Small Cyclic Peptide for Pyrophosphate Dependent Ligation in Prebiotic Environments

Abstract

<jats:p>All life on Earth uses one universal biochemistry stemming from one universal common ancestor of all known living organisms. One of the most striking features of this universal biochemistry is its utter dependence on phosphate group transfer between biochemical molecules. Both nucleic acid and peptide biological synthesis relies heavily on phosphate group transfer. Such dependents strongly indicate very early incorporation of phosphate chemistry in the origin of life. Perhaps as early as prebiotic soup stage. We report here on a short cyclic peptide, c(RPDDHR), designed rationally for pyrophosphate interaction, which is able to create a new amide bond dependent on the presence of pyrophosphate. We believe this result to be a first step in the exploration of Phosphate Transfer Catalysts that must have been present and active in prebiotic soup and must have laid down foundations for the universal bioenergetics.</jats:p>

A Phage Display-Identified Short Peptide Capable of Hydrolyzing Calcium Pyrophosphate Crystals—The Etiological Factor of Chondrocalcinosis

“…Synthesized peptides were tested for CaPP hydrolysis properties along with peptide cyclo(RPDDHR) (C3) expressing some pyrophosphatase/synthetase properties [ 24 ]: serine–histidine (SH) dipeptide known from its hydrolytic abilities [ 25 , 26 ] and SGAGKT (W1) peptide designed to resemble a proteinaceous Walker A motif (p-loop) to bind inorganic phosphate ions [ 27 ]. Additionally, a sample with a 30 times higher concentration of Mg 2+ (-p30xM) was prepared, as high concentrations of this ion are also known to speed up the hydrolysis of pyrophosphate [ 28 ].…”

“…A Kaiser test was performed before every coupling and Fmoc deprotection. Peptide C3 synthesis was described elsewhere [ 24 ]. SerHis peptide was obtained from Bachem (Bubendorf, Switzerland).…”

Pyrophosphate and Irreversibility in Evolution, or why PPi Is Not an Energy Currency and why Nature Chose Triphosphates

“…Our present interest in PP i stems from comparative physiological investigations into the energetics of primordial metabolism (Martin and Russell, 2007;Sousa et al, 2013;Sousa and Martin, 2014;Preiner et al, 2020). We reasoned that if PP i had played any role in primordial energetics, as is widely assumed (de Duve, 1991;Russell et al, 2013Russell et al, , 2014Wang et al, 2019;Piast et al, 2020), evidence for that role should be preserved in the conserved core of metabolism within modern cells. This is the same conventional logic that is used to interpret other aspects of physiology as relicts of ancient metabolism: metal sulfide clusters in proteins (Eck and Dayhoff, 1966;Wächtershäuser, 1992;Heinen and Lauwers, 1997), the use of organic cofactors as catalysts (White, 1976), carbon metal bonds in enzyme active sites (Martin, 2019), thioesters as energy currencies (Semenov et al, 2016;Kitadai et al, 2021), or anaerobic chemolithoautotrophy (Mereschkowsky, 1910;Decker et al, 1970).…”

“…That finding, together with Reeves’ report of a PP i -dependent glycolytic enzyme ( Reeves, 1968 ), now called pyruvate orthophosphate dikinase, seemed to support an ancient bioenergetic role behind the possible evolutionary significance of PP i . Based on such findings, the view that PP i ’s evolutionary significance resides in primordial energetics established a long tradition that is still widely embraced ( de Duve, 1991 ; Russell and Hall, 1997 ; Russell et al, 2013 , 2014 ; Wang et al, 2019 ; Piast et al, 2020 ) though seldom critically inspected ( Martin, 2020 ).…”

A Prebiotic Precursor to Life’s Phosphate Transfer System with an ATP Analog and Histidyl Peptide Organocatalysts

“…35 Histidyl-containing cyclic peptides catalyze also the hydrolysis of pyrophosphate. 36 Histidine may also ligate metals, e.g., Zn 2+ , to form complexes that catalyze depsipeptide oligomerization. 37 Phosphorylated histidyl peptides have been shown to undergo liquid−liquid phase separation to form coacervates.…”