Abstract
The possible evolutionary significance of pyrophosphate (PPi) has been discussed since the early 1960s. Lipmann suggested that PPi could have been an ancient currency or a possible environmental source of metabolic energy at origins, while Kornberg proposed that PPi vectorializes metabolism because ubiquitous pyrophosphatases render PPi forming reactions kinetically irreversible. To test those ideas, we investigated the reactions that consume phosphoanhydride bonds among the 402 reactions of the universal biosynthetic core that generates amino acids, nucleotides, and cofactors from H2, CO2, and NH3. We find that 36% of the core’s phosphoanhydride hydrolyzing reactions generate PPi, while no reactions use PPi as an energy currency. The polymerization reactions that generate ~80% of cell mass – protein, RNA, and DNA synthesis – all generate PPi, while none use PPi as an energy source. In typical prokaryotic cells, aminoacyl tRNA synthetases (AARS) underlie ~80% of PPi production. We show that the irreversibility of the AARS reaction is a kinetic, not a thermodynamic effect. The data indicate that PPi is not an ancient energy currency and probably never was. Instead, PPi hydrolysis is an ancient mechanism that imparts irreversibility, as Kornberg suggested, functioning like a ratchet’s pawl to vectorialize the life process toward growth. The two anhydride bonds in nucleoside triphosphates offer ATP-cleaving enzymes an option to impart either thermodynamic control (Pi formation) or kinetic control (PPi formation) upon reactions. This dual capacity explains why nature chose the triphosphate moiety of ATP as biochemistry’s universal energy currency.
Highlights
Starting in the 1960s, thoughts on the possible evolutionary significance of inorganic pyrophosphate (PPi) have centered around two main concepts: irreversibility and energy
In Lipman’s view, PPi was an environmental energy source, a substrate that assumes a thermodynamic role as an educt residing on the left side of an enzymatic reaction, while in Kornberg’s view PPi is synthesized in metabolism via ATP hydrolysis and assumes a kinetic role as a product that is removed from the right side of the reaction
Were the role of PPi in the core thermodynamic, it could have readily been replaced in evolution by compounds with a similar or higher free energy of hydrolysis, such as acetyl phosphate (∆Go′ = −43 kJ·mol−1), 1,3-bisphosphoglycerate (∆Go′ = −52 kJ·mol−1), or phosphoenolpyruvate (∆Go′ = −62 kJ·mol−1), the high energy bonds in all three of which are synthesized in metabolism using one ATP each
Summary
Starting in the 1960s, thoughts on the possible evolutionary significance of inorganic pyrophosphate (PPi) have centered around two main concepts: irreversibility and energy. Kornberg, who worked on nucleic acid polymerization, recognized that PPi producing biochemical steps confer the property of irreversibility upon reactions under physiological conditions because ubiquitous pyrophosphatases constantly degrade PPi in the cytosol of cells (Kornberg, 1962). Pyrophosphate Dependent Irreversibility of Life was straightforward: By degrading PPi, a substrate required for the enzymatic back reaction of the PPi producing step, the rate of the back reaction effectively approaches zero. Kornberg’s list of such irreversible PPi producing reactions included nucleic acid polymerization, translation, and cofactor biosynthetic routes (Kornberg, 1962) and this function, irreversibility, was seen as harboring the significance of PPi
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