Prebiotic synthesis of cysteine peptides that catalyze peptide ligation in neutral water.

Peptide biosynthesis is performed by ribosomes and several other classes of enzymes, but a simple chemical synthesis may have created the first peptides at the origins of life. α-Aminonitriles-prebiotic α-amino acid precursors-are generally produced by Strecker reactions. However, cysteine's aminothiol is incompatible with nitriles. Consequently, cysteine nitrile is not stable, and cysteine has been proposed to be a product of evolution, not prebiotic chemistry. We now report a high-yielding, prebiotic synthesis of cysteine peptides. Our biomimetic pathway converts serine to cysteine by nitrile-activated dehydroalanine synthesis. We also demonstrate that N-acylcysteines catalyze peptide ligation, directly coupling kinetically stable-but energy-rich-α-amidonitriles to proteinogenic amines. This rare example of selective and efficient organocatalysis in water implicates cysteine as both catalyst and precursor in prebiotic peptide synthesis.

Selective aqueous acetylation controls the photoanomerization of α-cytidine-5'-phosphate.

Nucleic acids are central to information transfer and replication in living systems, providing the molecular foundations of Darwinian evolution. Here we report that prebiotic acetylation of the non-natural, but prebiotically plausible, ribonucleotide α-cytidine-5'-phosphate, selectively protects the vicinal diol moiety. Vicinal diol acetylation blocks oxazolidinone formation and prevents C2'-epimerization upon irradiation with UV-light. Consequently, acetylation enhances (4-fold) the photoanomerization of α-cytidine-5'-phosphate to produce the natural ß-pyrimidine ribonucleotide-5'-phosphates required for RNA synthesis.

A Chemist's Perspective on the Role of Phosphorus at the Origins of Life.

The central role that phosphates play in biological systems, suggests they also played an important role in the emergence of life on Earth. In recent years, numerous important advances have been made towards understanding the influence that phosphates may have had on prebiotic chemistry, and here, we highlight two important aspects of prebiotic phosphate chemistry. Firstly, we discuss prebiotic phosphorylation reactions; we specifically contrast aqueous electrophilic phosphorylation, and aqueous nucleophilic phosphorylation strategies, with dry-state phosphorylations that are mediated by dissociative phosphoryl-transfer. Secondly, we discuss the non-structural roles that phosphates can play in prebiotic chemistry. Here, we focus on the mechanisms by which phosphate has guided prebiotic reactivity through catalysis or buffering effects, to facilitating selective transformations in neutral water. Several prebiotic routes towards the synthesis of nucleotides, amino acids, and core metabolites, that have been facilitated or controlled by phosphate acting as a general acid-base catalyst, pH buffer, or a chemical buffer, are outlined. These facile and subtle mechanisms for incorporation and exploitation of phosphates to orchestrate selective, robust prebiotic chemistry, coupled with the central and universally conserved roles of phosphates in biochemistry, provide an increasingly clear message that understanding phosphate chemistry will be a key element in elucidating the origins of life on Earth.