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Recreating Ancient Metabolic Pathways Before Enzymes Kamila B Recreating ancient metabolic pathways before enzymes Kamila B. Muchowska, Elodie Chevallot-Beroux, Joseph Moran To cite this version: Kamila B. Muchowska, Elodie Chevallot-Beroux, Joseph Moran. Recreating ancient metabolic path- ways before enzymes. Bioorganic and Medicinal Chemistry, Elsevier, 2019, 27 (12), pp.2292-2297. 10.1016/j.bmc.2019.03.012. hal-02516541 HAL Id: hal-02516541 https://hal.archives-ouvertes.fr/hal-02516541 Submitted on 23 Mar 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Graphical Abstract To create your abstract, type over the instructions in the template box below. Fonts or abstract dimensions should not be changed or altered. Recreating ancient metabolic pathways Leave this area blank for abstract info. before enzymes Kamila B. Muchowskaa* , Elodie Chevallot-Berouxa, and Joseph Morana* University of Strasbourg, CNRS, ISIS UMR 7006, 67000 Strasbourg, France Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com Recreating ancient metabolic pathways before enzymes Kamila B. Muchowska,a* Elodie Chevallot-Beroux,a and Joseph Morana* a University of Strasbourg, CNRS, ISIS UMR 7006, 67000 Strasbourg, France. ARTICLE INFO ABSTRACT Article history: The biochemistry of all living organisms uses complex, enzyme-catalyzed metabolic reaction Received networks. Yet, at life’s origins, enzymes had not yet evolved. Therefore, it has been postulated Received in revised form that non-enzymatic metabolic pathways predated their enzymatic counterparts. In this account Accepted article, we describe our recent work to evaluate whether two ancient carbon fixation pathways, Available online the rTCA (reductive tricarboxylic acid) cycle and the reductive AcCoA (Wood-Ljungdahl) pathway, could have operated without enzymes and therefore have originated as prebiotic KeyworDs: chemistry. We also describe the discovery of an Fe2+-promoted complex reaction network that Origin of life may represent a prebiotic predecessor to the TCA and glyoxylate cycles. The collective results Prebiotic chemistry support the idea that most central metabolic pathways could have roots in prebiotic chemistry. Biochemistry Metabolism Abiogenesis 2009 Elsevier Ltd. All rights reserved. 1. Introduction part20) have been proposed as candidates for what biochemistry may have looked like before enzymes, dating back to prebiotic Metabolic function is one of the most critical features of living chemistry. In opposition, some authors have argued that billions of systems, on par with replication and information transfer. For this years of evolution would have erased traces of prebiotic chemistry reason, the emergence of metabolism represents an important in the biological record and that prebiotic chemistry was likely 1 milestone in the transition from chemistry to biochemistry. As far radically different from biochemistry.5 In our view, the idea that as we know, anabolism (build-up) and catabolism (breakdown) prebiotic chemistry bore no resemblance to biochemistry seems have functioned together since life’s origins, forming dynamic unlikely. First, chemical networks can evolve to a limited extent in reaction networks that operate through a small number of “core” the absence of Darwinian selection.21 Therefore, if such a drastic 2,3 organic intermediates. The traditional approach of the organic change to life’s chemistry ever occurred, it had to have happened chemist towards understanding the origins of biochemistry has after the onset of genetics. A proto-metabolic system of a been a “bottom-up” methodology to search for potentially complexity sufficient to get life all the way to that point would 4-6 prebiotic syntheses of biomolecules. More recently, a “systems” have been very difficult to replace. Evolution tends to settle for approach has been made to uncover the possible common origins solutions that are easy to discover and “good enough”, rather than of several fundamental classes of biomolecules such as sugars, the ideal solution. Why then would life not simply have optimized 7-11 lipids, amino acids, and intermediary metabolites. While this existing metabolic networks, rather than re-written them new approach is welcomed, some important caveats to the results completely? We felt that the absence of evidence for a non- so far obtained are: 1) that they often require sequential reactions enzymatic proto-metabolism resembling biochemistry was simply that are not mutually compatible and are therefore unlikely to due to the lack of sustained experimental efforts. Indeed, until 12 occur without human intervention; 2) they employ reagents 2017 little chemical evidence for non-enzymatic metabolic foreign to biochemistry; and 3) the reactions used and the pathways existed, besides an accidentally discovered non- intermediates and pathways followed are very different from enzymatic glycolysis-like pathway catalyzed by Fe2+.22 biological metabolism. Several authors have noted that this set of traits make it unlikely for evolution to emerge and act on such In an attempt to unify “top-down” and “bottom-up” approaches, chemistry to produce the biochemistry we know today and have researchers in our laboratory set out to experimentally reconstruct questioned its relevance to abiogenesis.13-17 Counterpoised to this the ancient metabolic pathways identified by the top-down is a “top-down” approach to prebiotic chemistry in which ancestral approach without enzymes using simple inorganic catalysts and core metabolic pathways are inferred from qualitative or reagents that would have been found on a lifeless planet, such as quantitative network analysis of metabolism or from phylogenetic metals, metal ions and minerals. Reproducing ancestral metabolic 4,18 reconstructions. In this way, two ancient CO2-fixation chemistry non-enzymatically in a chemical laboratory is rooted in pathways, the reductive AcCoA pathway (also known as the bioorganic chemistry and catalysis, but requires inputs from Wood-Ljungdahl pathway)19 together with the reductive various other disciplines including biochemistry, evolutionary tricarboxylic acid (rTCA or reverse Krebs) cycle (in whole2 or in biology and geology. Thus, it may produce compelling examples of prebiotic chemistry that would have been likely to operate under Could metallic iron have been a prebiotic reagent on the early early Earth’s conditions while explaining the origins of the Earth? Metallic iron constitutes 80% of the Earth’s core but is biochemistry we know today.1,22 In the following sections, we relatively rare in the Earth’s crust.33 Native iron is found in report on the recent endeavors of our team to achieve this goal. meteorites34 and is generated transiently in the Earth’s mantle,35 but it is not clear whether it or a similar reduced mineral might be 2. Reductive AcCoA (Wood-Ljungdahl) pathway produced closer to the Earth’s surface, such as in hydrothermal The Wood-Ljungdahl pathway (Figure 1) is used to obtain vents. Alternatively, two recent models developed to account for activated acetate by both bacteria and archaea (in the latter case it the surprisingly high concentration of iron-loving elements in the does not have a net dependence on ATP).20 It is often considered Earths’ crust have proposed their presence resulted from a collision between Earth and a moon-sized object about 4.51 billion to be the most ancient of the six known biological CO2 fixation 36,37 pathways on the basis of phylogenetic reconstructions and network years ago. In one computer simulation consistent with physical analysis.17- 20, 22 The Wood-Ljungdhl pathway is short, linear, evidence from zircons, the collision fractures the impactor to its heavily reliant on transition metals and is therefore hypothesized core, causing a quantity of metallic Fe equivalent to three times the 19,25-27 Earth’s oceans to rain down to the young planet’s surface for many to have initially arisen as prebiotic chemistry. On the other 36 hand, how could it have started before enzymes when the millions of years. Although it remains to be seen whether this 5 hypothesis will survive further scrutiny, at this stage the potential propensity of CO2 to form C-C bonds in water is quite poor? Some studies tackle this problem by using C1 building blocks that are of metallic iron for prebiotic chemistry should not be ruled out. 28 more reactive than CO2 (carbon monoxide and methyl thiol), by 3. Reductive Tricarboxylic Acid cycle applying very high temperature and pressure to neat formic acid (250 °C, 2000 bar),29 or by using highly reducing (-1.1 V) Another of the most evolutionarily preserved biochemical (II) (III) 30 25 electrochemical potentials on greigite (Fe Fe 2S4) electrodes. pathways is the rTCA cycle (Figure 2). It is used by both bacteria 2 20 It has also been shown that fresh iron nanoparticles can reduce CO2 and archaea in both its complete and incomplete versions. Five 31 to acetate (minor product) at 200 °C under 40 bar CO2 pressure. intermediates of this hypothetical hybrid pathway (acetate, These reports, however, are either hard to support geochemically
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