PT  - JOURNAL ARTICLE
AU  - Foden, Callum S.
AU  - Islam, Saidul
AU  - Fernández-García, Christian
AU  - Maugeri, Leonardo
AU  - Sheppard, Tom D.
AU  - Powner, Matthew W.
TI  - Prebiotic synthesis of cysteine peptides that catalyze peptide ligation in neutral water
AID  - 10.1126/science.abd5680
DP  - 2020 Nov 13
TA  - Science
PG  - 865--869
VI  - 370
IP  - 6518
4099  - http://science.sciencemag.org/content/370/6518/865.short
4100  - http://science.sciencemag.org/content/370/6518/865.full
SO  - Science2020 Nov 13; 370
AB  - Among amino acids, cysteine is highly reactive as a nucleophile, metal ligand, and participant in redox and radical reactions. These properties make cysteine attractive as a component of prebiotic chemistry, but traditional Strecker synthesis of α-aminonitriles, which can serve as peptide precursors, cannot produce free cysteine. Foden et al. found that a simple acylation of the free amine prevented degradation of cysteine nitrile and enabled synthesis of this cysteine precursor from acetyl dehydroalanine nitrile and a sulfide donor (see the Perspective by Muchowska and Moran). When combined with other proteinogenic α-aminonitriles, acetylcysteine or derivative thiols catalyzed efficient peptide ligation in water. These results highlight how prebiotic synthesis of precursors can also generate function by creating a catalyst for polymerization.Science, this issue p. 865; see also p. 767Peptide 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.