Nonenzymatic Metabolic Reactions and Life’s Origins Kamila Muchowska, Sreejith Jayasree Varma, Joseph Moran To cite this version: Kamila Muchowska, Sreejith Jayasree Varma, Joseph Moran. Nonenzymatic Metabolic Reactions and Life’s Origins. Chemical Reviews, American Chemical Society, 2020, 120 (15), pp.7708-7744. 10.1021/acs.chemrev.0c00191. hal-03024701 HAL Id: hal-03024701 https://hal.archives-ouvertes.fr/hal-03024701 Submitted on 25 Nov 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. Non-enzymatic metabolic reactions and life’s origins Kamila B. Muchowska,1* Sreejith J. Varma,1 and Joseph Moran1* 1University of Strasbourg, CNRS, ISIS UMR 7006, 67000 Strasbourg, France *Correspondence: [email protected], [email protected] KEYWORDS Origin of life; prebiotic chemistry; protometabolism; biological metabolism; CO2 fixation ABSTRACT: Prebiotic chemistry aims to explain how the biochemistry of life as we know it came to be. Most efforts in this area have focused on provisioning compounds of importance to life by multi-step synthetic routes that do not resemble biochemistry. However, gaining insight into why core metabolism uses the molecules, reactions, pathways, and overall organization that it does requires us to consider molecules not only as synthetic end goals. Equally important are the dynamic processes that build them up and break them down. This perspective has led many researchers to the hypothesis that the first stage of the origin of life began with the onset of a primitive non-enzymatic version of metabolism, initially catalyzed by naturally occurring minerals and metal ions. This view of life’s origins has come to be known as “metabolism first”. Continuity with modern metabolism would require a primitive version of metabolism to build and break down ketoacids, sugars, amino acids, and ribonucleotides in much the same way as the pathways that do it today. This review discusses metabolic pathways of relevance to the origin of life in a manner accessible to chemists, and summarizes experiments suggesting several pathways might have their roots in prebiotic chemistry. Finally, key re- maining milestones for the protometabolic hypothesis are highlighted. CONTENTS 4.8 Summary and future directions 1. Introduction 5. Prebiotic thioester chemistry and the emergence of bioener- 2. Terminology and modern thinking on the evolution and or- getics ganization of metabolism 5.1 Thioesters in biological energy conservation 2.1 Mechanisms for the evolution of biochemical pathways 5.2 Prebiotic thioester chemistry in the context of bioenergetics 2.2 Ecology and energy sources for metabolism 5.3 Summary and future directions 2.3 Five universal metabolic precursors 6. Amino acids 2.4 A primer on core carbon metabolism 6.1 Amino acid biosynthesis and its relationship to the genetic 3. The Acetyl-CoA pathway code 3.1 Overview 6.2 Prebiotic synthesis of amino acids from α-ketoacids 3.2 Enzymes and mechanism 6.3 Summary and future directions 3.3 The search for a prebiotic analogue of the acetyl-CoA path- 7. Carbohydrate metabolism way 7.1 Biological sugar metabolism 3.4 Summary and future directions 7.2 Prebiotic synthesis and breakdown of carbohydrates mirror- ing metabolism 4. The tricarboxylic acid cycles 4.1 Biochemistry of the reductive tricarboxylic acid (rTCA) cy- 7.3 Summary and future directions cle 8. Genetics as an outgrowth of protometabolism 4.2 Could the rTCA cycle have originated in prebiotic chemis- 8.1 Biosynthesis of ribonucleotides try? 8.2 Prebiotic synthesis of nucleobases and nucleotides that par- 4.3 Experimental search for a prebiotic analog of the rTCA cy- allel biosynthesis cle 8.3 Summary and future directions 4.4 Biochemistry of the oxidative tricarboxylic acid (TCA) cy- 9. Conclusions and outlook cle 4.5 Could the TCA cycle have originated in prebiotic chemis- try? 4.6 Experimental search for a prebiotic analog of the oxidative TCA cycle 4.7 Prebiotic carbon metabolism without ATP BIOGRAPHY Kamila B. Muchowska Kamila B. Muchowska is a CNRS research scientist at the In- stitut de Science et d’Ingénierie Supramoléculaires (University of Strasbourg & CNRS), associated with the Laboratory of Chemical Catalysis. She obtained her MSc Eng degree in chem- ical technology from the Gdansk University of Technology (Po- land) in 2011. In 2015, she was awarded her PhD in physical organic chemistry (Prof. Scott Cockroft, University of Edin- burgh, UK). After 3.5 years as a postdoctoral researcher with Prof. Joseph Moran, where she studied metabolism-like reac- tions potentially related to the origin of life on Earth, she joined the CNRS (French National Center for Scientific Research) in 2019 in the molecular biology/biochemistry section. Her re- search interests include prebiotic chemistry, evolutionary (bio)chemistry and complex systems. Sreejith J. Varma Sreejith J. Varma was born in Kochi, India. He completed his integrated BS-MS dual degree from IISER Pune, India. Shortly afterwards, he joined the group of Prof. Joseph Moran at the Institut de Science et d’Ingénierie Supramoléculaires (Univer- sity of Strasbourg & CNRS) to pursue his doctoral studies. In 2019, he obtained an FRC Thesis Prize for his PhD thesis on the chemical origins of metabolic pathways. Currently, he is a post- doctoral researcher with Prof. Markus Ralser at the Charité Uni- versitätsmedizin Berlin. Joseph Moran Joseph Moran is a Professor and director of the Laboratory of Chemical Catalysis at the Institut de Science et d’Ingénierie Su- pramoléculaires (University of Strasbourg & CNRS). Origi- nally from Montréal, Canada, he completed his undergraduate studies and Ph.D. in chemistry at the University of Ottawa un- der Prof. André Beauchemin. After six months as a visiting re- searcher with Prof. John Pezacki at NRC Canada and two years as an NSERC postdoctoral fellow with Prof. Michael Krische at the University of Texas, he joined the Institut de Science et d’Ingénierie Supramoléculaires as an assistant professor in 2012 and was promoted to full professor in 2018. His research interests include systems chemistry that mimics metabolism, supramolecular catalysis, and the use of vibrational strong cou- pling in organic chemistry. 1. INTRODUCTION producing the building blocks of RNA or compartments.8,9 A large fraction of prebiotic chemistry research published over the Understanding how and why geochemistry transitioned past 65 years, even if not explicitly performed in the guise of an into biochemistry at the origins of life is one of the grand chal- RNA world scenario, fits into this broad conception and has st 1 lenges for the chemical sciences in the 21 century. Over the been reviewed many times from different angles.10–13 past 65 years, “top-down” analysis of biological metabolism and genetics, as well as “bottom-up” experimental approaches There has been no shortage of criticism for the approach involving simple chemistry have both tried to address this ques- to the origin of life described above, and by proxy, much exper- tion. The former has advanced appealing theories and the latter imental research on prebiotic chemistry.14-16 Some is related to has uncovered intriguing chemical hints. However, a lack of the fact that, by prioritizing one single characteristic of life overlap between the two approaches has left those researching above all others, namely the ability to self-replicate and undergo the chemical origins of life struggling to agree on a path for- Darwinian selection, “genetics-first” theories provide very little ward. Each scientist working on the origins problem enters the explanatory power about why other aspects of life work the way area with their own viewpoints biased by their prior training, they do. Below, we briefly explore these considerations. the present authors included. These diverging viewpoints have First, focusing exclusively on the synthesis of the building polarized researchers in prebiotic chemistry around three cen- blocks of RNA and cellular compartments fails to capture sev- tral fault-lines: 1) Whether genetics or metabolism began first eral of life’s other equally essential characteristics. Life is not and gave rise to the other; 2) The need for continuity between just a collection of compounds, but also a collection of pro- prebiotic chemistry and biochemistry; 3) Whether prebiotic cesses, which are collectively described as metabolism.17 These chemistry began as a reaction network in which reactions were include synthesis (anabolism), breakdown (catabolism), and en- kinetically coupled or whether prebiotic synthesis scenarios in- ergy capture and transmission (energy conservation), among volving sequential chance events should also be considered. others. Life seems to manifest itself in almost endless varieties, Although these three points are, in principle, distinct, opinions but just as remarkable is the extent to which certain aspects of on the first point tend to dictate those on others. biochemistry show regularities or have eluded innovation de- Those who follow a “genetics-first” approach to the origin