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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.


Simplified reaction mechanism for the reduction of ribonucleotides (for simplicity only the ribose moiety is shown). The reaction is initiated through abstraction of the 3'-H atom by e.g., dAdo•, followed by rearrangement and reduction of the 2'-C position. During the reaction formate serves the role of both base and H-atom donor. We suggest three ways of reforming the 3' C–H bond: (i) e.g., formate donates a second H-atom, terminating the reaction; (ii) the H-atom is abstracted from a second ribonucleotide; or (iii) the H-atom is reabstracted from dAdoH. The two latter possibilities (marked with dashed lines) would make the system catalytic, but are less likely from kinetic and thermodynamic viewpoints, respectively.
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life-05-00604-f003: Simplified reaction mechanism for the reduction of ribonucleotides (for simplicity only the ribose moiety is shown). The reaction is initiated through abstraction of the 3'-H atom by e.g., dAdo•, followed by rearrangement and reduction of the 2'-C position. During the reaction formate serves the role of both base and H-atom donor. We suggest three ways of reforming the 3' C–H bond: (i) e.g., formate donates a second H-atom, terminating the reaction; (ii) the H-atom is abstracted from a second ribonucleotide; or (iii) the H-atom is reabstracted from dAdoH. The two latter possibilities (marked with dashed lines) would make the system catalytic, but are less likely from kinetic and thermodynamic viewpoints, respectively.

Mentions: Following the initial 3' H-atom abstraction we have arrived at the first intermediate of the reaction (Figure 3). However, ribonucleotide reduction is not only dependent on H-atom abstraction but also requires a source of protons and reducing equivalents. While most RNRs today utilize glutaredoxins or thioredoxins as terminal reductants, there are oxygen sensitive forms of RNR that utilize a small molecule, formate, as electron and proton donor [29]. Thus, in line with the latter, once the reaction has been initiated in the protoRNR it could proceed via electron and proton transfer from a small molecule like formate. Once the radical has returned to the 3’ carbon (Figure 3, right), the formation of the final product can proceed via H-atom abstraction from (i) a sacrificial H-atom donor (e.g., a second equivalent of formate; Figure 3, solid arrow); (ii) another nucleotide (Figure 3, right dashed arrow), resulting in a radical chain reaction; or (iii) dAdoH, in which scenario the catalytic cycle is closed as the H-atom is reabstracted from dAdoH to form the product deoxyribonucleotide while dAdo• is regenerated (Figure 3, left dashed arrow). The latter reaction would be thermodynamically unfavored [30], nevertheless such a catalytic role of AdoMet/dAdo• has been suggested in for example radical-SAM mutases such as lysine 2,3-aminomutase and spore photoproduct lyase [19,31], and it is reminiscent of the cobalamin-stabilized dAdo• observed for class II RNR.


The origin and evolution of ribonucleotide reduction.

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

Simplified reaction mechanism for the reduction of ribonucleotides (for simplicity only the ribose moiety is shown). The reaction is initiated through abstraction of the 3'-H atom by e.g., dAdo•, followed by rearrangement and reduction of the 2'-C position. During the reaction formate serves the role of both base and H-atom donor. We suggest three ways of reforming the 3' C–H bond: (i) e.g., formate donates a second H-atom, terminating the reaction; (ii) the H-atom is abstracted from a second ribonucleotide; or (iii) the H-atom is reabstracted from dAdoH. The two latter possibilities (marked with dashed lines) would make the system catalytic, but are less likely from kinetic and thermodynamic viewpoints, respectively.
© Copyright Policy
Related In: Results  -  Collection

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

life-05-00604-f003: Simplified reaction mechanism for the reduction of ribonucleotides (for simplicity only the ribose moiety is shown). The reaction is initiated through abstraction of the 3'-H atom by e.g., dAdo•, followed by rearrangement and reduction of the 2'-C position. During the reaction formate serves the role of both base and H-atom donor. We suggest three ways of reforming the 3' C–H bond: (i) e.g., formate donates a second H-atom, terminating the reaction; (ii) the H-atom is abstracted from a second ribonucleotide; or (iii) the H-atom is reabstracted from dAdoH. The two latter possibilities (marked with dashed lines) would make the system catalytic, but are less likely from kinetic and thermodynamic viewpoints, respectively.
Mentions: Following the initial 3' H-atom abstraction we have arrived at the first intermediate of the reaction (Figure 3). However, ribonucleotide reduction is not only dependent on H-atom abstraction but also requires a source of protons and reducing equivalents. While most RNRs today utilize glutaredoxins or thioredoxins as terminal reductants, there are oxygen sensitive forms of RNR that utilize a small molecule, formate, as electron and proton donor [29]. Thus, in line with the latter, once the reaction has been initiated in the protoRNR it could proceed via electron and proton transfer from a small molecule like formate. Once the radical has returned to the 3’ carbon (Figure 3, right), the formation of the final product can proceed via H-atom abstraction from (i) a sacrificial H-atom donor (e.g., a second equivalent of formate; Figure 3, solid arrow); (ii) another nucleotide (Figure 3, right dashed arrow), resulting in a radical chain reaction; or (iii) dAdoH, in which scenario the catalytic cycle is closed as the H-atom is reabstracted from dAdoH to form the product deoxyribonucleotide while dAdo• is regenerated (Figure 3, left dashed arrow). The latter reaction would be thermodynamically unfavored [30], nevertheless such a catalytic role of AdoMet/dAdo• has been suggested in for example radical-SAM mutases such as lysine 2,3-aminomutase and spore photoproduct lyase [19,31], and it is reminiscent of the cobalamin-stabilized dAdo• observed for class II RNR.

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.