Subsystem: Pseudouridine Metabolism

This subsystem's description is:

Pseudouridines are found in virtually all ribosomal RNAs but their function is unknown. There are four to eight times more pseudouridines in eukaryotes than in eubacteria.
Pseudouridine is a nucleoside that is formed post-transcriptionally in RNAs such as tRNAs, ribosomal RNAs, and small RNAs, where it represents one of the main non-classical nucleosides.

Pseudouridine can be used by Escherichia coli as a source of uracil for a strain deficient in pyrimidine synthesis (uridine auxotroph). Pseudouridine was shown to be phosphorylated in E. coli extracts by a kinase to pseudouridine 5'-phosphate, which is hydrolyzed to ribose 5-phosphate and uracil. Neither of these enzymes has been identified earlier, so this Subsystem is based on the resent work of Van Schaftingen's group -See ref.1 -identifying pseudouridine-metabolizing enzymes in E.coli.

The first enzyme, coded by the gene yeiC, specifically phosphorylates pseudouridine to pseudouridine 5'-phosphate. Accordingly, yeiC– mutants are unable to metabolize pseudouridine, in contrast to wild-type E. coli UTI89. The second enzyme, encoded by the gene yeiN belonging to the same operon as yeiC, catalyzes the conversion of pseudouridine 5'-phosphate to uracil and ribose 5-phosphate in a divalent cation-dependent manner. Remarkably, the glycosidic C-C bond of pseudouridine is cleaved in the course of this reaction, indicating that YeiN is the first molecularly identified enzyme able to hydrolyze a glycosidic C-C bond. Though this reaction is easily reversible, the association of YeiN with pseudouridine kinase indicates that it serves physiologically to metabolize pseudouridine 5'-phosphate rather than to form it. YeiN is homologous to Thermotoga maritima IndA, a protein with a new fold, which we now show to act also as a pseudouridine-5'-phosphate glycosidase. Data base mining indicates that most eukaryotes possess homologues of pseudouridine kinase and pseudouridine-5'-phosphate glycosidase and that these are most often associated in a single bifunctional protein. The gene encoding this bifunctional protein is absent from the genomes of man and other mammals, indicating that the capacity for metabolizing pseudouridine has been lost late in evolution.

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DiagramFunctional RolesSubsystem SpreadsheetDescriptionAdditional Notes 

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Hyp1Hyp2YeiMTranspYeiNYeiCRsuAYeiI
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Pseudouridines are found in virtually all ribosomal RNAs but their function is unknown. There are four to eight times more pseudouridines in eukaryotes than in eubacteria.
Pseudouridine is a nucleoside that is formed post-transcriptionally in RNAs such as tRNAs, ribosomal RNAs, and small RNAs, where it represents one of the main non-classical nucleosides.

Pseudouridine can be used by Escherichia coli as a source of uracil for a strain deficient in pyrimidine synthesis (uridine auxotroph). Pseudouridine was shown to be phosphorylated in E. coli extracts by a kinase to pseudouridine 5'-phosphate, which is hydrolyzed to ribose 5-phosphate and uracil. Neither of these enzymes has been identified earlier, so this Subsystem is based on the resent work of Van Schaftingen's group -See ref.1 -identifying pseudouridine-metabolizing enzymes in E.coli.

The first enzyme, coded by the gene yeiC, specifically phosphorylates pseudouridine to pseudouridine 5'-phosphate. Accordingly, yeiC– mutants are unable to metabolize pseudouridine, in contrast to wild-type E. coli UTI89. The second enzyme, encoded by the gene yeiN belonging to the same operon as yeiC, catalyzes the conversion of pseudouridine 5'-phosphate to uracil and ribose 5-phosphate in a divalent cation-dependent manner. Remarkably, the glycosidic C-C bond of pseudouridine is cleaved in the course of this reaction, indicating that YeiN is the first molecularly identified enzyme able to hydrolyze a glycosidic C-C bond. Though this reaction is easily reversible, the association of YeiN with pseudouridine kinase indicates that it serves physiologically to metabolize pseudouridine 5'-phosphate rather than to form it. YeiN is homologous to Thermotoga maritima IndA, a protein with a new fold, which we now show to act also as a pseudouridine-5'-phosphate glycosidase. Data base mining indicates that most eukaryotes possess homologues of pseudouridine kinase and pseudouridine-5'-phosphate glycosidase and that these are most often associated in a single bifunctional protein. The gene encoding this bifunctional protein is absent from the genomes of man and other mammals, indicating that the capacity for metabolizing pseudouridine has been lost late in evolution.
===REFERENCES:=============

1. Preumont A, Snoussi K, Stroobant V, Collet JF, Van Schaftingen E. Molecular identification of pseudouridine-metabolizing enzymes. J Biol Chem. 2008 Sep 12;283(37):25238-46. PMID: 18591240