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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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Pseudo-ATCase subtree with its 3 subgroups and their gene contexts. Group 1 includes Bilophila wadsworthia 3_1_6 (GenBank Project:PRJNA41963), Clostridium ljungdahlii DSM 13528 (GenBank Project: PRJNA202264) and Rubrobacter xylanophilus DSM 9941 (GenBank Project: PRJNA58057); group 2 includes Nocardioides sp. JS614 (GenBank Project: PRJNA58149); group 3 includes Rhodopirellula baltica SH1 (GenBank Project: PRJNA61589), Nitrosococcus oceani ATCC 19707 (GenBank Project: PRJNA58403), Synechococcus sp. WH 8102 (GenBank Project: PRJNA61581) and Kangiella koreensis DSM 16069 (GenBank Project: PRJNA59209). The gene encoding the pseudo-ATCase is highlighted in the yellow rectangle.
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Figure 5: Pseudo-ATCase subtree with its 3 subgroups and their gene contexts. Group 1 includes Bilophila wadsworthia 3_1_6 (GenBank Project:PRJNA41963), Clostridium ljungdahlii DSM 13528 (GenBank Project: PRJNA202264) and Rubrobacter xylanophilus DSM 9941 (GenBank Project: PRJNA58057); group 2 includes Nocardioides sp. JS614 (GenBank Project: PRJNA58149); group 3 includes Rhodopirellula baltica SH1 (GenBank Project: PRJNA61589), Nitrosococcus oceani ATCC 19707 (GenBank Project: PRJNA58403), Synechococcus sp. WH 8102 (GenBank Project: PRJNA61581) and Kangiella koreensis DSM 16069 (GenBank Project: PRJNA59209). The gene encoding the pseudo-ATCase is highlighted in the yellow rectangle.

Mentions: However, we now find, at the root of the ATC II subtree, a small polyphyletic subgroup which is composed of uncharacterized proteins. We call them pseudo-ATCases since these paralogues - annotated as ATCases in public databases - can be simply discriminated from the authentic ATCases found in the same organism as detailed below (see Figure 5 and Table 1). For example, in the case of Rhodopirellula baltica, it is easy to distinguish the gene RB7429, encoding a genuine ATCase (PyrB, UniProtKB: Q7UNR3), and found next to the gene RB7430, encoding a DHOase (PyrC, UniProtKB: Q7UNR2), from its paralogue RB13301, encoding the pseudo-ATCase (UniProtKB: Q7UHC6), and located in a completely different context (see Figure 5).


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)

Pseudo-ATCase subtree with its 3 subgroups and their gene contexts. Group 1 includes Bilophila wadsworthia 3_1_6 (GenBank Project:PRJNA41963), Clostridium ljungdahlii DSM 13528 (GenBank Project: PRJNA202264) and Rubrobacter xylanophilus DSM 9941 (GenBank Project: PRJNA58057); group 2 includes Nocardioides sp. JS614 (GenBank Project: PRJNA58149); group 3 includes Rhodopirellula baltica SH1 (GenBank Project: PRJNA61589), Nitrosococcus oceani ATCC 19707 (GenBank Project: PRJNA58403), Synechococcus sp. WH 8102 (GenBank Project: PRJNA61581) and Kangiella koreensis DSM 16069 (GenBank Project: PRJNA59209). The gene encoding the pseudo-ATCase is highlighted in the yellow rectangle.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Pseudo-ATCase subtree with its 3 subgroups and their gene contexts. Group 1 includes Bilophila wadsworthia 3_1_6 (GenBank Project:PRJNA41963), Clostridium ljungdahlii DSM 13528 (GenBank Project: PRJNA202264) and Rubrobacter xylanophilus DSM 9941 (GenBank Project: PRJNA58057); group 2 includes Nocardioides sp. JS614 (GenBank Project: PRJNA58149); group 3 includes Rhodopirellula baltica SH1 (GenBank Project: PRJNA61589), Nitrosococcus oceani ATCC 19707 (GenBank Project: PRJNA58403), Synechococcus sp. WH 8102 (GenBank Project: PRJNA61581) and Kangiella koreensis DSM 16069 (GenBank Project: PRJNA59209). The gene encoding the pseudo-ATCase is highlighted in the yellow rectangle.
Mentions: However, we now find, at the root of the ATC II subtree, a small polyphyletic subgroup which is composed of uncharacterized proteins. We call them pseudo-ATCases since these paralogues - annotated as ATCases in public databases - can be simply discriminated from the authentic ATCases found in the same organism as detailed below (see Figure 5 and Table 1). For example, in the case of Rhodopirellula baltica, it is easy to distinguish the gene RB7429, encoding a genuine ATCase (PyrB, UniProtKB: Q7UNR3), and found next to the gene RB7430, encoding a DHOase (PyrC, UniProtKB: Q7UNR2), from its paralogue RB13301, encoding the pseudo-ATCase (UniProtKB: Q7UHC6), and located in a completely different context (see Figure 5).

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