Prebiotically plausible chemoselective pantetheine synthesis in water

Abstract

Coenzyme A (CoA) is essential to all life on Earth, and its functional subunit, pantetheine, is important in many origin-of-life scenarios, but how pantetheine emerged on the early Earth remains a mystery. Earlier attempts to selectively synthesize pantetheine failed, leading to suggestions that “simpler” thiols must have preceded pantetheine at the origin of life. In this work, we report high-yielding and selective prebiotic syntheses of pantetheine in water. Chemoselective multicomponent aldol, iminolactone, and aminonitrile reactions delivered spontaneous differentiation of pantoic acid and proteinogenic amino acid syntheses, as well as the dihydroxyl, gem-dimethyl, and β-alanine-amide moieties of pantetheine in dilute water. Our results are consistent with a role for canonical pantetheine at the outset of life on Earth.

Spontaneous Peptide Ligation Mediated by Cysteamine

“…However, despite these advances, the spontaneous synthesis of peptides remains an elusive goal with direct ligation of α-aminonitriles yielding amino-imidazoles that block peptide synthesis (Figure 1A). 20 We recently demonstrated a chemoselective prebiotic synthesis of pantetheine (Figure 1C), 20 the functional fragment of the universal cofactor, coenzyme A, which is essential throughout all domains of life as an acyl-carrier. 13,14 The deep-seated role of pantetheine in biochemistry, for example in the Krebs cycle, fatty acid, and polyketide syntheses, has suggested that thiols may have played a key role in prebiotic chemistry, the "Thioester World" model for the origins of life.…”

“… − Coupling these nitriles, through transformation into thioacids 3 or thioimidates 4 (Figure B), allows efficient protecting-group-free peptide synthesis in water. However, despite these advances, the spontaneous synthesis of peptides remains an elusive goal with direct ligation of α-aminonitriles yielding amino-imidazoles that block peptide synthesis (Figure A) …”

“…Our observations support a scenario in which nitriles may have served as activated substrates for peptide synthesis on the primordial Earth, with cysteamine ( 5 ) playing a role in their ligation. It is of note that 5 is a component of pantetheine, ,− which is essential throughout all domains of life as an acyl-carrier, suggesting that 5 could have been intimately associated with peptide synthesis since the origins of life.…”

“…We recently demonstrated a chemoselective prebiotic synthesis of pantetheine (Figure C), the functional fragment of the universal cofactor, coenzyme A, which is essential throughout all domains of life as an acyl-carrier. , The deep-seated role of pantetheine in biochemistry, for example in the Krebs cycle, fatty acid, and polyketide syntheses, has suggested that thiols may have played a key role in prebiotic chemistry, the “Thioester World” model for the origins of life. − Importantly, in the context of peptides, pantetheine is required in nonribosomal protein modules to generate active thioesters for peptide elongation, and it has been previously proposed that this mode of peptide synthesis may predate ribosomal peptide synthesis during the evolution of life . Therefore, our prebiotic pantetheine synthesis opens exciting questions about the role of pantetheine and its precursor, cysteamine ( 5 ), ,− in prebiotic peptide synthesis. Specifically, whether 5 could play a role in developing and directing a mechanism for spontaneous peptide synthesis in water that would prevent amino-imidazole formation and foreshadow its incorporation into nonribosomal peptide synthesis as a component of pantetheine.…”

“…However, despite these advances, the spontaneous synthesis of peptides remains an elusive goal with direct ligation of α-aminonitriles yielding amino-imidazoles that block peptide synthesis ( Figure 1 A). 20 …”