, amphiphilic NPAA derivatives spontaneously self-assemble into vesicles and selectively condense peptides at membrane interfaces, whereas the in situ generation of N-fatty acyl amino acids further enhances membrane stability. Collectively, these findings support a phosphorus-centered model for the integrated origin of nucleic acids, proteins, and membranes.
Jianxi Ying, Yan Liu, Songsen Fu et al.· Accounts of Chemical Researc...· 0 citations
Aminoacyl-tRNA synthetases (aaRSs) catalyze the attachment of amino acids (AAs) to their cognate tRNAs during protein synthesis. As aaRSs possess highly selective amino acid-binding sites, a distinct enzyme is generally required for each amino acid in the genetic code. Recently, genetic code expansion (GCE) has emerged as a powerful strategy for incorporating non-canonical amino acids (ncAAs) during ribosomal translation, enabling the production of proteins with novel structures and functions. In this study, we propose that aaRSs can recognize halogenated ncAAs through halogen bonding (XB), and that the stronger XB-forming ability of iodine, compared with chlorine or bromine, enables the selective incorporation of 3,5-diiodo-l-tyrosine into proteins. We demonstrate the successful generation of aaRSs that specifically recognize 3,5-diiodo-l-tyrosine during translation, even in the presence of closely related amino acids such as 3,5-dichloro-, 3,5-dibromo-, and 3,5-dimethyl-l-tyrosine. These results confirm that ncAA recognition by aaRSs occurs through XB. Overall, this study not only shows that XB can serve as a driving force for expanding the genetic code with ncAAs, but also demonstrates that aaRSs can be engineered to discriminate among structurally similar ncAAs that differ by only a single atom.
Surendar R Jakka, Sandhya Jaiswal, K. M. Reddy et al.· Angewandte Chemie· 0 citations
The search for life beyond Earth has focused on planets and moons with liquid water, reflecting the assumption that complex biomolecules require aqueous environments to remain stable and functional. Such a view excludes a wide class of planetary settings, including the concentrated sulfuric acid clouds of Venus, where extreme acidity and minimal water are thought to preclude molecular structure despite suitable temperatures. A growing body of evidence shows that a wide range of organic molecules can remain stable in concentrated sulfuric acid, including nucleic acid bases, amino acids, lipid micelles and vesicles, and peptide nucleic acid (PNA), but such stability does not address whether macromolecules can retain folded structures required for function. Using NMR spectroscopy, here we show that three peptides adopt stable, well-defined folded structures in concentrated (98% w/w) sulfuric acid, an extreme solvent environment that has been long assumed to be incompatible with biomolecules. The peptides form compact Ω-loop conformations stabilized by solvent-mediated interactions and intramolecular hydrogen bonding. This finding strongly counters conventional thinking where sulfuric acid would destroy peptide bonds via acid-catalyzed hydrolysis. Here, the near absence of water in 98% (w/w) sulfuric acid means hydrolysis does not occur. The result identifies a regime in which macromolecular structure persists under conditions long considered incompatible with life. The finding expands the range of planetary environments that may support complex chemistry and motivates renewed consideration of chemically diverse exoplanets in the search for signs of life beyond Earth.
Unknown authors· Proceedings of the National...· 0 citations
We have demonstrated the potential of amino acids to polymerise into peptides, proteins, and form cell-like structures in the absence of cellular machinery, including nucleic acids, lipids or sugars. Not only has cell-free protein replication been observed, but evidence of protein templating strongly suggests protein mediated replication. We believe this is the first experimental demonstration of the link between the Miller-Urey experiment which produced amino acids from elemental starting material, and cell-like structures. Life, by definition, is the condition that distinguishes animals and plants from inorganic matter, including the capacity for growth, reproduction, functional activity, and continual change preceding death. Here we have characterised peptides which form reproducibly, into structures with longevity and which subsequently catalyse the polymerisation of free amino acids into copies of themselves. The proteomic analysis of these samples over time also enables evolution of peptide sequences to be seen and quantified. This evolution of both complex structure and functionally active proteins may potentially demonstrate a credible path to the beginnings of life, which we call the Spontaneous Evolution of Biology (SEB) Theory. One Sentence Summary We have shown how peptides and proteins can be made from amino acids in an aqueous media without cells, lipids or nucleic acids, duplicating themselves and forming complex structures which resemble cells.
S. ten Have, Ewan McMillan, Tim Medway et al.· bioRxiv· 0 citations
The rapid advancement of protein engineering and genetic code expansion technologies over the last decade has reshaped how researchers rationally design proteins with novel catalytic functions. Among these approaches, the site-specific incorporation of unnatural amino acids has enabled the introduction of chemical functionalities that are inaccessible to the canonical amino acid space. In this perspective, we highlight the metal-chelating UAA (2,2′-bipyridin-5-yl) alanine (BpyAla) and its emerging utility in mediating nucleic acid cleavage. Multiple studies have demonstrated the successful site-specific incorporation of BpyAla into proteins of interest, where subsequent metal coordination enables catalytic cleavage of DNA and RNA substrates. Here, we discuss the potential of BpyAla-mediated nucleic acid cleavage, with emphasis on the development of next-generation BpyAla analogues, the exploration of alternative metal cofactors, cooperative and multi-residue design strategies, and the expansion of compatible protein scaffolds and nucleic acid substrates. Designable BpyAla-engineered systems represent an emerging frontier in artificial metallonuclease design, with potential long-term relevance to targeted nucleic acid therapeutics.
E. Lundrigan, Matthew T. O’Neill, J. P. Pezacki· Frontiers in Chemical Biolog...· 0 citations
The abiotic formation of peptides in water remains a fundamental challenge in origin-of-life research. Direct aqueous condensation of amino acids is thermodynamically hindered; consequently, existing models frequently depend on activation agents or require extreme conditions. We have developed and implemented an aqueous pathway for peptide synthesis mediated by carbamoyl phosphate (CAP) within a mild, “warm little pond” scenario. Co-incubation of diverse proteinogenic amino acids with CAP and metal cations promoted peptide bond formation. Our analysis reveals that magnesium ions operate synergistically with CAP, driving a dual-activation mechanism through
N
-carbamoylation and
O
-phosphorylation intermediates. Crucially, we establish that CAP can be generated in situ directly from early-Earth accessible precursors, urea and orthophosphate. This continuous aqueous pathway entirely bypasses the necessity for destructive dry-state cycles. CAP continues to play a vital role in nitrogen metabolism and the de novo synthesis of pyrimidine nucleotides in extant organisms. Therefore, we suggest that CAP serves as an evolutionary bridge, linking primordial geochemical conditions to the emergence of functional biochemical machinery.
Xiangxiao Zheng, Fude Chen, Min Zhang et al.· Communications Chemistry· 0 citations
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