Hepatitis delta virus ribozyme
|Hepatitis delta virus ribozyme|
|Predicted secondary structure and sequence conservation of HDV ribozyme|
|RNA type||Gene; ribozyme|
The hepatitis delta virus (HDV) ribozyme is a non-coding RNA found in the hepatitis delta virus that is necessary for viral replication and is thought to be the only catalytic RNA known to be required for viability of a human pathogen. The ribozyme acts to process the RNA transcripts to unit lengths in a self-cleavage reaction. The ribozyme is found to be active in vivo in the absence of any protein factors and is the fastest known naturally occurring self-cleaving RNA.
In addition to the sense (genomic version), all HDV viruses also have an anti-genomic version of the HDV ribozyme. This version is not the exact complementary sequence but adopts the same structure as the sense (genomic) strand. The only "significant" differences between the two are a small bulge in P4 stem and a shorter J4/2 junction.
The hepatitis delta virus ribozyme is structurally and biochemically related to the Mammalian CPEB3 ribozyme. Unrelated sequences with high similarity to the HDV ribozyme have evolved through convergent evolution in some retrotransposons (e.g. in the R2 RNA element in insects and in the L1Tc and probably other retrotransposons in trypanosomatids).
General Acid Base Chemistry
Similar to the hairpin ribozyme, the HDV ribosome has reactions that is characterized by acid-base catalysis. The functional groups within the protein has neutral pH’s has close pH values that allows it to interchange between the acid and base phase. This behavior shows that the HDV ribozyme must have some form of functional groups that has neutral like pH around 6 to 7. Within RNA, typical pKa values for the free nucleosides are around 3.5 to 4.2, a lower pKa acidic value that would unlikely become basic. However, due to the shifted pKa values that causes the acid-base catalysis, there is a likelihood that it may be caused form the structural environment within the nucleoside.
Within the HDV Ribozyme, there is a network of hydrogen bonds to the cytosine that is able to stabilize the protonated form of the cytosine. It will allow the donation and acceptance of the proton at some during the catalysis. In a set of experiments, a point mutations was done to the critical cytosine. Afterwards there was a drop activity and was partially restored when imidazole was added.
With support data, the current model of cytosine acting as a general acid within the reaction to donate a proton to the 5’-bridging oxygen (See figure)
. There is also a metal ion that coordinates near the ribozyme active site to abstract a proton from the 2’-hydroxyl nucleophile (37).
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