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The origin and evolution of ribonucleotide reduction.

Lundin D, Berggren G, Logan DT, Sjöberg BM - Life (Basel) (2015)

Bottom Line: Ribonucleotide reduction is the only pathway for de novo synthesis of deoxyribonucleotides in extant organisms.This chemically demanding reaction, which proceeds via a carbon-centered free radical, is catalyzed by ribonucleotide reductase (RNR).While it is entirely possible that a different pathway was later replaced with the modern mechanism, here we explore the evolutionary and biochemical limits for an origin of the mechanism in the RNA + protein world and suggest a model for a prototypical ribonucleotide reductase (protoRNR).

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Biophysics, Arrhenius Laboratories, Stockholm University, SE-106 91 Stockholm, Sweden. daniel.lundin@scilifelab.se.

ABSTRACT
Ribonucleotide reduction is the only pathway for de novo synthesis of deoxyribonucleotides in extant organisms. This chemically demanding reaction, which proceeds via a carbon-centered free radical, is catalyzed by ribonucleotide reductase (RNR). The mechanism has been deemed unlikely to be catalyzed by a ribozyme, creating an enigma regarding how the building blocks for DNA were synthesized at the transition from RNA- to DNA-encoded genomes. While it is entirely possible that a different pathway was later replaced with the modern mechanism, here we explore the evolutionary and biochemical limits for an origin of the mechanism in the RNA + protein world and suggest a model for a prototypical ribonucleotide reductase (protoRNR). From the protoRNR evolved the ancestor to modern RNRs, the urRNR, which diversified into the modern three classes. Since the initial radical generation differs between the three modern classes, it is difficult to establish how it was generated in the urRNR. Here we suggest a model that is similar to the B12-dependent mechanism in modern class II RNRs.

No MeSH data available.


Activation of the protoRNR by formation of a nucleosyl radical (bottom) and evolution of the protoRNR to the urRNR (top). The protoRNR is a general substrate activator—shown here with an R-H substrate—acting e.g., via H-atom abstraction like in RNR (Section 2.2). Some of the generality may have remained in the urRNR, but we have chosen to draw a nucleotide as substrate in the urRNR (key members of the H-atom transfer pathway are shown in radical form). The “M” in a dashed circle denotes the metal center of the protoRNR and urRNR, respectively. See main text and Table 1 for a description of the urRNR.
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life-05-00604-f004: Activation of the protoRNR by formation of a nucleosyl radical (bottom) and evolution of the protoRNR to the urRNR (top). The protoRNR is a general substrate activator—shown here with an R-H substrate—acting e.g., via H-atom abstraction like in RNR (Section 2.2). Some of the generality may have remained in the urRNR, but we have chosen to draw a nucleotide as substrate in the urRNR (key members of the H-atom transfer pathway are shown in radical form). The “M” in a dashed circle denotes the metal center of the protoRNR and urRNR, respectively. See main text and Table 1 for a description of the urRNR.

Mentions: In the case of the protoRNR we dealt with evolution prior to the common ancestor of modern enzymes, forcing us to rely on general principles informed by modern RNRs and other enzymes performing reactions involving free radicals. We are on firmer ground when we now turn to the later evolution of ribonucleotide reduction and in particular to the origin of the common ancestor of modern RNRs, the urRNR, and how it diverged into the modern three classes. However, lacking fossils, evolutionary reconstructions of proteins are limited to inferences based on modern proteins, which allow us to reconstruct the common ancestor of modern proteins by observing the traits of modern proteins. Following the principle of parsimony, urging us to propose the minimum complexity in the process leading to the current state, we will reconstruct the urRNR from commonalities found between modern RNRs. Bearing in mind that modern RNRs are highly evolved enzymes that have acquired many characteristics since divergence from a common ancestor, we proceed by discussing the path from the urRNR to the modern RNR classes. Furthermore, by defining the urRNR, we can outline the necessary steps on the way from the protoRNR to the urRNR (Figure 4). However, it is important to note that the protoRNR is a hypothesis while the urRNR is a parsimonious reconstruction based on existing enzymes. Since the transitional steps between the hypothetical protoRNR and the reconstructed urRNR are dependent on the hypothesis as well as the reconstruction, we discuss the transition only to clarify the consequences of assuming the hypothesis being true.


The origin and evolution of ribonucleotide reduction.

Lundin D, Berggren G, Logan DT, Sjöberg BM - Life (Basel) (2015)

Activation of the protoRNR by formation of a nucleosyl radical (bottom) and evolution of the protoRNR to the urRNR (top). The protoRNR is a general substrate activator—shown here with an R-H substrate—acting e.g., via H-atom abstraction like in RNR (Section 2.2). Some of the generality may have remained in the urRNR, but we have chosen to draw a nucleotide as substrate in the urRNR (key members of the H-atom transfer pathway are shown in radical form). The “M” in a dashed circle denotes the metal center of the protoRNR and urRNR, respectively. See main text and Table 1 for a description of the urRNR.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4390871&req=5

life-05-00604-f004: Activation of the protoRNR by formation of a nucleosyl radical (bottom) and evolution of the protoRNR to the urRNR (top). The protoRNR is a general substrate activator—shown here with an R-H substrate—acting e.g., via H-atom abstraction like in RNR (Section 2.2). Some of the generality may have remained in the urRNR, but we have chosen to draw a nucleotide as substrate in the urRNR (key members of the H-atom transfer pathway are shown in radical form). The “M” in a dashed circle denotes the metal center of the protoRNR and urRNR, respectively. See main text and Table 1 for a description of the urRNR.
Mentions: In the case of the protoRNR we dealt with evolution prior to the common ancestor of modern enzymes, forcing us to rely on general principles informed by modern RNRs and other enzymes performing reactions involving free radicals. We are on firmer ground when we now turn to the later evolution of ribonucleotide reduction and in particular to the origin of the common ancestor of modern RNRs, the urRNR, and how it diverged into the modern three classes. However, lacking fossils, evolutionary reconstructions of proteins are limited to inferences based on modern proteins, which allow us to reconstruct the common ancestor of modern proteins by observing the traits of modern proteins. Following the principle of parsimony, urging us to propose the minimum complexity in the process leading to the current state, we will reconstruct the urRNR from commonalities found between modern RNRs. Bearing in mind that modern RNRs are highly evolved enzymes that have acquired many characteristics since divergence from a common ancestor, we proceed by discussing the path from the urRNR to the modern RNR classes. Furthermore, by defining the urRNR, we can outline the necessary steps on the way from the protoRNR to the urRNR (Figure 4). However, it is important to note that the protoRNR is a hypothesis while the urRNR is a parsimonious reconstruction based on existing enzymes. Since the transitional steps between the hypothetical protoRNR and the reconstructed urRNR are dependent on the hypothesis as well as the reconstruction, we discuss the transition only to clarify the consequences of assuming the hypothesis being true.

Bottom Line: Ribonucleotide reduction is the only pathway for de novo synthesis of deoxyribonucleotides in extant organisms.This chemically demanding reaction, which proceeds via a carbon-centered free radical, is catalyzed by ribonucleotide reductase (RNR).While it is entirely possible that a different pathway was later replaced with the modern mechanism, here we explore the evolutionary and biochemical limits for an origin of the mechanism in the RNA + protein world and suggest a model for a prototypical ribonucleotide reductase (protoRNR).

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Biophysics, Arrhenius Laboratories, Stockholm University, SE-106 91 Stockholm, Sweden. daniel.lundin@scilifelab.se.

ABSTRACT
Ribonucleotide reduction is the only pathway for de novo synthesis of deoxyribonucleotides in extant organisms. This chemically demanding reaction, which proceeds via a carbon-centered free radical, is catalyzed by ribonucleotide reductase (RNR). The mechanism has been deemed unlikely to be catalyzed by a ribozyme, creating an enigma regarding how the building blocks for DNA were synthesized at the transition from RNA- to DNA-encoded genomes. While it is entirely possible that a different pathway was later replaced with the modern mechanism, here we explore the evolutionary and biochemical limits for an origin of the mechanism in the RNA + protein world and suggest a model for a prototypical ribonucleotide reductase (protoRNR). From the protoRNR evolved the ancestor to modern RNRs, the urRNR, which diversified into the modern three classes. Since the initial radical generation differs between the three modern classes, it is difficult to establish how it was generated in the urRNR. Here we suggest a model that is similar to the B12-dependent mechanism in modern class II RNRs.

No MeSH data available.