Ribozymes hepatitis delta virus ribozyme

The ribozymes were widely modified and can be further subdivided according to their structural features in group I ribozymes, hammerhaed ribozymes, hairpin ribozymes, ribonucelase P (RNase P), and hepatitis delta virus ribozymes. 

In mid-1997 an international conference took place in Santa Cruz, USA, in which, for the first time, the exclusive topic was structural aspects of RNA molecules. A report covering this meeting contains an impressive graphic which shows the RNA structures, RNA/DNA complexes, and RNA/protein complexes contained in the brookhaven database as a function of the year of their publication [29]. Between 1988 and 1993 there were just 20. However, in 1996 alone no less than 41 structures appeared. These new dimensions were headed by the crystal structural elucidation of the first larger RNA molecule since the first crystal structure of tRNA in 1973 [30], the 48 nucleotide long hammerhead ribo-zyme (HHR) [31-33]. This landmark achievement was followed by a crystal structure analysis of the P4-P6-domain of a group I intron [34-36] and, more recently, a crystal structure of the hepatitis delta virus ribozyme [37]. 

The hepatitis delta virus (HDV) ribozyme is part of the circular single stranded RNA genome of the hepatitis delta virus which consists of a total of 1700 nucleotides. The HDV ribozyme is required for the processing of multimers of the genomic linear RNA transcripts to unit length by catalyzing a transesterification reaction that results in self cleavage [23]. 

Fig. 3. The hepatitis delta virus ribozyme. A Secondary structure of the genomic HDV ribo-zyme RNA used for the determination of the crystal structure [37]. The color code is reflected In the three dimensional structure B of this ribozyme. PI to P4 indicate the base-paired regions. Nucleotides in small letters indicate the U1 A binding site that was engineered into the ribozyme without affecting the overall tertiary structure. The yellow region indicates close contacts between the RNA and the U1 A protein...

HDV ribozymes are derived from the genomic and the antigenomic RNAs of hepatitis delta virus [99-102]. Studies by three groups have revolutionized our understanding of the mechanism of HDV ribozyme-catalyzed reactions [28, 103, 104]. They demonstrated recently that an intramolecular functional group, namely N3 at Gye in the antigenomic HDV ribozyme and N3 at C75 in the genomic HDV ribozyme, can, in fact, act as a true catalyst. However,... 

Isambert, H. and Siggia, E. D. (2000). Modeling RNA folding paths with pseudoknots application to hepatitis delta virus ribozyme. Proc. Natl. Acad. Sci. USA 97, 6515-6520. 

Perrotta, A.T. and Been, M.D. (1993) Assessment of disparate structural features in three models of the hepatitis delta virus ribozyme. Nucleic Acids Res., 21, 3959-3965. 

Shih IH, Been MD. Catalytic strategies of the hepatitis delta virus ribozymes. Annu. Rev. Biochem. 2002 71 887—917. 

Evidence for Acid/Base Catalysis in the Hepatitis Delta Virus Ribozyme Active Site... 

The hepatitis delta virus (HDV) ribozyme is a member of the class of small ribozymes and functions as a self-cleaving RNA sequence critical to the replication of the virus RNA genome (1, 8, 40). HDV ribozymes are proposed to employ several catalytic strategies that include an important example of general acid/base catalysis that involves a specific cytosine residue in the active site. Indeed, a milestone in our understanding of RNA catalysis was the observation that HDV and other small ribozymes could function in the absence of divalent metal ion cofactors, provided that high (molar) concentrations of monovalent ions are present (41, 42). These high monovalent ion concentrations are believed to stabilize the active RNA conformation, which implies that the primary role of divalent metal ions is in structural stabilization (42). 

Eerre-D Amare, A.R., K. Zhou, and J.A. Doudna, Crystal structure of a hepatitis delta virus ribozyme. Namre, 1998. 395(6702) p. 567-74. 

Perrotta AT, Shih I, Been MD. Imidazole rescue of a cytosine mutation in a self-cleaving rihozyme. Science 1999 286 123-126. Nakano S, Chadalavada DM, Bevilacqua PC. General acid-base catalysis in the mechanism of a hepatitis delta virus ribozyme. Science 2000 287 1493-1497. 

Oyelere AK, Kardon JR, Strobel SA. pK(a) perturbation in genomic Hepatitis Delta Virus ribozyme catalysis evidenced by nucleotide analogue interference mapping. Biochemistry 2002 41 3667-3675. 

Das SR, Piccirilli JA. General acid catalysis by the hepatitis delta virus ribozyme. Nat. Chem. Biol. 2005 1 45-52. 

Ke A, Zhou K, Ding F, Cate JH, Doudna JA. A conformational switch controls hepatitis delta virus ribozyme catalysis. Nature 2004 429 201-205. 

M.J.B. Pereira, D.A. Harris, D. Rueda, N.G. Walter, Reaction pathway of the transacting hepatitis delta virus ribozyme A conformational change accompanies catalysis. Biochemistry 41, 730-740 (2002)... 

J. Rogers, A. H. Chang, U. von Ahsen, R. Schroeder, and J. Davies, Inhibition of the selfcleavage reaction of the human hepatitis delta virus ribozyme by antibiotics, J. Mol Biol, 259 (1996) 916-925. 

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