Theoretical origin of life: from early polypeptides (Introduction)

by David Turell , Thursday, November 12, 2020, 23:13 (1472 days ago) @ David Turell

Another hopeful approach:

https://science.sciencemag.org/content/370/6518/767

"It is unsurprising, however, that nature provides a guide to its own beginnings. In biochemistry, most amino acid polymerization occurs by translation, which requires ribosomes—a massive assembly of proteins and RNA. Building a primordial ribosome under the conditions of a lifeless planet is a hefty and, as of now, unmet challenge. However, microorganisms use biological nonribosomal peptide synthesis for the production of peptide-based natural products. The nonribosomal peptide synthetases that perform this reaction are chemically much simpler than ribosomes.

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"...most scientists do not believe that cysteine commonly participated in prebiotic chemistry at its earliest stages. Cysteine is often regarded as a late evolutionary addition to the proteinogenic amino acid pool

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"Devising a plausible prebiotic route to cysteine has proven to be challenging. In biology, cysteine synthesis starts from serine and proceeds through a pyridoxal phosphate cofactor-bound dehydroalanine, an intermediate that has a markedly short lifetime in the absence of the cofactor. Foden et al. proposed how this inherent instability might be overcome by beginning the prebiotic synthesis of cysteine from a nonbiological nitrile analog of the amino acid serine.

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"The process began with amino nitriles, but under conditions of alternating reducing and oxidizing environments and excess quantities of sulfide. Such step-changes in reaction conditions pose a problem for a realistic early Earth scenario. However, by exploiting the fact that thiols reversibly add to α-amidonitriles, Foden et al. proposed a strategy for catalytic and redox-neutral oligopeptide synthesis proceeding via a thioimidate intermediate in neutral water. The authors subjected acetylated glycinyl nitrile and free glycine to acetylated cysteine (a hypothetical phosphopantetheine precursor) at 60°C in neutral water. Within 24 hours, an acetylated Gly-Gly peptidyl amidine had formed, at a 60% yield, without the need for synthetic activating agents. This reactivity occurred with a variety of thiols and amino acids. Only amino-terminal serine, threonine, and cysteine could be coupled to α-amidonitriles stereoselectively, which might have implications for the origins of biological homochirality. (my bolds)

"Foden et al. highlight the potential of small-molecule organocatalysis and the pivotal role that thiols might have played in the emergence of biochemistry. Could nature have made peptides this way before the advent of enzymes or the ribosome? This exciting question reveals how much we do not know about the rationale behind the shaping of life's biochemical pathways and the chemical structures used as cofactors and metabolites. If life did once use nitrile-based chemistry, it is unclear why it would have shifted to a biochemistry where nitriles are rare. Also, why does life—seemingly so wastefully—use the phosphopantetheine moiety in nonribosomal peptide synthesis, when it might have used a much simpler thiol, such as cysteine? Experimental insights into these questions will illuminate the currently opaque middle ground between reactions that attempt to recreate life's earliest chemistry and the biochemistry we study today." (my bolds)

Comment: The usual wishful thinking as humans try to design a reasonable natural path to origin of life. The first bold in the second paragraph above points out the guesswork about early Earth and what was available to do the job. The second bold reminds us about all amino acids being left-handed and we do not know why, since it should not naturally happen that way. In the final paragraph the first bold how big the problem is and the second bold questions the chemical design of life as being too complex. I would remind everyone the stupid decisions by so-called thinking humans that our appendix is not necessary and our backwards retina is wrong, have all been disproven.