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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.


(a) and (b) Topological diagrams of the class II and class III RNRs from T. maritima (PDB: 1XJE [50]) and Bacteriophage T4 (PDB: 1HK8 [38]), respectively. The 10-stranded β/α barrel is blue (β) and yellow (α). Secondary motifs outside the conserved barrel are green, except the B12-binding domain in class II, which is orange. The radical cysteine is indicated with a red S• and the radical harboring glycine in class III is indicated by a boxed red G. Loops 1 and 2, implicated in substrate specificity regulation in class II, are indicated in both diagrams; note that only loop 2 is involved in the class III regulation (Section 3.5). (c) and (d) Structure of the same proteins as in (a) and (b) with substrate specificity effectors bound (dTTP for class II, dGTP for class III; stick representation) and colored like the topological diagrams. The class II structure has a substrate nucleotide (GDP; stick representation) bound in addition to the specificity effector.
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life-05-00604-f006: (a) and (b) Topological diagrams of the class II and class III RNRs from T. maritima (PDB: 1XJE [50]) and Bacteriophage T4 (PDB: 1HK8 [38]), respectively. The 10-stranded β/α barrel is blue (β) and yellow (α). Secondary motifs outside the conserved barrel are green, except the B12-binding domain in class II, which is orange. The radical cysteine is indicated with a red S• and the radical harboring glycine in class III is indicated by a boxed red G. Loops 1 and 2, implicated in substrate specificity regulation in class II, are indicated in both diagrams; note that only loop 2 is involved in the class III regulation (Section 3.5). (c) and (d) Structure of the same proteins as in (a) and (b) with substrate specificity effectors bound (dTTP for class II, dGTP for class III; stick representation) and colored like the topological diagrams. The class II structure has a substrate nucleotide (GDP; stick representation) bound in addition to the specificity effector.

Mentions: Above (Section 2.2.2), we propose a repeated β/α topology for the protoRNR based on that this type of fold is generally considered ancient. Another reason is that the 10-stranded β/α barrel of modern RNRs is also a repeated β/α fold. Topologically, the structure of the 10-stranded β/α barrel consists of two antiparallel halves, each with a (β/α)5 configuration (Figure 6). Still it has not, to our knowledge, been suggested to be homologous with the TIM barrel or flavodoxin-like folds. The 8-stranded TIM barrel has been suggested to have evolved from ancestors that only formed half a barrel, i.e., one with four β-strands [71], and a similar argument can be made for the 10-stranded β/α barrel. Presumed gene duplication led to the modern proteins. A possible selective advantage with longer genes coding for the whole protein, is that parts of the barrel are freer to evolve specialized sites for enzymatic activity, substrate binding, etc. Conversely, selection would act against longer genes in a small genome with competition for coding space.


The origin and evolution of ribonucleotide reduction.

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

(a) and (b) Topological diagrams of the class II and class III RNRs from T. maritima (PDB: 1XJE [50]) and Bacteriophage T4 (PDB: 1HK8 [38]), respectively. The 10-stranded β/α barrel is blue (β) and yellow (α). Secondary motifs outside the conserved barrel are green, except the B12-binding domain in class II, which is orange. The radical cysteine is indicated with a red S• and the radical harboring glycine in class III is indicated by a boxed red G. Loops 1 and 2, implicated in substrate specificity regulation in class II, are indicated in both diagrams; note that only loop 2 is involved in the class III regulation (Section 3.5). (c) and (d) Structure of the same proteins as in (a) and (b) with substrate specificity effectors bound (dTTP for class II, dGTP for class III; stick representation) and colored like the topological diagrams. The class II structure has a substrate nucleotide (GDP; stick representation) bound in addition to the specificity effector.
© Copyright Policy
Related In: Results  -  Collection

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

life-05-00604-f006: (a) and (b) Topological diagrams of the class II and class III RNRs from T. maritima (PDB: 1XJE [50]) and Bacteriophage T4 (PDB: 1HK8 [38]), respectively. The 10-stranded β/α barrel is blue (β) and yellow (α). Secondary motifs outside the conserved barrel are green, except the B12-binding domain in class II, which is orange. The radical cysteine is indicated with a red S• and the radical harboring glycine in class III is indicated by a boxed red G. Loops 1 and 2, implicated in substrate specificity regulation in class II, are indicated in both diagrams; note that only loop 2 is involved in the class III regulation (Section 3.5). (c) and (d) Structure of the same proteins as in (a) and (b) with substrate specificity effectors bound (dTTP for class II, dGTP for class III; stick representation) and colored like the topological diagrams. The class II structure has a substrate nucleotide (GDP; stick representation) bound in addition to the specificity effector.
Mentions: Above (Section 2.2.2), we propose a repeated β/α topology for the protoRNR based on that this type of fold is generally considered ancient. Another reason is that the 10-stranded β/α barrel of modern RNRs is also a repeated β/α fold. Topologically, the structure of the 10-stranded β/α barrel consists of two antiparallel halves, each with a (β/α)5 configuration (Figure 6). Still it has not, to our knowledge, been suggested to be homologous with the TIM barrel or flavodoxin-like folds. The 8-stranded TIM barrel has been suggested to have evolved from ancestors that only formed half a barrel, i.e., one with four β-strands [71], and a similar argument can be made for the 10-stranded β/α barrel. Presumed gene duplication led to the modern proteins. A possible selective advantage with longer genes coding for the whole protein, is that parts of the barrel are freer to evolve specialized sites for enzymatic activity, substrate binding, etc. Conversely, selection would act against longer genes in a small genome with competition for coding space.

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.