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Schematic of top-down and bottom-up approaches to study proto-metabolism and the origins of metabolism.

Proto-metabolism refers to a series of linked chemical reactions in a prebiotic environment. Combining ongoing research in astrobiology and prebiotic chemistry, work in this area focuses on reconstructing the connections between potential metabolic processes that may have occurred in early Earth conditions. Proto-metabolism is believed to be simpler than extant (modern) metabolism and LUCA, as simple organic molecules likely gave rise to more complex metabolic networks. Prebiotic chemists have demonstrated abiotic generation of many simple organic molecules including amino acids,^[1] fatty acids,^[2] simple sugars,^[3] and nucleobases.^[4] There are multiple scenarios bridging prebiotic chemistry to early metabolic networks that occurred before the origins of life. In addition, there are hypotheses made on the evolution of biochemical pathways including the metabolism-first hypothesis.^[5] Scientists have also analyzed LUCA and modern metabolism to determine the composition of key early metabolic networks.

Proto-metabolism is a key area of research approaching abiogenesis.

Autocatalytic Prebiotic Chemistries

Autocatalytic reactions are reactions where the reaction product acts as a catalyst for its own formation. Many research groups that study proto-metabolism agree that early metabolic networks likely originated as a set of chemical reactions that form self-sustaining networks.^[6]^[7]^[8] This set of reactions is commonly referred to as an autocatalytic set. Some prebiotic chemistries focus on these autocatalytic reactions including the formose reaction, HCN oligomerization, and formamide chemistry.

Formose Reaction

Discovered in 1861 by Aleksandr Butlerov, the formose reaction is a set of two reactions converting formaldehyde (CH₂O) to a mixture of simple sugars.^[9]^[10] Formaldehyde is an intermediate in the oxidation of simple carbon molecules (eg. methane) and was likely present in early Earth's atmosphere.^[11] The first reaction is the slow conversion of formaldehyde (C1 carbon) to glycoaldehyde (C2 carbon) and occurs through an unknown mechanism. The second reaction is the faster and autocatalytic formation of higher weight aldoses and ketoses.^[12] The kinetics of the formose reaction are often described as autocatalytic, as the alkaline reaction uses lowest molecular weight sugars as feedstocks into the reaction.^[7] Self-organized autocatalytic networks, like the formose reaction, would allow for adaptation to changing prebiotic environmental conditions.^[7] As a proof-of-concept, Robinson and colleagues demonstrated how changing environmental conditions and catalyst availability can impact the resultant sugar products.^[8]

This reaction is particular significant to abiogenesis and the origins of metabolism, as it can lead to ribose. Ribose is a building block of RNA and an important precursor in proto-metabolism. However, there are still limitations for the formose reaction to be the chemical origin of sugars including the low chemoselectivity for ribose and high complexity of the final reaction mixture.^[13]

HCN Oligomerization

On Earth, hydrogen cyanide (HCN) is abundant in volcanic eruptions and hydrothermal vents.^[14] On the Hadean Earth, large impactor events and active hydrothermal processes likely contributed to widespread metal production and metal-based proto-metabolism.^[15] Hydrogen cyanide has also been detected in meteorites and atmospheres in the solar system.^[16]^[17]

HCN-derived polymers are the oligomer or hydrolysis products of HCN.^[18] These polymers can be synthesized from HCN or cyanide salts often in alkaline conditions, but they have been observed in a wide range of experimental conditions.^[4]^[19] HCN readily reacts with itself^[20] to produce many HCN polymers and biologically-relevant compounds like nucleobases,^[4]^[21] amino acids,^[22] and carboxylic acids.^[23] The diversity of products could point to a plausible proto-metabolic network of HCN oligomerization reactions. However, many groups point to low HCN concentrations in early Earth and low chemioselectivity of key biologically-relevant products, similar to the formose reaction.^[24]

Formamide Chemistry

Formamide (NH₂CHO) is the simplest naturally-occurring amide. Similar to HCN, formamide is equally abundant in the universe.^[25] Formamide has specific physical and stability properties suitable for a universal prebiotic precursor.^[7] For example, it has four universal atomic elements ubiquitous to life: C, H, O, N. The presence of unique functional groups involving oxygen and nitrogen allow for unique reaction chemistries to build key biomolecules like amino acids, sugars, nucleosides and other key intermediates of other prebiotic reactions (eg. TCA cycle).^[7]^[26] In addition, early Earth geological features like hydrothermal pores could support formamide chemistry and synthesis of key prebiotic biomolecules with concentration requirements.^[27]

Overall, formamide chemistry can support connections and substrates needed to support prebiotic biomolecule synthesis including the formose reaction, Strecker synthesis, HCN oligomerization, or the Fischer-Tropsch process.^[7]^[28] In addition, formamide can be easily concentrated through evaporation reactions as it has a boiling point of 210C.^[25]^[29] Although this reaction has the highest versatility across one-carbon atom precursors, the connections between different biosynthetic pathways are yet to be directly explored experimentally.

Experimental Reconstruction of Proto-metabolism

Many research groups are actively attempting experimental reconstruction of the interactions between prebiotic reactions. One major consideration is the ability for these reactions to operate in the same environmental conditions.^[30] These one-pot syntheses would likely push the reaction towards specific subgroups of molecules likely missing key biological precursors of interest.^[24] The key to building proto-metabolic scenarios involves coupling constructive and interconversion reactions.^[7] Constructive reactions use autocatalytic prebiotic chemistries to increase the structural complexity of the base molecule, while interconversion reactions connect different prebiotic chemistries through functional group transformations.

Cyanosulfidic Scenario

[add in link to Jsacks page here]

Cyanosulfidic scenarios is a proposed mechanisms for proto-metabolism proposed by the Eschenmoser and Sutherland groups.^[31]^[30] Research from the Eschenmoser group suggest interactions between HCN and aldehydes can catalyze the formation of diaminomaleodinitrile (DAMN). Iterations of this cycle would generate multiple intermediate metabolites and key biomolecular precursors through functional group transformations by hydrolytic and redox processes. To expand upon this finding, the Sutherland group experimentally assessed the assembly of biomolecular building blocks from prebiotic intermediates and one-carbon feedstocks.^[30] They synthesized precursors of ribonucleotides, amino acids and lipids from the reactants of hydrogen cyanide, acetylene, acrylonitrile (product of cyanide and acetylene), and dihydroxyacetone (stable triose isomer of glyceraldehyde and phosphate). These reactions are driven by UV light and use hydrogen sulfide (H₂S) as the primary reductant in these reactions. As each of these synthesis reactions was tested independently and some reactions require periodic input of additional reactants, these biomolecular precursors were not generated through the one-pot synthesis expected of early Earth environments. In the same work, these authors argue that flow chemistry or the movement of reactants through water could generate the conditions favorable for the synthesis of these molecules.

Glyoxylate Scenario

Eschenmoser also proposed a parallel scenario were the connections between prebiotic reactions would be connected by glyoxylate, a simple α-ketoacid, produced by HCN oligomerization and hydrolysis.^[32] In this work, Eschenmoser proposes potential schemes to generate both informational oligomers and other key autocatalytic reactions from plausible one-carbon sources (HCN, CO, CO₂). The Krishnamurthy group at Scripps experimentally expanded on this theory.^[33] In mild aqueous conditions, Stubbs and colleagues demonstrated the reaction of glyoxylate and pyruvate can produce a series of α-ketoacid intermediates constituting the reductive TCA cycle. This reaction proceeded without metal or enzyme catalysts as glyoxylate acted as both the carbon source and reducing agent in the reaction. Similarly, the Moran group have also reported pyruvate and glyoxylate can react in warm iron-rich water to produce TCA intermediates and some amino acids.^[34]^[35] Their work has successfully reconstructed 9 out of 11 TCA intermediates and 5 universal metabolic precursors.^[7]^[34]^[35]^[36]^[37] Additional experimental analysis is needed to connect this scenario to modern metabolism.

Energy Sources for Proto-metabolism

Unlike proto-metabolism, the bioenergetic pathways powering modern metabolism are well understood. In early Earth conditions, Deamer and Weber suggest the presence of three kinds of energy: high energy sources to catalyze monomers, lower energy sources to support condensation or polymerization, and energy carriers that support transfer of energy from the environment to metabolic networks.^[20] Examples of high energy sources include photochemical energy from UV light, atmospheric electric discharge, and geological electrochemical energy. These energy sources would support synthesis of biological monomers or feedstocks for proto-metabolism. In contrast, examples of lower energy sources for assembly of more complex molecules include anhydrous heat, mineral-catalyzed synthesis, and sugar-driven reactions. The last set of energy carriers would allow for propagation of the energy through the metabolic networks likely resembled modern energy carriers including ATP and NADH. Both energy carriers are nucleotide-based molecules and likely originated early in metabolism.^[38]

Metabolism-first Hypothesis

Metabolism-first hypothesis suggests that autocatalytic networks of metabolic reactions were the first forms of life. This is an alternative hypothesis to RNA-world and genes-first hypotheses. It was first proposed by Freeman Dyson through multiple editions of a book titled "Origins of Life".^[39] Many recent work in this area is focused in computational modeling of theoretical prebiotic networks.^[40]^[41]^[42]

Metabolism-first proponents push that replication and genetic machinery could not arise without the accumulation of the molecules needed for replication.^[43]^[5] Alone, simple connections between prebiotic synthesis reactions could form key organic molecules and once encapsulated by a membrane would constitute the first cells. These reactions could be catalyzed by various inorganic molecules or ions and stabilized by solid surfaces.^[44] Molecular self-replicators and enzymes would emerge later, with these future metabolisms better resembling modern metabolism.

One critique for the metabolism-first hypothesis for abiogenesis is they would also need self-replicating abilities with a high degree of fidelity.^[45] If not, the chemical networks with greater fitness in early Earth would not be preserved. There is limited experimental evidence for these theories, so additional exploration in this area is needed to determine the feasibility of a metabolism-first origins of life.

References

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[1] Islam, Saidul; Powner, Matthew W. (April 2017). "Prebiotic Systems Chemistry: Complexity Overcoming Clutter". Chem. 2 (4): 470–501. doi:10.1016/j.chempr.2017.03.001. ISSN 2451-9294.

[2] McCollom, Thomas M.; Ritter, Gilles; Simoneit, Bernd R. T. (1999). "Lipid Synthesis Under Hydrothermal Conditions by Fischer- Tropsch-Type Reactions". Origins of Life and Evolution of the Biosphere. 29 (2): 153–166. Bibcode:1999OLEB...29..153M. doi:10.1023/a:1006592502746. ISSN 0169-6149. PMID 10227201. S2CID 25687489.

[3] Benner, Steven A.; Kim, Hyo-Joong; Carrigan, Matthew A. (2012-03-28). "Asphalt, Water, and the Prebiotic Synthesis of Ribose, Ribonucleosides, and RNA". Accounts of Chemical Research. 45 (12): 2025–2034. doi:10.1021/ar200332w. ISSN 0001-4842. PMID 22455515.

[:1-4] Oro, J.; Kimball, A. P. (August 1961). "Synthesis of purines under possible primitive earth conditions. I. Adenine from hydrogen cyanide". Archives of Biochemistry and Biophysics. 94 (2): 217–227. doi:10.1016/0003-9861(61)90033-9. ISSN 0003-9861. PMID 13731263.

[Scossa_2020_482–500-5] Scossa, Federico; Fernie, Alisdair R. (2020). "The evolution of metabolism: How to test evolutionary hypotheses at the genomic level". Computational and Structural Biotechnology Journal. 18: 482–500. doi:10.1016/j.csbj.2020.02.009. ISSN 2001-0370. PMC 7063335. PMID 32180906.

[6] Hordijk, Wim; Steel, Mike (2018-12-08). "Autocatalytic Networks at the Basis of Life's Origin and Organization". Life. 8 (4): 62. Bibcode:2018Life....8...62H. doi:10.3390/life8040062. ISSN 2075-1729. PMC 6315399. PMID 30544834.

[:0-7] ^ ^a ^b ^c ^d ^e ^f ^g ^h Nogal, Noemí; Sanz-Sánchez, Marcos; Vela-Gallego, Sonia; Ruiz-Mirazo, Kepa; de la Escosura, Andrés (2023). "The protometabolic nature of prebiotic chemistry". Chemical Society Reviews. 52 (21): 7359–7388. doi:10.1039/D3CS00594A. ISSN 0306-0012. PMC 10614573. PMID 37855729.

[:2-8] Robinson, William E.; Daines, Elena; van Duppen, Peer; de Jong, Thijs; Huck, Wilhelm T. S. (June 2022). "Environmental conditions drive self-organization of reaction pathways in a prebiotic reaction network". Nature Chemistry. 14 (6): 623–631. Bibcode:2022NatCh..14..623R. doi:10.1038/s41557-022-00956-7. ISSN 1755-4330. PMID 35668214. S2CID 238709887.

[9] Cleaves II, H. James (2008-07-30). "The prebiotic geochemistry of formaldehyde". Precambrian Research. 164 (3–4): 111–118. Bibcode:2008PreR..164..111C. doi:10.1016/j.precamres.2008.04.002.

[10] Butlerow, A. (January 1861). "Bildung einer zuckerartigen Substanz durch Synthese". Justus Liebigs Annalen der Chemie. 120 (3): 295–298. doi:10.1002/jlac.18611200308. ISSN 0075-4617.

[11] Masuda, Saeka; Furukawa, Yoshihiro; Kobayashi, Takamichi; Sekine, Toshimori; Kakegawa, Takeshi (April 2021). "Experimental Investigation of the Formation of Formaldehyde by Hadean and Noachian Impacts". Astrobiology. 21 (4): 413–420. Bibcode:2021AsBio..21..413M. doi:10.1089/ast.2020.2320. ISSN 1531-1074. PMID 33784199. S2CID 232429925.

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@@ Line 2: / Line 2: @@
 [[File:Origins metabolism.png|thumb|329x329px|Schematic of top-down and bottom-up approaches to study proto-metabolism and the origins of metabolism.]]
-'''Proto-metabolism''' refers to a series of linked chemical reactions in a prebiotic environment. Combining ongoing research in [[astrobiology]] and [[prebiotic chemistry]], work in this area focuses on reconstructing the connections between potential metabolic processes that may have occurred in [[early Earth]] conditions. Proto-metabolism is believed to be simpler than extant (modern) [[metabolism]] and [[Last universal common ancestor|LUCA]], as simple organic molecules likely gave rise to more complex metabolic networks. Prebiotic chemists have demonstrated [[Abiotic component|abiotic]] generation of many simple organic molecules including [[amino acid]]s,<ref>{{Cite journal |last=Islam |first=Saidul |last2=Powner |first2=Matthew W. |date=April 2017 |title=Prebiotic Systems Chemistry: Complexity Overcoming Clutter |url=http://dx.doi.org/10.1016/j.chempr.2017.03.001 |journal=Chem |volume=2 |issue=4 |pages=470–501 |doi=10.1016/j.chempr.2017.03.001 |issn=2451-9294}}</ref> [[fatty acid]]s,<ref>{{Cite journal |last=McCollom |first=Thomas M. |last2=Ritter |first2=Gilles |last3=Simoneit |first3=Bernd R. T. |date=1999 |title=Lipid Synthesis Under Hydrothermal Conditions by Fischer- Tropsch-Type Reactions |url=http://dx.doi.org/10.1023/a:1006592502746 |journal=Origins of Life and Evolution of the Biosphere |volume=29 |issue=2 |pages=153–166 |doi=10.1023/a:1006592502746 |issn=0169-6149}}</ref> simple [[sugar]]s,<ref>{{Cite journal |last=Benner |first=Steven A. |last2=Kim |first2=Hyo-Joong |last3=Carrigan |first3=Matthew A. |date=2012-03-28 |title=Asphalt, Water, and the Prebiotic Synthesis of Ribose, Ribonucleosides, and RNA |url=http://dx.doi.org/10.1021/ar200332w |journal=Accounts of Chemical Research |volume=45 |issue=12 |pages=2025–2034 |doi=10.1021/ar200332w |issn=0001-4842}}</ref> and [[nucleobase]]s.<ref name=":1">{{Cite journal |last=Oro |first=J. |last2=Kimball |first2=A. P. |date=August 1961 |title=Synthesis of purines under possible primitive earth conditions. I. Adenine from hydrogen cyanide |url=https://pubmed.ncbi.nlm.nih.gov/13731263/ |journal=Archives of Biochemistry and Biophysics |volume=94 |pages=217–227 |doi=10.1016/0003-9861(61)90033-9 |issn=0003-9861 |pmid=13731263}}</ref> There are multiple scenarios bridging prebiotic chemistry to early metabolic networks that occurred before the origins of life. In addition, there are hypotheses made on the evolution of biochemical pathways including the metabolism-first hypothesis.<ref name="Scossa 2020 482–500">{{Cite journal |last=Scossa |first=Federico |last2=Fernie |first2=Alisdair R. |date=2020 |title=The evolution of metabolism: How to test evolutionary hypotheses at the genomic level |url=https://doi.org/10.1016/j.csbj.2020.02.009 |journal=Computational and Structural Biotechnology Journal |volume=18 |pages=482–500 |doi=10.1016/j.csbj.2020.02.009 |issn=2001-0370 |pmc=PMC7063335 |pmid=32180906}}</ref> Scientists have also analyzed LUCA and modern metabolism to determine the composition of key early metabolic networks.
+'''Proto-metabolism''' refers to a series of linked chemical reactions in a prebiotic environment. Combining ongoing research in [[astrobiology]] and [[prebiotic chemistry]], work in this area focuses on reconstructing the connections between potential metabolic processes that may have occurred in [[early Earth]] conditions. Proto-metabolism is believed to be simpler than extant (modern) [[metabolism]] and [[Last universal common ancestor|LUCA]], as simple organic molecules likely gave rise to more complex metabolic networks. Prebiotic chemists have demonstrated [[Abiotic component|abiotic]] generation of many simple organic molecules including [[amino acid]]s,<ref>{{Cite journal |last1=Islam |first1=Saidul |last2=Powner |first2=Matthew W. |date=April 2017 |title=Prebiotic Systems Chemistry: Complexity Overcoming Clutter |url=http://dx.doi.org/10.1016/j.chempr.2017.03.001 |journal=Chem |volume=2 |issue=4 |pages=470–501 |doi=10.1016/j.chempr.2017.03.001 |issn=2451-9294}}</ref> [[fatty acid]]s,<ref>{{Cite journal |last1=McCollom |first1=Thomas M. |last2=Ritter |first2=Gilles |last3=Simoneit |first3=Bernd R. T. |date=1999 |title=Lipid Synthesis Under Hydrothermal Conditions by Fischer- Tropsch-Type Reactions |url=http://dx.doi.org/10.1023/a:1006592502746 |journal=Origins of Life and Evolution of the Biosphere |volume=29 |issue=2 |pages=153–166 |doi=10.1023/a:1006592502746 |pmid=10227201 |bibcode=1999OLEB...29..153M |s2cid=25687489 |issn=0169-6149}}</ref> simple [[sugar]]s,<ref>{{Cite journal |last1=Benner |first1=Steven A. |last2=Kim |first2=Hyo-Joong |last3=Carrigan |first3=Matthew A. |date=2012-03-28 |title=Asphalt, Water, and the Prebiotic Synthesis of Ribose, Ribonucleosides, and RNA |url=http://dx.doi.org/10.1021/ar200332w |journal=Accounts of Chemical Research |volume=45 |issue=12 |pages=2025–2034 |doi=10.1021/ar200332w |pmid=22455515 |issn=0001-4842}}</ref> and [[nucleobase]]s.<ref name=":1">{{Cite journal |last1=Oro |first1=J. |last2=Kimball |first2=A. P. |date=August 1961 |title=Synthesis of purines under possible primitive earth conditions. I. Adenine from hydrogen cyanide |url=https://pubmed.ncbi.nlm.nih.gov/13731263/ |journal=Archives of Biochemistry and Biophysics |volume=94 |issue=2 |pages=217–227 |doi=10.1016/0003-9861(61)90033-9 |issn=0003-9861 |pmid=13731263}}</ref> There are multiple scenarios bridging prebiotic chemistry to early metabolic networks that occurred before the origins of life. In addition, there are hypotheses made on the evolution of biochemical pathways including the metabolism-first hypothesis.<ref name="Scossa 2020 482–500">{{Cite journal |last1=Scossa |first1=Federico |last2=Fernie |first2=Alisdair R. |date=2020 |title=The evolution of metabolism: How to test evolutionary hypotheses at the genomic level |url=https://doi.org/10.1016/j.csbj.2020.02.009 |journal=Computational and Structural Biotechnology Journal |volume=18 |pages=482–500 |doi=10.1016/j.csbj.2020.02.009 |issn=2001-0370 |pmc=7063335 |pmid=32180906}}</ref> Scientists have also analyzed LUCA and modern metabolism to determine the composition of key early metabolic networks.
 Proto-metabolism is a key area of research approaching '''[[abiogenesis]]'''.
@@ Line 8: / Line 8: @@
 == Autocatalytic Prebiotic Chemistries ==
 {{Further|Autocatalysis|Autocatalytic set}}
-[[Autocatalysis|Autocatalytic reactions]] are reactions where the reaction product acts as a catalyst for its own formation. Many research groups that study proto-metabolism agree that early metabolic networks likely originated as a set of chemical reactions that form self-sustaining networks.<ref>{{Cite journal |last=Hordijk |first=Wim |last2=Steel |first2=Mike |date=2018-12-08 |title=Autocatalytic Networks at the Basis of Life’s Origin and Organization |url=http://www.mdpi.com/2075-1729/8/4/62 |journal=Life |language=en |volume=8 |issue=4 |pages=62 |doi=10.3390/life8040062 |issn=2075-1729 |pmc=PMC6315399 |pmid=30544834}}</ref><ref name=":0" /><ref name=":2" /> This set of reactions is commonly referred to as an [[autocatalytic set]]. Some prebiotic chemistries focus on these autocatalytic reactions including the formose reaction, HCN oligomerization, and formamide chemistry.
+[[Autocatalysis|Autocatalytic reactions]] are reactions where the reaction product acts as a catalyst for its own formation. Many research groups that study proto-metabolism agree that early metabolic networks likely originated as a set of chemical reactions that form self-sustaining networks.<ref>{{Cite journal |last1=Hordijk |first1=Wim |last2=Steel |first2=Mike |date=2018-12-08 |title=Autocatalytic Networks at the Basis of Life's Origin and Organization |journal=Life |language=en |volume=8 |issue=4 |pages=62 |doi=10.3390/life8040062 |issn=2075-1729 |pmc=6315399 |pmid=30544834 |bibcode=2018Life....8...62H |doi-access=free }}</ref><ref name=":0" /><ref name=":2" /> This set of reactions is commonly referred to as an [[autocatalytic set]]. Some prebiotic chemistries focus on these autocatalytic reactions including the formose reaction, HCN oligomerization, and formamide chemistry.
 === Formose Reaction ===
 {{Further|Formose reaction}}
-Discovered in 1861 by [[Alexander Butlerov|Aleksandr Butlerov]], the [[formose reaction]] is a set of two reactions converting [[formaldehyde]] (CH<sub>2</sub>O) to a mixture of simple sugars.<ref>{{Cite journal |last=Cleaves II |first=H. James |date=2008-07-30 |title=The prebiotic geochemistry of formaldehyde |url=https://linkinghub.elsevier.com/retrieve/pii/S0301926808000909 |journal=Precambrian Research |language=en |volume=164 |issue=3-4 |pages=111–118 |doi=10.1016/j.precamres.2008.04.002}}</ref><ref>{{Cite journal |last=Butlerow |first=A. |date=1861-01 |title=Bildung einer zuckerartigen Substanz durch Synthese |url=https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/jlac.18611200308 |journal=Justus Liebigs Annalen der Chemie |language=en |volume=120 |issue=3 |pages=295–298 |doi=10.1002/jlac.18611200308 |issn=0075-4617}}</ref> Formaldehyde is an intermediate in the oxidation of simple carbon molecules (eg. methane) and was likely present in early Earth's atmosphere.<ref>{{Cite journal |last=Masuda |first=Saeka |last2=Furukawa |first2=Yoshihiro |last3=Kobayashi |first3=Takamichi |last4=Sekine |first4=Toshimori |last5=Kakegawa |first5=Takeshi |date=April 2021 |title=Experimental Investigation of the Formation of Formaldehyde by Hadean and Noachian Impacts |url=https://www.liebertpub.com/doi/10.1089/ast.2020.2320 |journal=Astrobiology |volume=21 |issue=4 |pages=413–420 |doi=10.1089/ast.2020.2320 |issn=1531-1074}}</ref> The first reaction is the slow conversion of formaldehyde (C1 carbon) to glycoaldehyde (C2 carbon) and occurs through an unknown mechanism. The second reaction is the faster and [[Autocatalysis|autocatalytic]] formation of higher weight [[aldose]]s and [[ketose]]s.<ref>{{Cite journal |last=Delidovich |first=Irina V. |last2=Simonov |first2=Alexandr N. |last3=Taran |first3=Oxana P. |last4=Parmon |first4=Valentin N. |date=July 2014 |title=Catalytic Formation of Monosaccharides: From the Formose Reaction towards Selective Synthesis |url=https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cssc.201400040 |journal=ChemSusChem |language=en |volume=7 |issue=7 |pages=1833–1846 |doi=10.1002/cssc.201400040 |issn=1864-5631}}</ref> The kinetics of the formose reaction are often described as [[Autocatalysis|autocatalytic]], as the [[alkali]]ne reaction uses lowest molecular weight sugars as feedstocks into the reaction.<ref name=":0">{{Cite journal |last=Nogal |first=Noemí |last2=Sanz-Sánchez |first2=Marcos |last3=Vela-Gallego |first3=Sonia |last4=Ruiz-Mirazo |first4=Kepa |last5=de la Escosura |first5=Andrés |date=2023 |title=The protometabolic nature of prebiotic chemistry |url=http://xlink.rsc.org/?DOI=D3CS00594A |journal=Chemical Society Reviews |language=en |volume=52 |issue=21 |pages=7359–7388 |doi=10.1039/D3CS00594A |issn=0306-0012 |pmc=PMC10614573 |pmid=37855729}}</ref> Self-organized autocatalytic networks, like the formose reaction, would allow for adaptation to changing prebiotic environmental conditions.<ref name=":0" /> As a proof-of-concept, Robinson and colleagues demonstrated how changing environmental conditions and catalyst availability can impact the resultant sugar products.<ref name=":2">{{Cite journal |last=Robinson |first=William E. |last2=Daines |first2=Elena |last3=van Duppen |first3=Peer |last4=de Jong |first4=Thijs |last5=Huck |first5=Wilhelm T. S. |date=June 2022 |title=Environmental conditions drive self-organization of reaction pathways in a prebiotic reaction network |url=https://www.nature.com/articles/s41557-022-00956-7 |journal=Nature Chemistry |language=en |volume=14 |issue=6 |pages=623–631 |doi=10.1038/s41557-022-00956-7 |issn=1755-4330}}</ref>
+Discovered in 1861 by [[Alexander Butlerov|Aleksandr Butlerov]], the [[formose reaction]] is a set of two reactions converting [[formaldehyde]] (CH<sub>2</sub>O) to a mixture of simple sugars.<ref>{{Cite journal |last=Cleaves II |first=H. James |date=2008-07-30 |title=The prebiotic geochemistry of formaldehyde |url=https://linkinghub.elsevier.com/retrieve/pii/S0301926808000909 |journal=Precambrian Research |language=en |volume=164 |issue=3–4 |pages=111–118 |doi=10.1016/j.precamres.2008.04.002|bibcode=2008PreR..164..111C }}</ref><ref>{{Cite journal |last=Butlerow |first=A. |date=January 1861 |title=Bildung einer zuckerartigen Substanz durch Synthese |url=https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/jlac.18611200308 |journal=Justus Liebigs Annalen der Chemie |language=en |volume=120 |issue=3 |pages=295–298 |doi=10.1002/jlac.18611200308 |issn=0075-4617}}</ref> Formaldehyde is an intermediate in the oxidation of simple carbon molecules (eg. methane) and was likely present in early Earth's atmosphere.<ref>{{Cite journal |last1=Masuda |first1=Saeka |last2=Furukawa |first2=Yoshihiro |last3=Kobayashi |first3=Takamichi |last4=Sekine |first4=Toshimori |last5=Kakegawa |first5=Takeshi |date=April 2021 |title=Experimental Investigation of the Formation of Formaldehyde by Hadean and Noachian Impacts |url=https://www.liebertpub.com/doi/10.1089/ast.2020.2320 |journal=Astrobiology |volume=21 |issue=4 |pages=413–420 |doi=10.1089/ast.2020.2320 |pmid=33784199 |bibcode=2021AsBio..21..413M |s2cid=232429925 |issn=1531-1074}}</ref> The first reaction is the slow conversion of formaldehyde (C1 carbon) to glycoaldehyde (C2 carbon) and occurs through an unknown mechanism. The second reaction is the faster and [[Autocatalysis|autocatalytic]] formation of higher weight [[aldose]]s and [[ketose]]s.<ref>{{Cite journal |last1=Delidovich |first1=Irina V. |last2=Simonov |first2=Alexandr N. |last3=Taran |first3=Oxana P. |last4=Parmon |first4=Valentin N. |date=July 2014 |title=Catalytic Formation of Monosaccharides: From the Formose Reaction towards Selective Synthesis |url=https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cssc.201400040 |journal=ChemSusChem |language=en |volume=7 |issue=7 |pages=1833–1846 |doi=10.1002/cssc.201400040 |pmid=24930572 |bibcode=2014ChSCh...7.1833D |issn=1864-5631}}</ref> The kinetics of the formose reaction are often described as [[Autocatalysis|autocatalytic]], as the [[alkali]]ne reaction uses lowest molecular weight sugars as feedstocks into the reaction.<ref name=":0">{{Cite journal |last1=Nogal |first1=Noemí |last2=Sanz-Sánchez |first2=Marcos |last3=Vela-Gallego |first3=Sonia |last4=Ruiz-Mirazo |first4=Kepa |last5=de la Escosura |first5=Andrés |date=2023 |title=The protometabolic nature of prebiotic chemistry |url=http://xlink.rsc.org/?DOI=D3CS00594A |journal=Chemical Society Reviews |language=en |volume=52 |issue=21 |pages=7359–7388 |doi=10.1039/D3CS00594A |issn=0306-0012 |pmc=10614573 |pmid=37855729}}</ref> Self-organized autocatalytic networks, like the formose reaction, would allow for adaptation to changing prebiotic environmental conditions.<ref name=":0" /> As a proof-of-concept, Robinson and colleagues demonstrated how changing environmental conditions and catalyst availability can impact the resultant sugar products.<ref name=":2">{{Cite journal |last1=Robinson |first1=William E. |last2=Daines |first2=Elena |last3=van Duppen |first3=Peer |last4=de Jong |first4=Thijs |last5=Huck |first5=Wilhelm T. S. |date=June 2022 |title=Environmental conditions drive self-organization of reaction pathways in a prebiotic reaction network |url=https://www.nature.com/articles/s41557-022-00956-7 |journal=Nature Chemistry |language=en |volume=14 |issue=6 |pages=623–631 |doi=10.1038/s41557-022-00956-7 |pmid=35668214 |bibcode=2022NatCh..14..623R |s2cid=238709887 |issn=1755-4330}}</ref>
-This reaction is particular significant to [[abiogenesis]] and the origins of metabolism, as it can lead to [[ribose]]. Ribose is a building block of [[RNA]] and an important precursor in proto-metabolism. However, there are still limitations for the formose reaction to be the chemical origin of sugars including the low [[chemoselectivity]] for ribose and high complexity of the final reaction mixture.<ref>{{Cite journal |last=Zhao |first=Ze-Run |last2=Wang |first2=Xiao |date=December 2021 |title=A plausible prebiotic selection of ribose for RNA - formation, dynamic isolation, and nucleotide synthesis based on metal-doped-clays |url=https://doi.org/10.1016/j.chempr.2021.09.002 |journal=Chem |volume=7 |issue=12 |pages=3292–3308 |doi=10.1016/j.chempr.2021.09.002 |issn=2451-9294}}</ref>
+This reaction is particular significant to [[abiogenesis]] and the origins of metabolism, as it can lead to [[ribose]]. Ribose is a building block of [[RNA]] and an important precursor in proto-metabolism. However, there are still limitations for the formose reaction to be the chemical origin of sugars including the low [[chemoselectivity]] for ribose and high complexity of the final reaction mixture.<ref>{{Cite journal |last1=Zhao |first1=Ze-Run |last2=Wang |first2=Xiao |date=December 2021 |title=A plausible prebiotic selection of ribose for RNA - formation, dynamic isolation, and nucleotide synthesis based on metal-doped-clays |url=https://doi.org/10.1016/j.chempr.2021.09.002 |journal=Chem |volume=7 |issue=12 |pages=3292–3308 |doi=10.1016/j.chempr.2021.09.002 |s2cid=240543960 |issn=2451-9294}}</ref>
 === HCN Oligomerization ===
-On Earth, [[hydrogen cyanide]] (HCN) is abundant in [[Volcano|volcanic]] eruptions and [[hydrothermal vent]]s.<ref>{{Cite journal |last=Bada |first=Jeffrey L. |date=2023-04-10 |title=Volcanic Island lightning prebiotic chemistry and the origin of life in the early Hadean eon |url=https://www.nature.com/articles/s41467-023-37894-y |journal=Nature Communications |language=en |volume=14 |issue=1 |doi=10.1038/s41467-023-37894-y |issn=2041-1723 |pmc=PMC10086016 |pmid=37037857}}</ref> On the Hadean Earth, large impactor events and active [[Hydrothermal vent|hydrothermal]] processes likely contributed to widespread metal production and metal-based proto-metabolism.<ref>{{Cite journal |last=Kitadai |first=Norio |last2=Nakamura |first2=Ryuhei |last3=Yamamoto |first3=Masahiro |last4=Takai |first4=Ken |last5=Yoshida |first5=Naohiro |last6=Oono |first6=Yoshi |date=2019-06-07 |title=Metals likely promoted protometabolism in early ocean alkaline hydrothermal systems |url=https://www.science.org/doi/10.1126/sciadv.aav7848 |journal=Science Advances |language=en |volume=5 |issue=6 |doi=10.1126/sciadv.aav7848 |issn=2375-2548 |pmc=PMC6584212 |pmid=31223650}}</ref> Hydrogen cyanide has also been detected in [[meteorite]]s and atmospheres in the solar system.<ref>{{Cite journal |last=Smith |first=Karen E. |last2=House |first2=Christopher H. |last3=Arevalo |first3=Ricardo D. |last4=Dworkin |first4=Jason P. |last5=Callahan |first5=Michael P. |date=2019-06-25 |title=Organometallic compounds as carriers of extraterrestrial cyanide in primitive meteorites |url=https://www.nature.com/articles/s41467-019-10866-x |journal=Nature Communications |language=en |volume=10 |issue=1 |pages=2777 |doi=10.1038/s41467-019-10866-x |issn=2041-1723 |pmc=PMC6592946 |pmid=31239434}}</ref><ref>{{Cite journal |last=Rimmer |first=P. B. |last2=Rugheimer |first2=S. |date=2019-09-01 |title=Hydrogen cyanide in nitrogen-rich atmospheres of rocky exoplanets |url=https://www.sciencedirect.com/science/article/pii/S0019103518303221 |journal=Icarus |volume=329 |pages=124–131 |doi=10.1016/j.icarus.2019.02.020 |issn=0019-1035}}</ref>
+On Earth, [[hydrogen cyanide]] (HCN) is abundant in [[Volcano|volcanic]] eruptions and [[hydrothermal vent]]s.<ref>{{Cite journal |last=Bada |first=Jeffrey L. |date=2023-04-10 |title=Volcanic Island lightning prebiotic chemistry and the origin of life in the early Hadean eon |journal=Nature Communications |language=en |volume=14 |issue=1 |page=2011 |doi=10.1038/s41467-023-37894-y |issn=2041-1723 |pmc=10086016 |pmid=37037857|bibcode=2023NatCo..14.2011B }}</ref> On the Hadean Earth, large impactor events and active [[Hydrothermal vent|hydrothermal]] processes likely contributed to widespread metal production and metal-based proto-metabolism.<ref>{{Cite journal |last1=Kitadai |first1=Norio |last2=Nakamura |first2=Ryuhei |last3=Yamamoto |first3=Masahiro |last4=Takai |first4=Ken |last5=Yoshida |first5=Naohiro |last6=Oono |first6=Yoshi |date=2019-06-07 |title=Metals likely promoted protometabolism in early ocean alkaline hydrothermal systems |journal=Science Advances |language=en |volume=5 |issue=6 |pages=eaav7848 |doi=10.1126/sciadv.aav7848 |issn=2375-2548 |pmc=6584212 |pmid=31223650|bibcode=2019SciA....5.7848K }}</ref> Hydrogen cyanide has also been detected in [[meteorite]]s and atmospheres in the solar system.<ref>{{Cite journal |last1=Smith |first1=Karen E. |last2=House |first2=Christopher H. |last3=Arevalo |first3=Ricardo D. |last4=Dworkin |first4=Jason P. |last5=Callahan |first5=Michael P. |date=2019-06-25 |title=Organometallic compounds as carriers of extraterrestrial cyanide in primitive meteorites |journal=Nature Communications |language=en |volume=10 |issue=1 |pages=2777 |doi=10.1038/s41467-019-10866-x |issn=2041-1723 |pmc=6592946 |pmid=31239434|bibcode=2019NatCo..10.2777S }}</ref><ref>{{Cite journal |last1=Rimmer |first1=P. B. |last2=Rugheimer |first2=S. |date=2019-09-01 |title=Hydrogen cyanide in nitrogen-rich atmospheres of rocky exoplanets |url=https://www.sciencedirect.com/science/article/pii/S0019103518303221 |journal=Icarus |volume=329 |pages=124–131 |doi=10.1016/j.icarus.2019.02.020 |arxiv=1902.08022 |bibcode=2019Icar..329..124R |s2cid=119208979 |issn=0019-1035}}</ref>
-HCN-derived polymers are the oligomer or hydrolysis products of HCN.<ref>{{Cite journal |last=Ruiz-Bermejo |first=Marta |last2=de la Fuente |first2=José Luis |last3=Pérez-Fernández |first3=Cristina |last4=Mateo-Martí |first4=Eva |date=April 2021 |title=A Comprehensive Review of HCN-Derived Polymers |url=https://www.mdpi.com/2227-9717/9/4/597 |journal=Processes |language=en |volume=9 |issue=4 |pages=597 |doi=10.3390/pr9040597 |issn=2227-9717}}</ref> These polymers can be synthesized from HCN or cyanide salts often in alkaline conditions, but they have been observed in a wide range of experimental conditions.<ref name=":1" /><ref>{{Cite journal |last=Cleaves |first=H. James |date=September 2012 |title=Prebiotic Chemistry: What We Know, What We Don't |url=https://evolution-outreach.biomedcentral.com/articles/10.1007/s12052-012-0443-9 |journal=Evolution: Education and Outreach |language=en |volume=5 |issue=3 |pages=342–360 |doi=10.1007/s12052-012-0443-9 |issn=1936-6434}}</ref> HCN readily reacts with itself<ref name=":6">{{Cite journal |last=Deamer |first=D. |last2=Weber |first2=A. L. |date=2010-02-01 |title=Bioenergetics and Life's Origins |url=http://cshperspectives.cshlp.org/lookup/doi/10.1101/cshperspect.a004929 |journal=Cold Spring Harbor Perspectives in Biology |language=en |volume=2 |issue=2 |pages=a004929–a004929 |doi=10.1101/cshperspect.a004929 |issn=1943-0264 |pmc=PMC2828274 |pmid=20182625}}</ref> to produce many HCN polymers and biologically-relevant compounds like [[nucleobase]]s,<ref name=":1" /><ref>{{Cite journal |last=Oró |first=J. |date=June 1960 |title=Synthesis of adenine from ammonium cyanide |url=http://dx.doi.org/10.1016/0006-291x(60)90138-8 |journal=Biochemical and Biophysical Research Communications |volume=2 |issue=6 |pages=407–412 |doi=10.1016/0006-291x(60)90138-8 |issn=0006-291X}}</ref> [[amino acid]]s,<ref>{{Cite journal |last=ORÓ |first=J. |last2=KAMAT |first2=S. S. |date=April 1961 |title=Amino-acid Synthesis from Hydrogen Cyanide under Possible Primitive Earth Conditions |url=http://dx.doi.org/10.1038/190442a0 |journal=Nature |volume=190 |issue=4774 |pages=442–443 |doi=10.1038/190442a0 |issn=0028-0836}}</ref> and [[carboxylic acid]]s.<ref>{{Cite journal |last=Negrón-Mendoza |first=A. |last2=Draganić |first2=Z. D. |last3=Navarro-González |first3=R. |last4=Draganić |first4=I. G. |last5=Negron-Mendoza |first5=A. |last6=Draganic |first6=Z. D. |last7=Navarro-Gonzalez |first7=R. |last8=Draganic |first8=I. G. |date=August 1983 |title=Aldehydes, Ketones, and Carboxylic Acids Formed Radiolytically in Aqueous Solutions of Cyanides and Simple Nitriles |url=http://dx.doi.org/10.2307/3576253 |journal=Radiation Research |volume=95 |issue=2 |pages=248 |doi=10.2307/3576253 |issn=0033-7587}}</ref> The diversity of products could point to a plausible proto-metabolic network of HCN oligomerization reactions. However, many groups point to low HCN concentrations in early Earth and low chemioselectivity of key biologically-relevant products, similar to the formose reaction.<ref name=":4">{{Cite journal |last=Das |first=Tamal |last2=Ghule |first2=Siddharth |last3=Vanka |first3=Kumar |date=2019-09-25 |title=Insights Into the Origin of Life: Did It Begin from HCN and H 2 O? |url=https://pubs.acs.org/doi/10.1021/acscentsci.9b00520 |journal=ACS Central Science |language=en |volume=5 |issue=9 |pages=1532–1540 |doi=10.1021/acscentsci.9b00520 |issn=2374-7943 |pmc=PMC6764159 |pmid=31572780}}</ref>
+HCN-derived polymers are the oligomer or hydrolysis products of HCN.<ref>{{Cite journal |last1=Ruiz-Bermejo |first1=Marta |last2=de la Fuente |first2=José Luis |last3=Pérez-Fernández |first3=Cristina |last4=Mateo-Martí |first4=Eva |date=April 2021 |title=A Comprehensive Review of HCN-Derived Polymers |journal=Processes |language=en |volume=9 |issue=4 |pages=597 |doi=10.3390/pr9040597 |issn=2227-9717 |doi-access=free }}</ref> These polymers can be synthesized from HCN or cyanide salts often in alkaline conditions, but they have been observed in a wide range of experimental conditions.<ref name=":1" /><ref>{{Cite journal |last=Cleaves |first=H. James |date=September 2012 |title=Prebiotic Chemistry: What We Know, What We Don't |url=https://evolution-outreach.biomedcentral.com/articles/10.1007/s12052-012-0443-9 |journal=Evolution: Education and Outreach |language=en |volume=5 |issue=3 |pages=342–360 |doi=10.1007/s12052-012-0443-9 |s2cid=255493640 |issn=1936-6434}}</ref> HCN readily reacts with itself<ref name=":6">{{Cite journal |last1=Deamer |first1=D. |last2=Weber |first2=A. L. |date=2010-02-01 |title=Bioenergetics and Life's Origins |journal=Cold Spring Harbor Perspectives in Biology |language=en |volume=2 |issue=2 |pages=a004929 |doi=10.1101/cshperspect.a004929 |issn=1943-0264 |pmc=2828274 |pmid=20182625}}</ref> to produce many HCN polymers and biologically-relevant compounds like [[nucleobase]]s,<ref name=":1" /><ref>{{Cite journal |last=Oró |first=J. |date=June 1960 |title=Synthesis of adenine from ammonium cyanide |url=http://dx.doi.org/10.1016/0006-291x(60)90138-8 |journal=Biochemical and Biophysical Research Communications |volume=2 |issue=6 |pages=407–412 |doi=10.1016/0006-291x(60)90138-8 |issn=0006-291X}}</ref> [[amino acid]]s,<ref>{{Cite journal |last1=ORÓ |first1=J. |last2=KAMAT |first2=S. S. |date=April 1961 |title=Amino-acid Synthesis from Hydrogen Cyanide under Possible Primitive Earth Conditions |url=http://dx.doi.org/10.1038/190442a0 |journal=Nature |volume=190 |issue=4774 |pages=442–443 |doi=10.1038/190442a0 |bibcode=1961Natur.190..442O |s2cid=4219284 |issn=0028-0836}}</ref> and [[carboxylic acid]]s.<ref>{{Cite journal |last1=Negrón-Mendoza |first1=A. |last2=Draganić |first2=Z. D. |last3=Navarro-González |first3=R. |last4=Draganić |first4=I. G. |last5=Negron-Mendoza |first5=A. |last6=Draganic |first6=Z. D. |last7=Navarro-Gonzalez |first7=R. |last8=Draganic |first8=I. G. |date=August 1983 |title=Aldehydes, Ketones, and Carboxylic Acids Formed Radiolytically in Aqueous Solutions of Cyanides and Simple Nitriles |url=http://dx.doi.org/10.2307/3576253 |journal=Radiation Research |volume=95 |issue=2 |pages=248 |doi=10.2307/3576253 |jstor=3576253 |bibcode=1983RadR...95..248N |issn=0033-7587}}</ref> The diversity of products could point to a plausible proto-metabolic network of HCN oligomerization reactions. However, many groups point to low HCN concentrations in early Earth and low chemioselectivity of key biologically-relevant products, similar to the formose reaction.<ref name=":4">{{Cite journal |last1=Das |first1=Tamal |last2=Ghule |first2=Siddharth |last3=Vanka |first3=Kumar |date=2019-09-25 |title=Insights Into the Origin of Life: Did It Begin from HCN and H 2 O? |journal=ACS Central Science |language=en |volume=5 |issue=9 |pages=1532–1540 |doi=10.1021/acscentsci.9b00520 |issn=2374-7943 |pmc=6764159 |pmid=31572780}}</ref>
 === Formamide Chemistry ===
 {{Further|Formamide-based prebiotic chemistry}}
-[[Formamide]] (NH<sub>2</sub>CHO) is the simplest naturally-occurring amide. Similar to HCN, formamide is equally abundant in the universe.<ref name=":3">{{Cite journal |last=Bizzarri |first=Bruno Mattia |last2=Saladino |first2=Raffaele |last3=Delfino |first3=Ines |last4=García-Ruiz |first4=Juan Manuel |last5=Di Mauro |first5=Ernesto |date=2021-01-18 |title=Prebiotic Organic Chemistry of Formamide and the Origin of Life in Planetary Conditions: What We Know and What Is the Future |url=https://www.mdpi.com/1422-0067/22/2/917 |journal=International Journal of Molecular Sciences |language=en |volume=22 |issue=2 |pages=917 |doi=10.3390/ijms22020917 |issn=1422-0067 |pmc=PMC7831497 |pmid=33477625}}</ref> Formamide has specific physical and stability properties suitable for a universal prebiotic precursor.<ref name=":0" /> For example, it has four [[CHON|universal atomic elements]] ubiquitous to life: C, H, O, N. The presence of unique functional groups involving oxygen and nitrogen allow for unique reaction chemistries to build key biomolecules like amino acids, sugars, nucleosides and other key intermediates of other prebiotic reactions (eg. TCA cycle).<ref name=":0" /><ref>{{Cite journal |last=Saladino |first=Raffaele |last2=Ciambecchini |first2=Umberto |last3=Crestini |first3=Claudia |last4=Costanzo |first4=Giovanna |last5=Negri |first5=Rodolfo |last6=Di Mauro |first6=Ernesto |date=2003-06-06 |title=One‐Pot TiO 2 ‐Catalyzed Synthesis of Nucleic Bases and Acyclonucleosides from Formamide: Implications for the Origin of Life |url=https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cbic.200300567 |journal=ChemBioChem |language=en |volume=4 |issue=6 |pages=514–521 |doi=10.1002/cbic.200300567 |issn=1439-4227}}</ref> In addition, early Earth geological features like [[Hydrothermal vent|hydrothermal pores]] could support formamide chemistry and synthesis of key prebiotic biomolecules with concentration requirements.<ref>{{Cite journal |last=Niether |first=Doreen |last2=Afanasenkau |first2=Dzmitry |last3=Dhont |first3=Jan K. G. |last4=Wiegand |first4=Simone |date=2016-04-04 |title=Accumulation of formamide in hydrothermal pores to form prebiotic nucleobases |url=http://dx.doi.org/10.1073/pnas.1600275113 |journal=Proceedings of the National Academy of Sciences |volume=113 |issue=16 |pages=4272–4277 |doi=10.1073/pnas.1600275113 |issn=0027-8424}}</ref>
+[[Formamide]] (NH<sub>2</sub>CHO) is the simplest naturally-occurring amide. Similar to HCN, formamide is equally abundant in the universe.<ref name=":3">{{Cite journal |last1=Bizzarri |first1=Bruno Mattia |last2=Saladino |first2=Raffaele |last3=Delfino |first3=Ines |last4=García-Ruiz |first4=Juan Manuel |last5=Di Mauro |first5=Ernesto |date=2021-01-18 |title=Prebiotic Organic Chemistry of Formamide and the Origin of Life in Planetary Conditions: What We Know and What Is the Future |journal=International Journal of Molecular Sciences |language=en |volume=22 |issue=2 |pages=917 |doi=10.3390/ijms22020917 |issn=1422-0067 |pmc=7831497 |pmid=33477625 |doi-access=free }}</ref> Formamide has specific physical and stability properties suitable for a universal prebiotic precursor.<ref name=":0" /> For example, it has four [[CHON|universal atomic elements]] ubiquitous to life: C, H, O, N. The presence of unique functional groups involving oxygen and nitrogen allow for unique reaction chemistries to build key biomolecules like amino acids, sugars, nucleosides and other key intermediates of other prebiotic reactions (eg. TCA cycle).<ref name=":0" /><ref>{{Cite journal |last1=Saladino |first1=Raffaele |last2=Ciambecchini |first2=Umberto |last3=Crestini |first3=Claudia |last4=Costanzo |first4=Giovanna |last5=Negri |first5=Rodolfo |last6=Di Mauro |first6=Ernesto |date=2003-06-06 |title=One‐Pot TiO 2 ‐Catalyzed Synthesis of Nucleic Bases and Acyclonucleosides from Formamide: Implications for the Origin of Life |url=https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cbic.200300567 |journal=ChemBioChem |language=en |volume=4 |issue=6 |pages=514–521 |doi=10.1002/cbic.200300567 |pmid=12794862 |s2cid=2349609 |issn=1439-4227}}</ref> In addition, early Earth geological features like [[Hydrothermal vent|hydrothermal pores]] could support formamide chemistry and synthesis of key prebiotic biomolecules with concentration requirements.<ref>{{Cite journal |last1=Niether |first1=Doreen |last2=Afanasenkau |first2=Dzmitry |last3=Dhont |first3=Jan K. G. |last4=Wiegand |first4=Simone |date=2016-04-04 |title=Accumulation of formamide in hydrothermal pores to form prebiotic nucleobases |journal=Proceedings of the National Academy of Sciences |volume=113 |issue=16 |pages=4272–4277 |doi=10.1073/pnas.1600275113 |pmid=27044100 |pmc=4843465 |bibcode=2016PNAS..113.4272N |issn=0027-8424 |doi-access=free }}</ref>
-Overall, formamide chemistry can support connections and substrates needed to support prebiotic biomolecule synthesis including the [[formose reaction]], [[Strecker amino acid synthesis|Strecker synthesis]], HCN oligomerization, or the [[Fischer–Tropsch process|Fischer-Tropsch process]].<ref name=":0" /><ref>{{Cite journal |last=Andersen |first=Jakob |last2=Andersen |first2=Tommy |last3=Flamm |first3=Christoph |last4=Hanczyc |first4=Martin |last5=Merkle |first5=Daniel |last6=Stadler |first6=Peter |date=2013-09-25 |title=Navigating the Chemical Space of HCN Polymerization and Hydrolysis: Guiding Graph Grammars by Mass Spectrometry Data |url=http://www.mdpi.com/1099-4300/15/10/4066 |journal=Entropy |language=en |volume=15 |issue=12 |pages=4066–4083 |doi=10.3390/e15104066 |issn=1099-4300}}</ref> In addition, formamide can be easily concentrated through [[Evaporation|evaporation reactions]] as it has a boiling point of 210C.<ref name=":3" /><ref>{{Cite journal |last=Saladino |first=Raffaele |last2=Crestini |first2=Claudia |last3=Pino |first3=Samanta |last4=Costanzo |first4=Giovanna |last5=Di Mauro |first5=Ernesto |date=2012-03-01 |title=Formamide and the origin of life |url=https://www.sciencedirect.com/science/article/pii/S1571064511001473 |journal=Physics of Life Reviews |volume=9 |issue=1 |pages=84–104 |doi=10.1016/j.plrev.2011.12.002 |issn=1571-0645}}</ref> Although this reaction has the highest versatility across one-carbon atom precursors, the connections between different biosynthetic pathways are yet to be directly explored experimentally.
+Overall, formamide chemistry can support connections and substrates needed to support prebiotic biomolecule synthesis including the [[formose reaction]], [[Strecker amino acid synthesis|Strecker synthesis]], HCN oligomerization, or the [[Fischer–Tropsch process|Fischer-Tropsch process]].<ref name=":0" /><ref>{{Cite journal |last1=Andersen |first1=Jakob |last2=Andersen |first2=Tommy |last3=Flamm |first3=Christoph |last4=Hanczyc |first4=Martin |last5=Merkle |first5=Daniel |last6=Stadler |first6=Peter |date=2013-09-25 |title=Navigating the Chemical Space of HCN Polymerization and Hydrolysis: Guiding Graph Grammars by Mass Spectrometry Data |journal=Entropy |language=en |volume=15 |issue=12 |pages=4066–4083 |doi=10.3390/e15104066 |bibcode=2013Entrp..15.4066A |issn=1099-4300 |doi-access=free }}</ref> In addition, formamide can be easily concentrated through [[Evaporation|evaporation reactions]] as it has a boiling point of 210C.<ref name=":3" /><ref>{{Cite journal |last1=Saladino |first1=Raffaele |last2=Crestini |first2=Claudia |last3=Pino |first3=Samanta |last4=Costanzo |first4=Giovanna |last5=Di Mauro |first5=Ernesto |date=2012-03-01 |title=Formamide and the origin of life |url=https://www.sciencedirect.com/science/article/pii/S1571064511001473 |journal=Physics of Life Reviews |volume=9 |issue=1 |pages=84–104 |doi=10.1016/j.plrev.2011.12.002 |pmid=22196896 |bibcode=2012PhLRv...9...84S |issn=1571-0645}}</ref> Although this reaction has the highest versatility across one-carbon atom precursors, the connections between different biosynthetic pathways are yet to be directly explored experimentally.
 == Experimental Reconstruction of Proto-metabolism ==
-Many research groups are actively attempting experimental reconstruction of the interactions between prebiotic reactions. One major consideration is the ability for these reactions to operate in the same environmental conditions.<ref name=":5">{{Cite journal |last=Patel |first=Bhavesh H. |last2=Percivalle |first2=Claudia |last3=Ritson |first3=Dougal J. |last4=Duffy |first4=Colm D. |last5=Sutherland |first5=John D. |date=April 2015 |title=Common origins of RNA, protein and lipid precursors in a cyanosulfidic protometabolism |url=https://www.nature.com/articles/nchem.2202 |journal=Nature Chemistry |language=en |volume=7 |issue=4 |pages=301–307 |doi=10.1038/nchem.2202 |issn=1755-4330 |pmc=PMC4568310 |pmid=25803468}}</ref> These one-pot syntheses would likely push the reaction towards specific subgroups of molecules likely missing key biological precursors of interest.<ref name=":4" /> The key to building proto-metabolic scenarios involves coupling constructive and interconversion reactions.<ref name=":0" /> Constructive reactions use autocatalytic prebiotic chemistries to increase the structural complexity of the base molecule, while interconversion reactions connect different prebiotic chemistries through functional group transformations.
+Many research groups are actively attempting experimental reconstruction of the interactions between prebiotic reactions. One major consideration is the ability for these reactions to operate in the same environmental conditions.<ref name=":5">{{Cite journal |last1=Patel |first1=Bhavesh H. |last2=Percivalle |first2=Claudia |last3=Ritson |first3=Dougal J. |last4=Duffy |first4=Colm D. |last5=Sutherland |first5=John D. |date=April 2015 |title=Common origins of RNA, protein and lipid precursors in a cyanosulfidic protometabolism |journal=Nature Chemistry |language=en |volume=7 |issue=4 |pages=301–307 |doi=10.1038/nchem.2202 |issn=1755-4330 |pmc=4568310 |pmid=25803468|bibcode=2015NatCh...7..301P }}</ref> These one-pot syntheses would likely push the reaction towards specific subgroups of molecules likely missing key biological precursors of interest.<ref name=":4" /> The key to building proto-metabolic scenarios involves coupling constructive and interconversion reactions.<ref name=":0" /> Constructive reactions use autocatalytic prebiotic chemistries to increase the structural complexity of the base molecule, while interconversion reactions connect different prebiotic chemistries through functional group transformations.
 === Cyanosulfidic Scenario ===
@@ Line 35: / Line 35: @@
 [add in link to Jsacks page here]
-Cyanosulfidic scenarios is a proposed mechanisms for proto-metabolism proposed by the [[Albert Eschenmoser|Eschenmoser]] and [[John Sutherland (chemist)|Sutherland]] groups.<ref>{{Cite journal |last=Koch |first=Klemens |last2=Schweizer |first2=W. Bernd |last3=Eschenmoser |first3=Albert |date=April 2007 |title=Reactions of the HCN‐Tetramer with Aldehydes |url=https://onlinelibrary.wiley.com/doi/10.1002/cbdv.200790049 |journal=Chemistry & Biodiversity |language=en |volume=4 |issue=4 |pages=541–553 |doi=10.1002/cbdv.200790049 |issn=1612-1872}}</ref><ref name=":5" /> Research from the Eschenmoser group suggest interactions between HCN and aldehydes can catalyze the formation of diaminomaleodinitrile (DAMN). Iterations of this cycle would generate multiple intermediate metabolites and key biomolecular precursors through functional group transformations by hydrolytic and redox processes. To expand upon this finding, the Sutherland group experimentally assessed the assembly of biomolecular building blocks from prebiotic intermediates and one-carbon feedstocks.<ref name=":5" /> They synthesized precursors of ribonucleotides, amino acids and lipids from the reactants of hydrogen cyanide, acetylene, acrylonitrile (product of cyanide and acetylene), and dihydroxyacetone (stable [[triose]] isomer of glyceraldehyde and phosphate). These reactions are driven by UV light and use hydrogen sulfide (H<sub>2</sub>S) as the primary [[Reducing agent|reductant]] in these reactions. As each of these synthesis reactions was tested independently and some reactions require periodic input of additional reactants, these biomolecular precursors were not generated through the [[one-pot synthesis]] expected of early Earth environments. In the same work, these authors argue that [[flow chemistry]] or the movement of reactants through water could generate the conditions favorable for the synthesis of these molecules.
+Cyanosulfidic scenarios is a proposed mechanisms for proto-metabolism proposed by the [[Albert Eschenmoser|Eschenmoser]] and [[John Sutherland (chemist)|Sutherland]] groups.<ref>{{Cite journal |last1=Koch |first1=Klemens |last2=Schweizer |first2=W. Bernd |last3=Eschenmoser |first3=Albert |date=April 2007 |title=Reactions of the HCN‐Tetramer with Aldehydes |url=https://onlinelibrary.wiley.com/doi/10.1002/cbdv.200790049 |journal=Chemistry & Biodiversity |language=en |volume=4 |issue=4 |pages=541–553 |doi=10.1002/cbdv.200790049 |s2cid=38695557 |issn=1612-1872}}</ref><ref name=":5" /> Research from the Eschenmoser group suggest interactions between HCN and aldehydes can catalyze the formation of diaminomaleodinitrile (DAMN). Iterations of this cycle would generate multiple intermediate metabolites and key biomolecular precursors through functional group transformations by hydrolytic and redox processes. To expand upon this finding, the Sutherland group experimentally assessed the assembly of biomolecular building blocks from prebiotic intermediates and one-carbon feedstocks.<ref name=":5" /> They synthesized precursors of ribonucleotides, amino acids and lipids from the reactants of hydrogen cyanide, acetylene, acrylonitrile (product of cyanide and acetylene), and dihydroxyacetone (stable [[triose]] isomer of glyceraldehyde and phosphate). These reactions are driven by UV light and use hydrogen sulfide (H<sub>2</sub>S) as the primary [[Reducing agent|reductant]] in these reactions. As each of these synthesis reactions was tested independently and some reactions require periodic input of additional reactants, these biomolecular precursors were not generated through the [[one-pot synthesis]] expected of early Earth environments. In the same work, these authors argue that [[flow chemistry]] or the movement of reactants through water could generate the conditions favorable for the synthesis of these molecules.
 === Glyoxylate Scenario ===
-{{Further|TCA cycle}}Eschenmoser also proposed a parallel scenario were the connections between prebiotic reactions would be connected by glyoxylate, a simple α-ketoacid, produced by HCN oligomerization and hydrolysis.<ref>{{Cite journal |last=Eschenmoser |first=Albert |date=2007-12 |title=The search for the chemistry of life's origin |url=http://dx.doi.org/10.1016/j.tet.2007.10.012 |journal=Tetrahedron |volume=63 |issue=52 |pages=12821–12844 |doi=10.1016/j.tet.2007.10.012 |issn=0040-4020}}</ref> In this work, Eschenmoser proposes potential schemes to generate both informational oligomers and other key autocatalytic reactions from plausible one-carbon sources (HCN, CO, CO<sub>2</sub>). The Krishnamurthy group at Scripps experimentally expanded on this theory.<ref>{{Cite journal |last=Stubbs |first=R. Trent |last2=Yadav |first2=Mahipal |last3=Krishnamurthy |first3=Ramanarayanan |last4=Springsteen |first4=Greg |date=November 2020 |title=A plausible metal-free ancestral analogue of the Krebs cycle composed entirely of α-ketoacids |url=https://www.nature.com/articles/s41557-020-00560-7 |journal=Nature Chemistry |language=en |volume=12 |issue=11 |pages=1016–1022 |doi=10.1038/s41557-020-00560-7 |issn=1755-4330 |pmc=PMC8570912 |pmid=33046840}}</ref> In mild aqueous conditions, Stubbs and colleagues demonstrated the reaction of glyoxylate and pyruvate can produce a series of α-ketoacid intermediates constituting the reductive TCA cycle. This reaction proceeded without metal or enzyme catalysts as glyoxylate acted as both the carbon source and reducing agent in the reaction. Similarly, the Moran group have also reported pyruvate and glyoxylate can react in warm iron-rich water to produce TCA intermediates and some amino acids.<ref name=":7">{{Cite journal |last=Muchowska |first=Kamila B. |last2=Varma |first2=Sreejith J. |last3=Chevallot-Beroux |first3=Elodie |last4=Lethuillier-Karl |first4=Lucas |last5=Li |first5=Guang |last6=Moran |first6=Joseph |date=2017-10-02 |title=Metals promote sequences of the reverse Krebs cycle |url=http://dx.doi.org/10.1038/s41559-017-0311-7 |journal=Nature Ecology &amp; Evolution |volume=1 |issue=11 |pages=1716–1721 |doi=10.1038/s41559-017-0311-7 |issn=2397-334X}}</ref><ref name=":8">{{Cite journal |last=Mayer |first=Robert J. |last2=Kaur |first2=Harpreet |last3=Rauscher |first3=Sophia A. |last4=Moran |first4=Joseph |date=2021-11-03 |title=Mechanistic Insight into Metal Ion-Catalyzed Transamination |url=http://dx.doi.org/10.1021/jacs.1c08535 |journal=Journal of the American Chemical Society |volume=143 |issue=45 |pages=19099–19111 |doi=10.1021/jacs.1c08535 |issn=0002-7863}}</ref> Their work has successfully reconstructed 9 out of 11 TCA intermediates and 5 universal metabolic precursors.<ref name=":0" /><ref name=":7" /><ref name=":8" /><ref>{{Cite journal |last=Mayer |first=Robert J. |last2=Moran |first2=Joseph |date=2022-11-25 |title=Quantifying Reductive Amination in Nonenzymatic Amino Acid Synthesis |url=https://onlinelibrary.wiley.com/doi/10.1002/anie.202212237 |journal=Angewandte Chemie International Edition |language=en |volume=61 |issue=48 |doi=10.1002/anie.202212237 |issn=1433-7851 |pmc=PMC9828492 |pmid=36121198}}</ref><ref>{{Cite journal |last=Rauscher |first=Sophia A. |last2=Moran |first2=Joseph |date=2022-12-19 |title=Hydrogen Drives Part of the Reverse Krebs Cycle under Metal or Meteorite Catalysis |url=https://onlinelibrary.wiley.com/doi/10.1002/anie.202212932 |journal=Angewandte Chemie International Edition |language=en |volume=61 |issue=51 |doi=10.1002/anie.202212932 |issn=1433-7851 |pmc=PMC10100321 |pmid=36251920}}</ref> Additional experimental analysis is needed to connect this scenario to modern metabolism.
+{{Further|TCA cycle}}Eschenmoser also proposed a parallel scenario were the connections between prebiotic reactions would be connected by glyoxylate, a simple α-ketoacid, produced by HCN oligomerization and hydrolysis.<ref>{{Cite journal |last=Eschenmoser |first=Albert |date=December 2007 |title=The search for the chemistry of life's origin |url=http://dx.doi.org/10.1016/j.tet.2007.10.012 |journal=Tetrahedron |volume=63 |issue=52 |pages=12821–12844 |doi=10.1016/j.tet.2007.10.012 |issn=0040-4020}}</ref> In this work, Eschenmoser proposes potential schemes to generate both informational oligomers and other key autocatalytic reactions from plausible one-carbon sources (HCN, CO, CO<sub>2</sub>). The Krishnamurthy group at Scripps experimentally expanded on this theory.<ref>{{Cite journal |last1=Stubbs |first1=R. Trent |last2=Yadav |first2=Mahipal |last3=Krishnamurthy |first3=Ramanarayanan |last4=Springsteen |first4=Greg |date=November 2020 |title=A plausible metal-free ancestral analogue of the Krebs cycle composed entirely of α-ketoacids |journal=Nature Chemistry |language=en |volume=12 |issue=11 |pages=1016–1022 |doi=10.1038/s41557-020-00560-7 |issn=1755-4330 |pmc=8570912 |pmid=33046840|bibcode=2020NatCh..12.1016S }}</ref> In mild aqueous conditions, Stubbs and colleagues demonstrated the reaction of glyoxylate and pyruvate can produce a series of α-ketoacid intermediates constituting the reductive TCA cycle. This reaction proceeded without metal or enzyme catalysts as glyoxylate acted as both the carbon source and reducing agent in the reaction. Similarly, the Moran group have also reported pyruvate and glyoxylate can react in warm iron-rich water to produce TCA intermediates and some amino acids.<ref name=":7">{{Cite journal |last1=Muchowska |first1=Kamila B. |last2=Varma |first2=Sreejith J. |last3=Chevallot-Beroux |first3=Elodie |last4=Lethuillier-Karl |first4=Lucas |last5=Li |first5=Guang |last6=Moran |first6=Joseph |date=2017-10-02 |title=Metals promote sequences of the reverse Krebs cycle |url=http://dx.doi.org/10.1038/s41559-017-0311-7 |journal=Nature Ecology & Evolution |volume=1 |issue=11 |pages=1716–1721 |doi=10.1038/s41559-017-0311-7 |pmid=28970480 |pmc=5659384 |bibcode=2017NatEE...1.1716M |issn=2397-334X}}</ref><ref name=":8">{{Cite journal |last1=Mayer |first1=Robert J. |last2=Kaur |first2=Harpreet |last3=Rauscher |first3=Sophia A. |last4=Moran |first4=Joseph |date=2021-11-03 |title=Mechanistic Insight into Metal Ion-Catalyzed Transamination |url=http://dx.doi.org/10.1021/jacs.1c08535 |journal=Journal of the American Chemical Society |volume=143 |issue=45 |pages=19099–19111 |doi=10.1021/jacs.1c08535 |pmid=34730975 |s2cid=242937134 |issn=0002-7863}}</ref> Their work has successfully reconstructed 9 out of 11 TCA intermediates and 5 universal metabolic precursors.<ref name=":0" /><ref name=":7" /><ref name=":8" /><ref>{{Cite journal |last1=Mayer |first1=Robert J. |last2=Moran |first2=Joseph |date=2022-11-25 |title=Quantifying Reductive Amination in Nonenzymatic Amino Acid Synthesis |journal=Angewandte Chemie International Edition |language=en |volume=61 |issue=48 |pages=e202212237 |doi=10.1002/anie.202212237 |issn=1433-7851 |pmc=9828492 |pmid=36121198}}</ref><ref>{{Cite journal |last1=Rauscher |first1=Sophia A. |last2=Moran |first2=Joseph |date=2022-12-19 |title=Hydrogen Drives Part of the Reverse Krebs Cycle under Metal or Meteorite Catalysis |journal=Angewandte Chemie International Edition |language=en |volume=61 |issue=51 |pages=e202212932 |doi=10.1002/anie.202212932 |issn=1433-7851 |pmc=10100321 |pmid=36251920}}</ref> Additional experimental analysis is needed to connect this scenario to modern metabolism.
 == Energy Sources for Proto-metabolism ==
-Unlike proto-metabolism, the bioenergetic pathways powering modern metabolism are well understood. In early Earth conditions, Deamer and Weber suggest the presence of three kinds of energy: high energy sources to catalyze monomers, lower energy sources to support condensation or polymerization, and energy carriers that support transfer of energy from the environment to metabolic networks.<ref name=":6" /> Examples of high energy sources include photochemical energy from UV light, atmospheric electric discharge, and geological electrochemical energy. These energy sources would support synthesis of biological monomers or feedstocks for proto-metabolism. In contrast, examples of lower energy sources for assembly of more complex molecules include anhydrous heat, mineral-catalyzed synthesis, and sugar-driven reactions. The last set of energy carriers would allow for propagation of the energy through the metabolic networks likely resembled modern energy carriers including ATP and NADH. Both energy carriers are nucleotide-based molecules and likely originated early in metabolism.<ref>{{Cite journal |last=Pinna |first=Silvana |last2=Kunz |first2=Cäcilia |last3=Halpern |first3=Aaron |last4=Harrison |first4=Stuart A. |last5=Jordan |first5=Sean F. |last6=Ward |first6=John |last7=Werner |first7=Finn |last8=Lane |first8=Nick |date=2022-10-04 |title=A prebiotic basis for ATP as the universal energy currency |url=https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3001437 |journal=PLOS Biology |language=en |volume=20 |issue=10 |pages=e3001437 |doi=10.1371/journal.pbio.3001437 |issn=1545-7885 |pmc=PMC9531788 |pmid=36194581}}</ref>
+Unlike proto-metabolism, the bioenergetic pathways powering modern metabolism are well understood. In early Earth conditions, Deamer and Weber suggest the presence of three kinds of energy: high energy sources to catalyze monomers, lower energy sources to support condensation or polymerization, and energy carriers that support transfer of energy from the environment to metabolic networks.<ref name=":6" /> Examples of high energy sources include photochemical energy from UV light, atmospheric electric discharge, and geological electrochemical energy. These energy sources would support synthesis of biological monomers or feedstocks for proto-metabolism. In contrast, examples of lower energy sources for assembly of more complex molecules include anhydrous heat, mineral-catalyzed synthesis, and sugar-driven reactions. The last set of energy carriers would allow for propagation of the energy through the metabolic networks likely resembled modern energy carriers including ATP and NADH. Both energy carriers are nucleotide-based molecules and likely originated early in metabolism.<ref>{{Cite journal |last1=Pinna |first1=Silvana |last2=Kunz |first2=Cäcilia |last3=Halpern |first3=Aaron |last4=Harrison |first4=Stuart A. |last5=Jordan |first5=Sean F. |last6=Ward |first6=John |last7=Werner |first7=Finn |last8=Lane |first8=Nick |date=2022-10-04 |title=A prebiotic basis for ATP as the universal energy currency |journal=PLOS Biology |language=en |volume=20 |issue=10 |pages=e3001437 |doi=10.1371/journal.pbio.3001437 |issn=1545-7885 |pmc=9531788 |pmid=36194581 |doi-access=free }}</ref>
 == Metabolism-first Hypothesis ==
 {{Further|Abiogenesis}}
-Metabolism-first hypothesis suggests that autocatalytic networks of metabolic reactions were the first forms of life. This is an alternative hypothesis to [[RNA World Hypothesis|RNA-world]] and genes-first hypotheses. It was first proposed by Freeman Dyson through multiple editions of a book titled "Origins of Life".<ref>{{Cite book |last=Dyson |first=Freeman |url=http://dx.doi.org/10.1017/cbo9780511546303 |title=Origins of Life |date=1999-09-28 |publisher=Cambridge University Press |isbn=978-0-521-62668-2}}</ref> Many recent work in this area is focused in computational modeling of theoretical prebiotic networks.<ref>{{Cite journal |last=Lindahl |first=Paul A. |date=2004-08 |title=Stepwise Evolution of Nonliving to Living Chemical Systems |url=http://dx.doi.org/10.1023/b:orig.0000029880.76881.f5 |journal=Origins of Life and Evolution of the Biosphere |volume=34 |issue=4 |pages=371–389 |doi=10.1023/b:orig.0000029880.76881.f5 |issn=0169-6149}}</ref><ref>{{Cite journal |last=Yaman |first=Tolga |last2=Harvey |first2=Jeremy N. |date=2021-12-04 |title=Computational Analysis of a Prebiotic Amino Acid Synthesis with Reference to Extant Codon–Amino Acid Relationships |url=https://www.mdpi.com/2075-1729/11/12/1343 |journal=Life |language=en |volume=11 |issue=12 |pages=1343 |doi=10.3390/life11121343 |issn=2075-1729 |pmc=PMC8707928 |pmid=34947874}}</ref><ref>{{Cite journal |last=Sharma |first=Siddhant |last2=Arya |first2=Aayush |last3=Cruz |first3=Romulo |last4=Cleaves II |first4=Henderson |date=2021-10-26 |title=Automated Exploration of Prebiotic Chemical Reaction Space: Progress and Perspectives |url=https://www.mdpi.com/2075-1729/11/11/1140 |journal=Life |language=en |volume=11 |issue=11 |pages=1140 |doi=10.3390/life11111140 |issn=2075-1729 |pmc=PMC8624352 |pmid=34833016}}</ref>
+Metabolism-first hypothesis suggests that autocatalytic networks of metabolic reactions were the first forms of life. This is an alternative hypothesis to [[RNA World Hypothesis|RNA-world]] and genes-first hypotheses. It was first proposed by Freeman Dyson through multiple editions of a book titled "Origins of Life".<ref>{{Cite book |last=Dyson |first=Freeman |url=http://dx.doi.org/10.1017/cbo9780511546303 |title=Origins of Life |date=1999-09-28 |publisher=Cambridge University Press |doi=10.1017/cbo9780511546303 |isbn=978-0-521-62668-2}}</ref> Many recent work in this area is focused in computational modeling of theoretical prebiotic networks.<ref>{{Cite journal |last=Lindahl |first=Paul A. |date=August 2004 |title=Stepwise Evolution of Nonliving to Living Chemical Systems |url=http://dx.doi.org/10.1023/b:orig.0000029880.76881.f5 |journal=Origins of Life and Evolution of the Biosphere |volume=34 |issue=4 |pages=371–389 |doi=10.1023/b:orig.0000029880.76881.f5 |pmid=15279172 |bibcode=2004OLEB...34..371L |s2cid=36069513 |issn=0169-6149}}</ref><ref>{{Cite journal |last1=Yaman |first1=Tolga |last2=Harvey |first2=Jeremy N. |date=2021-12-04 |title=Computational Analysis of a Prebiotic Amino Acid Synthesis with Reference to Extant Codon–Amino Acid Relationships |journal=Life |language=en |volume=11 |issue=12 |pages=1343 |doi=10.3390/life11121343 |issn=2075-1729 |pmc=8707928 |pmid=34947874 |bibcode=2021Life...11.1343Y |doi-access=free }}</ref><ref>{{Cite journal |last1=Sharma |first1=Siddhant |last2=Arya |first2=Aayush |last3=Cruz |first3=Romulo |last4=Cleaves II |first4=Henderson |date=2021-10-26 |title=Automated Exploration of Prebiotic Chemical Reaction Space: Progress and Perspectives |journal=Life |language=en |volume=11 |issue=11 |pages=1140 |doi=10.3390/life11111140 |issn=2075-1729 |pmc=8624352 |pmid=34833016 |bibcode=2021Life...11.1140S |doi-access=free }}</ref>
-Metabolism-first proponents push that [[replication]] and genetic machinery could not arise without the accumulation of the molecules needed for replication.<ref>{{Cite journal |last=Tessera |first=Marc |date=January 2018 |title=Is pre-Darwinian evolution plausible? |url=https://biologydirect.biomedcentral.com/articles/10.1186/s13062-018-0216-7 |journal=Biology Direct |language=en |volume=13 |issue=1 |doi=10.1186/s13062-018-0216-7 |issn=1745-6150 |pmc=PMC6151046 |pmid=30241560}}</ref><ref name="Scossa 2020 482–500"/> Alone, simple connections between prebiotic synthesis reactions could form key organic molecules and once encapsulated by a [[Cell membrane|membrane]] would constitute the first cells. These reactions could be catalyzed by various inorganic molecules or ions and stabilized by solid surfaces.<ref>{{Cite journal |last=Kocher |first=Charles |last2=Dill |first2=Ken A. |date=January 2023 |title=Origins of life: first came evolutionary dynamics |url=https://www.cambridge.org/core/journals/qrb-discovery/article/origins-of-life-first-came-evolutionary-dynamics/A16FF663DD8AAD16DC5D1898CE990B3E#peer-review |journal=QRB Discovery |language=en |volume=4 |pages=e4 |doi=10.1017/qrd.2023.2 |issn=2633-2892}}</ref> Molecular self-replicators and enzymes would emerge later, with these future metabolisms better resembling modern metabolism.
+Metabolism-first proponents push that [[replication]] and genetic machinery could not arise without the accumulation of the molecules needed for replication.<ref>{{Cite journal |last=Tessera |first=Marc |date=January 2018 |title=Is pre-Darwinian evolution plausible? |journal=Biology Direct |language=en |volume=13 |issue=1 |page=18 |doi=10.1186/s13062-018-0216-7 |issn=1745-6150 |pmc=6151046 |pmid=30241560 |doi-access=free }}</ref><ref name="Scossa 2020 482–500"/> Alone, simple connections between prebiotic synthesis reactions could form key organic molecules and once encapsulated by a [[Cell membrane|membrane]] would constitute the first cells. These reactions could be catalyzed by various inorganic molecules or ions and stabilized by solid surfaces.<ref>{{Cite journal |last1=Kocher |first1=Charles |last2=Dill |first2=Ken A. |date=January 2023 |title=Origins of life: first came evolutionary dynamics |journal=QRB Discovery |language=en |volume=4 |pages=e4 |doi=10.1017/qrd.2023.2 |pmid=37529034 |pmc=10392681 |issn=2633-2892}}</ref> Molecular self-replicators and enzymes would emerge later, with these future metabolisms better resembling modern metabolism.
-One critique for the metabolism-first hypothesis for abiogenesis is they would also need self-replicating abilities with a high degree of fidelity.<ref>{{Cite journal |last=Anet |first=Frank AL |date=2004-12-01 |title=The place of metabolism in the origin of life |url=https://www.sciencedirect.com/science/article/pii/S1367593104001371 |journal=Current Opinion in Chemical Biology |volume=8 |issue=6 |pages=654–659 |doi=10.1016/j.cbpa.2004.10.005 |issn=1367-5931}}</ref> If not, the chemical networks with greater fitness in early Earth would not be preserved. There is limited experimental evidence for these theories, so additional exploration in this area is needed to determine the feasibility of a metabolism-first origins of life.
+One critique for the metabolism-first hypothesis for abiogenesis is they would also need self-replicating abilities with a high degree of fidelity.<ref>{{Cite journal |last=Anet |first=Frank AL |date=2004-12-01 |title=The place of metabolism in the origin of life |url=https://www.sciencedirect.com/science/article/pii/S1367593104001371 |journal=Current Opinion in Chemical Biology |volume=8 |issue=6 |pages=654–659 |doi=10.1016/j.cbpa.2004.10.005 |pmid=15556411 |issn=1367-5931}}</ref> If not, the chemical networks with greater fitness in early Earth would not be preserved. There is limited experimental evidence for these theories, so additional exploration in this area is needed to determine the feasibility of a metabolism-first origins of life.
 == References ==