From Catalysis of Evolution to Evolution of Catalysis

Abstract

The mystery of the origins of life is one of the most difficult yet intriguing challenges to which humanity has grappled. How did biopolymers emerge in the absence of enzymes (evolved biocatalysts), and how did long-lasting chemical evolution find a path to the highly selective complex biology that we observe today? In this paper, we discuss a chemical framework that explores the very roots of catalysis, demonstrating how standard catalytic activity based on chemical and physical principles can evolve into complex machineries. We provide several examples of how prebiotic catalysis by small molecules can be exploited to facilitate polymerization, which in biology has transformed the nature of catalysis. Thus, catalysis evolved, and evolution was catalyzed, during the transformation of prebiotic chemistry to biochemistry. Traditionally, a catalyst is defined as a substance that (i) speeds up a chemical reaction by lowering activation energy through different chemical mechanisms and (ii) is not consumed during the course of the reaction. However, considering prebiotic chemistry, which involved a highly diverse chemical space (i.e., high number of potential reactants and products) and constantly changing environment that lacked highly sophisticated catalytic machinery, we stress here that a more primitive, broader definition should be considered. Here, we consider a catalyst as any chemical species that lowers activation energy. We further discuss various demonstrations of how simple prebiotic molecules such as hydroxy acids and mercaptoacids promote the formation of peptide bonds via energetically favored exchange reactions. Even though the small molecules are partially regenerated and partially retained within the resulting oligomers, these prebiotic catalysts fulfill their primary role. Catalysis by metal ions and in complex chemical mixtures is also highlighted. We underline how chemical evolution is primarily dictated by kinetics rather than thermodynamics and demonstrate a novel concept to support this notion. Moreover, we propose a new perspective on the role of water in prebiotic catalysis. The role of water as simply a "medium" obscures its importance as an active participant in the chemistry of life, specifically as a very efficient catalyst and as a participant in many chemical transformations. Here we highlight the unusual contribution of water to increasing complexification over the course of chemical evolution. We discuss possible pathways by which prebiotic catalysis promoted chemical selection and complexification. Taken together, this Account draws a connection line between prebiotic catalysis and contemporary biocatalysis and demonstrates that the fundamental elements of chemical catalysis are embedded within today's biocatalysts. This Account illustrates how the evolution of catalysis was intertwined with chemical evolution from the very beginning.

Figure 1

Ester–amide exchange in model prebiotic reactions and in biochemical reactions. (a) Drying amino acids with hydroxy acids makes esters that convert into peptide bonds by an attack of an amine group of an amino acid on an ester. (b) In the peptidyl transferase center of the ribosome, the amine group on an amino acid attacks an ester on the nascent polypeptide linked at the 3′ end of a tRNA, converting an ester into a peptide bond. Modified with permission from ref (47). Copyright 2020 American Chemical Society.

Figure 2

During wet-dry cycling, oligomerization of α-amino acids is favored over oligomerization of β-amino acids. Differences between amino acid conversion percentage under dry-down conditions and wet–dry cycling are illustrated. Positive values indicate greater extent of conversion under dry-down conditions, while negative values indicate greater extent of conversion under wet–dry cycling. Reproduced with permission from ref (58). Copyright 2022 MDPI, Basel, Switzerland.

Figure 3

Depsipeptides containing proteinaceous cationic amino acids are formed via dry-down reactions of mixtures of hydroxy acids and cationic amino acids. (A) Examples of possible products of dry-down reactions of glycolic acid (glc) with lysine (Lys) are shown; Lys is preferentially amidated on the α-amine over the ε-amine. The percentages of products shown were determined by ¹H-NMR analyses. (B) A mixture of glc with Lys was dried at 85 °C for 7 days, and the resulting depsipeptides were analyzed by positive-mode ESI-MS. All labeled species correspond to [M + H]⁺ ions. Reproduced with permission from ref (1). Copyright 2019 U.S. National Academy of Sciences.

Figure 4

Proposed acyl substitutions during peptide bond formation (amidation) through thioester–amide exchange. Under dry conditions, mercaptoacids condense to form thioesters, which are converted to amide bonds in the presence of amino acids. Reproduced with permission from ref (2). Copyright 2022 Springer Nature.

Figure 5

Zinc increases the yield of long His-containing depsipeptides in dry-down reactions. Histidine (His)monomer was dried with glycolic acid (glc) at a 1:1 molar ratio at 85 °C for 7 days in the presence or absence of Zn²⁺ at a 1:1 molar ratio (His:Zn²⁺). Analysis of samples via C18-HPLC showed a dramatic increase in the yield of longer oligomers in the presence of Zn²⁺. A possible coordination complex between Zn²⁺ and two His monomers is also shown. Reproduced with permission from ref (97). Copyright 2021 The Royal Society of Chemistry.

Figure 6

Chemical transformations of water during the Krebs cycle. In this cycle, eight enzymes (green text) catalyze a series of reactions that in total consume three water molecules, produce one water molecule, protonate three water molecules, and convert an acetyl group into two carbon dioxide molecules. Unprotonated water molecules are red spheres and protonated water molecules are blue spheres. Water molecules that are mechanistically involved in the reactions are indicated by green spheres. Reproduced with permission from ref (4). Copyright 2021 Springer Nature.