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Identifying reaction modules in metabolic pathways: bioinformatic deduction and experimental validation of a new putative route in purine catabolism.

Barba M, Dutoit R, Legrain C, Labedan B - BMC Syst Biol (2013)

Bottom Line: Finally, we present experimental data supporting the conclusion that this UGTCase is likely to be involved in a new route in purine catabolism.It will help us to trace how the primordial promiscuous enzymes were assembled progressively in functional modules, as the present pathways diverged from ancestral pathways to give birth to the present-day mechanistically diversified superfamilies.In addition, the concept allows the determination of the actual function of misannotated proteins.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institut de Génétique et Microbiologie, CNRS UMR 8621, Université Paris Sud, Bâtiment 400, 91405, Orsay Cedex, France. bernard.labedan@igmors.u-psud.fr.

ABSTRACT

Background: Enzymes belonging to mechanistically diverse superfamilies often display similar catalytic mechanisms. We previously observed such an association in the case of the cyclic amidohydrolase superfamily whose members play a role in related steps of purine and pyrimidine metabolic pathways. To establish a possible link between enzyme homology and chemical similarity, we investigated further the neighbouring steps in the respective pathways.

Results: We identified that successive reactions of the purine and pyrimidine pathways display similar chemistry. These mechanistically-related reactions are often catalyzed by homologous enzymes. Detection of series of similar catalysis made by succeeding enzyme families suggested some modularity in the architecture of the central metabolism. Accordingly, we introduce the concept of a reaction module to define at least two successive steps catalyzed by homologous enzymes in pathways alignable by similar chemical reactions. Applying such a concept allowed us to propose new function for misannotated paralogues. In particular, we discovered a putative ureidoglycine carbamoyltransferase (UGTCase) activity. Finally, we present experimental data supporting the conclusion that this UGTCase is likely to be involved in a new route in purine catabolism.

Conclusions: Using the reaction module concept should be of great value. It will help us to trace how the primordial promiscuous enzymes were assembled progressively in functional modules, as the present pathways diverged from ancestral pathways to give birth to the present-day mechanistically diversified superfamilies. In addition, the concept allows the determination of the actual function of misannotated proteins.

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Illustrating the respective similarities found in alignable metabolic pathways. The chemical structures of the substrate and product of each enzyme are aligned to underline their respective similarities in the step catalyzed by the successive set of enzymes located in boxes numbered 1 to 3. The reaction modules described in the text are framed in light gray arrows labelled A (purine catabolism), B (pyrimidine catabolism), and C (pyrimidine anabolism). Although many reactions are reversible, the arrow orientation indicates the main direction found in vivo. The enzymes located in the same coloured box were found to be homologous. See list of abbreviations.
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Figure 1: Illustrating the respective similarities found in alignable metabolic pathways. The chemical structures of the substrate and product of each enzyme are aligned to underline their respective similarities in the step catalyzed by the successive set of enzymes located in boxes numbered 1 to 3. The reaction modules described in the text are framed in light gray arrows labelled A (purine catabolism), B (pyrimidine catabolism), and C (pyrimidine anabolism). Although many reactions are reversible, the arrow orientation indicates the main direction found in vivo. The enzymes located in the same coloured box were found to be homologous. See list of abbreviations.

Mentions: In a recent paper [12], we studied the evolutionary history of dihydroorotase (DHOase), which catalyzes the third step of pyrimidine biosynthesis, as well as that of its homologues, all members of the cyclic amidohydrolase superfamily [13,14]. We found that hydantoinase/dihydropyrimidinase, involved in degradation of pyrimidines [15], and allantoinase, a major enzyme of purine catabolism [16], are evolutionarily closer to the ancestral type of DHOase (Type I) than to the largely derived DHOases belonging to Type II and Type III. Thus, although all these homologues perform the same hydrolytic cleavage of a C-N bond in related molecules [13,14], there is no direct correlation between their respective molecular and cellular functions [12]. However, we observed that the catalyses carried out by these different homologues, defining related families which group into mechanistically diverse superfamilies, are performed on molecules displaying close chemical similarities (Figure 1, Box 2).


Identifying reaction modules in metabolic pathways: bioinformatic deduction and experimental validation of a new putative route in purine catabolism.

Barba M, Dutoit R, Legrain C, Labedan B - BMC Syst Biol (2013)

Illustrating the respective similarities found in alignable metabolic pathways. The chemical structures of the substrate and product of each enzyme are aligned to underline their respective similarities in the step catalyzed by the successive set of enzymes located in boxes numbered 1 to 3. The reaction modules described in the text are framed in light gray arrows labelled A (purine catabolism), B (pyrimidine catabolism), and C (pyrimidine anabolism). Although many reactions are reversible, the arrow orientation indicates the main direction found in vivo. The enzymes located in the same coloured box were found to be homologous. See list of abbreviations.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4016543&req=5

Figure 1: Illustrating the respective similarities found in alignable metabolic pathways. The chemical structures of the substrate and product of each enzyme are aligned to underline their respective similarities in the step catalyzed by the successive set of enzymes located in boxes numbered 1 to 3. The reaction modules described in the text are framed in light gray arrows labelled A (purine catabolism), B (pyrimidine catabolism), and C (pyrimidine anabolism). Although many reactions are reversible, the arrow orientation indicates the main direction found in vivo. The enzymes located in the same coloured box were found to be homologous. See list of abbreviations.
Mentions: In a recent paper [12], we studied the evolutionary history of dihydroorotase (DHOase), which catalyzes the third step of pyrimidine biosynthesis, as well as that of its homologues, all members of the cyclic amidohydrolase superfamily [13,14]. We found that hydantoinase/dihydropyrimidinase, involved in degradation of pyrimidines [15], and allantoinase, a major enzyme of purine catabolism [16], are evolutionarily closer to the ancestral type of DHOase (Type I) than to the largely derived DHOases belonging to Type II and Type III. Thus, although all these homologues perform the same hydrolytic cleavage of a C-N bond in related molecules [13,14], there is no direct correlation between their respective molecular and cellular functions [12]. However, we observed that the catalyses carried out by these different homologues, defining related families which group into mechanistically diverse superfamilies, are performed on molecules displaying close chemical similarities (Figure 1, Box 2).

Bottom Line: Finally, we present experimental data supporting the conclusion that this UGTCase is likely to be involved in a new route in purine catabolism.It will help us to trace how the primordial promiscuous enzymes were assembled progressively in functional modules, as the present pathways diverged from ancestral pathways to give birth to the present-day mechanistically diversified superfamilies.In addition, the concept allows the determination of the actual function of misannotated proteins.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institut de Génétique et Microbiologie, CNRS UMR 8621, Université Paris Sud, Bâtiment 400, 91405, Orsay Cedex, France. bernard.labedan@igmors.u-psud.fr.

ABSTRACT

Background: Enzymes belonging to mechanistically diverse superfamilies often display similar catalytic mechanisms. We previously observed such an association in the case of the cyclic amidohydrolase superfamily whose members play a role in related steps of purine and pyrimidine metabolic pathways. To establish a possible link between enzyme homology and chemical similarity, we investigated further the neighbouring steps in the respective pathways.

Results: We identified that successive reactions of the purine and pyrimidine pathways display similar chemistry. These mechanistically-related reactions are often catalyzed by homologous enzymes. Detection of series of similar catalysis made by succeeding enzyme families suggested some modularity in the architecture of the central metabolism. Accordingly, we introduce the concept of a reaction module to define at least two successive steps catalyzed by homologous enzymes in pathways alignable by similar chemical reactions. Applying such a concept allowed us to propose new function for misannotated paralogues. In particular, we discovered a putative ureidoglycine carbamoyltransferase (UGTCase) activity. Finally, we present experimental data supporting the conclusion that this UGTCase is likely to be involved in a new route in purine catabolism.

Conclusions: Using the reaction module concept should be of great value. It will help us to trace how the primordial promiscuous enzymes were assembled progressively in functional modules, as the present pathways diverged from ancestral pathways to give birth to the present-day mechanistically diversified superfamilies. In addition, the concept allows the determination of the actual function of misannotated proteins.

Show MeSH