Report

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

See allHide authors and affiliations

Science  13 Nov 2020:
Vol. 370, Issue 6518, pp. 865-869
DOI: 10.1126/science.abd5680

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

Cysteine as peptide precursor and catalyst

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. 767

Abstract

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.

View Full Text

Stay Connected to Science