Structural phylogenomics reveals gradual evolutionary replacement of abiotic chemistries by protein enzymes in purine metabolism

Abstract

The origin of metabolism has been linked to abiotic chemistries that existed in our planet at the beginning of life. While plausible chemical pathways have been proposed, including the synthesis of nucleobases, ribose and ribonucleotides, the cooption of these reactions by modern enzymes remains shrouded in mystery. Here we study the emergence of purine metabolism. The ages of protein domains derived from a census of fold family structure in hundreds of genomes were mapped onto enzymes in metabolic diagrams. We find that the origin of the nucleotide interconversion pathway benefited most parsimoniously from the prebiotic formation of adenine nucleosides. In turn, pathways of nucleotide biosynthesis, catabolism and salvage originated ∼300 million years later by concerted enzymatic recruitments and gradual replacement of abiotic chemistries. Remarkably, this process led to the emergence of the fully enzymatic biosynthetic pathway ∼3 billion years ago, concurrently with the appearance of a functional ribosome. The simultaneous appearance of purine biosynthesis and the ribosome probably fulfilled the expanding matter-energy and processing needs of genomic information.

Figure 1. The purine metabolic subnetwork (NUC 00230) of MANET 2.0.

Domain structures associated with individual enzymatic activities (described in EC nomenclature) are painted according to their age, in a scale of node distance (nd_F) that ranges from 0 (the oldest enzymes) to 1 (the most recent).

Figure 2. Evolutionary accumulation of protein domains at FF level of structural abstraction in the central pathways of purine metabolism.

Figure 3. Timeline describing the evolution of FF domain structures and the evolution of main pathways of purine metabolism.

The timeline was derived directly from the tree of FFs reconstructed from free-living organisms. Ages are given as node distances (nd_FF) and geological time (Gy). Time flows from top to bottom. The three evolutionary epochs of the protein world defined by Wang et al. , “architectural diversification” (epoch 1), “superkingdom specification” (epoch 2), and “organismal diversification” (epoch 3) are overlapped to the timeline (colored with different shades). Landmark discoveries , are identified with circles along the timeline. The inset below describes the evolution of the 54 most ancient FFs. Stars represent the fulfillment of a full repertoire of enzymes in a central pathway.

Figure 4. Early evolution of the purine metabolic network.

A. Origin of nucleotide metabolism ∼3.8 Gy ago; nd_FF  = 0). B. Emergence of the nucleotide interconversion (INT), catabolism and salvage (CAT) and biosynthetic (BIO) pathways ∼3.5 Gy ago (nd_FF  = 0.061–0.073). C. Fully connected INT, BIO and CAT pathways ∼3 Gy ago (nd_FF  = 0.187). Pathways mediated by prebiotic chemistries that are plausible and most parsimonious are depicted in red and enable the growth of the emergent protein enzyme-mediated pathways of purine metabolism by structural and functional innovation and piecemeal recruitment (recruited FFs are indicated with numbers). Unknown candidate or withering prebiotic pathways are indicated with dashed lines. We note that primordial reactions of the BIO pathway (top of metabolic diagram) in B could have been non-operational in the absence of suitable prebiotic chemistries until later in evolution. FF structures associated with individual enzymatic activities (described in EC nomenclature) are painted according to their age, in a scale of node distance (nd_FF) that ranges from 0 (the oldest enzymes; ∼3.8 Gy ago) to 0.2 (∼3.0 Gy ago).