A Plausible Prebiotic One‐Pot Synthesis of Orotate and Pyruvate Suggestive of Common Protometabolic Pathways

Clay, Alyssa P.; Cooke, Rachel E.; Kumar, Ritwik; Yadav, Mahipal; Krishnamurthy, Ramanarayanan; Springsteen, Greg

doi:10.1002/ange.202112572

Cited by 8 publications

(5 citation statements)

References 42 publications

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“…The beginnings of life's origin perhaps used pyruvate, heavy metals, and glyoxylate as catalysts for the TCA cycle development and anaerobic energetics. 55 Life then evolved fixed and moving structures from CO 2 using 5 energy metabolic hubs 56 that included pyruvate, acetate, oxaloacetate, succinate, and alpha-ketoglutarate. Early survival needed these chemicals without or with ATP to implement the universal survival principle of resistance and tolerance to environmental stressors.…”

Section: "Nothing In Biology Makes Sense Except In the Light Of Evolu...mentioning

confidence: 99%

“…The beginnings of life's origin perhaps used pyruvate, heavy metals, and glyoxylate as catalysts for the TCA cycle development and anaerobic energetics 55 . Life then evolved fixed and moving structures from CO 2 using 5 energy metabolic hubs 56 that included pyruvate, acetate, oxaloacetate, succinate, and alpha‐ketoglutarate.…”

Section: “Nothing In Biology Makes Sense Except In the Light Of Evolu...mentioning

confidence: 99%

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Sepsis, pyruvate, and mitochondria energy supply chain shortage

McCall

Zhu

Zabalawi

et al. 2022

Journal of Leukocyte Biology

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Balancing high energy-consuming danger resistance and low energy supply of disease tolerance is a universal survival principle that often fails during sepsis. Our research supports the concept that sepsis phosphorylates and deactivates mitochondrial pyruvate dehydrogenase complex control over the tricarboxylic cycle and the electron transport chain. StimulatIng mitochondrial energetics in septic mice and human sepsis cell models can be achieved by inhibiting pyruvate dehydrogenase kinases with the pyruvate structural analog dichloroacetate. Stimulating the pyruvate dehydrogenase complex by dichloroacetate reverses a disruption in the tricarboxylic cycle that induces itaconate, a key mediator of the disease tolerance pathway. Dichloroacetate treatment increases mitochondrial respiration and ATP synthesis, decreases oxidant stress, overcomes metabolic paralysis, regenerates tissue, organ, and innate and adaptive immune cells, and doubles the survival rate in a murine model of sepsis.

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Section: "Nothing In Biology Makes Sense Except In the Light Of Evolu...mentioning

confidence: 99%

Section: “Nothing In Biology Makes Sense Except In the Light Of Evolu...mentioning

confidence: 99%

Sepsis, pyruvate, and mitochondria energy supply chain shortage

McCall

Zhu

Zabalawi

et al. 2022

Journal of Leukocyte Biology

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“…This reaction of glyoxylate giving rise to hydantoin becomes signi cant in the context of the recent prebiotic synthesis of orotate from the reaction of hydantoin with glyoxylate. 28 And thus, not unexpectedly, traces (ca. 1%) of orotate was also observed in the reaction mixture (Supplementary Figs.…”

Section: Resultsmentioning

confidence: 91%

Prebiotic synthesis of α-amino acids and orotate from α-ketoacids potentiates transition to extant metabolic pathways

et al. 2022

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The Strecker reaction of aldehydes is the preeminent pathway to explain the prebiotic origins of a-amino acids. However, biology employs transamination of a-ketoacids to give rise to amino acids which are then transformed to nucleobases, implying subsequent evolution of the biosynthetic pathways -abiotically or biotically. Herein, we show that a-ketoacids react with cyanide and ammonia sources to form the corresponding a-amino acids -via the Bucherer-Bergs pathway. An e cient prebiotic transformation of oxaloacetate to aspartate via N-carbamoyl aspartate enables the simultaneous formation of dihydroorotate, paralleling the biochemical synthesis of orotate as the precursor to pyrimidine nucleobases. Glyoxylate forms both glycine and orotate, and reacts with malonate and urea to form aspartate and dihydroorotate. These results, along with the previously demonstrated protometabolic analogs of the Krebs cycle suggest that there can be a natural emergence of congruent forerunners of biological pathways with the potential for seamless transition from prebiotic chemistry to modern metabolism.

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“…Some theoretical mechanisms are based on third-order elementary reactions, which are comparatively rare in real-world chemistry (Cao et al, 2006). Complementing decades of research into the origins of protometabolism (Clay et al, 2022;Harrison et al, 2023;Nader et al, 2022;Patel et al, 2015), geochemical circumstances that would enable chemical logic gates to spontaneously emerge, be executed, and be reprogrammed are of fundamental interest to the prebiotic chemistry community.…”

Section: Introductionmentioning

confidence: 99%

Two mechanisms for the spontaneous emergence, execution, and reprogramming of chemical logic circuits

Peng,

Adam

2023

Preprint

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A key question in origin-of-life research is how primitive life or life-like systems obtained reusable and reprogrammable machineries of processing information to respond to various environmental and internal stimuli. One strategy to approach this question is viewing living systems as universal chemical computers. This approach focuses upon uncovering how reusable and reprogrammable chemical NOT, AND, and OR logic gates could appear under prebiotically possible scenarios where simple chemicals and second- or lower-order reactions are more frequent than macromolecules and higher-order reactions. Here, we model two theoretical mechanisms of forming Boolean gates based on geochemically plausible reaction systems that could have preceded complex biopolymers. The mechanisms exploit simple bistable autocatalytic systems to encode binary variables and use heterogeneous dilution rates to differentially activate or deactivate autocatalysis in different reactors. We found that NOT, AND, and OR gates, as well as more complex logic circuits, can spontaneously arise from connected, well-mixed flow reactors based on (i) catalysis by a heterodimer between mutually inhibitory autocatalysts or (ii) selectively permeable tunnels connecting reactors. Our results suggest that the prebiotic emergence of chemical logic circuits provides new guides for experimentally actualizing chemical computation.

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A Plausible Prebiotic One‐Pot Synthesis of Orotate and Pyruvate Suggestive of Common Protometabolic Pathways

Cited by 8 publications

References 42 publications

Sepsis, pyruvate, and mitochondria energy supply chain shortage

Sepsis, pyruvate, and mitochondria energy supply chain shortage

Prebiotic synthesis of α-amino acids and orotate from α-ketoacids potentiates transition to extant metabolic pathways

Two mechanisms for the spontaneous emergence, execution, and reprogramming of chemical logic circuits

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