Ribozymes

There was a time when proteins were considered the only biological macromolecules capable of catalysis. The discovery of the catalytic activity of RNA has thus had a profound impact on the way biochemists think. A few enzymes with RNA components had been discovered, such as telomerase (Chapter 10) and RNase P, an enzyme that cleaves extra nucleotides off the 5 ends of tRNA precursors. It was later shown that the RNA portion of RNase P has the catalytic activity. The field of catalytic RNA (ribozymes) was launched in earnest by the discovery of RNA that catalyzes its own selfsplicing. It is easy to see a connection between this process and the splicing 

Proteins are not the only biological molecules with catalytic properties. Some RNAs, called ribozymes, also catalyze certain reactions. 

Group I ribozymes require au external guanosine for reactivity. Group II ribozymes do not have this requirement. They carry out catalysis via a lariat mechanism. 

Proofreading in Transcription RNA Fills In Another Missing Piece 

In the first case, if the cookbook itself were wrong (DNA), then every attempt to read it would lead to a poor baking attempt. In the latter case, a person who misread the cookbook would make the mistake only once, analogous to making a poor RNA copy one time. Although there could be ramifications to making an incorrect RNA and/or protein, the consequences would be much worse if the DNA itself was wrong. 

The following two important statements were considered at one time to be established scientific dogma in molecular biology  

The information stored in DNA is translated in the living cell to RNA, which leads to proteins  

The two nucleic acids serve only as information carriers, while proteins (as enzymes) are only responsible for functions in the cell  

RNA — information carriers proteins (enzymes) — functions (catalysis) 

Both dogmas had to be revised or expanded, the first because of the discovery of reverse transcriptase (an RNA-dependent DNA-polymerase) by D. Baltimore (MIT) and H. M. Temin (University of Wisconsin). This is an enzyme which catalyses the synthesis of DNA from single-strand RNA  

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Cate J FI, Gooding A R, Podell E, Zhou K, Golden B L, Kundrot C E, Cech T R and Doudna J A 1996 Crystal structure of a group i ribozyme domain principles of RNA packing Science 273 1678-85... 

Reverse transcriptase (Section 28 13) Enzyme that catalyzes the transcription of RNA to DNA Ribozyme (Section 28 11) A polynucleotide that has catalytic activity... 

Hamamelis [84696-19-5] Hamamelis virginiana Ham curing Hammerhead ribozyme Hammer mills Hammett equation Hamposyl 0 Hamposyl C Hamposyl C-30 Hamposyl L Hamposyl L-30 Hand factor Hand lay-up... 

Ribozymes Ricamycin Ricard-Allenet sequence Rice... 

HammerheadRtbozyme. A small RNA molecule that catalyzes cleavage of the phosphodiester backbone of RNA is known as the hammerhead ribozyme. This ribozyme occurs namrally in certain vimses where it facihtates a site-specific self-cleavage at the phosphate and generates a 2 3 -cychc phosphate and a 5 -hydroxyl terminus. The reaction requires a divalent metal ion, such as or, as a cofactor. Whereas the... 

Fig. 10. Three-dimensional stmcmre of the hammerhead ribozyme (shaded cord) bound to a substrate oligonucleotide (nonshaded cord). The uridine mm...

To date, RNA calculations have been performed on a variety of systems of different topologies including helical duplexes, hairpin loops, and single strands from tRNA, rRNA, and ribozymes. In a simulation of an RNA tetraloop of the GRNA type, which is very common and known to be remarkably stable, it was found that without imposing any external infonnation the simulation found the right confonnation even when it started from the wrong one [72]. Studies have used Ewald summation methods to handle the... 

The discovery of ribozymes (Section 28.11) in the late 1970s and early 1980s by Sidney Altman of Yale University and Thomas Cech of the University of Colorado placed the RNA World idea on a more solid footing. Altman and Cech independently discovered that RNA can catalyze the formation and cleavage of phosphodiester bonds—exactly the kinds of bonds that unite individual ribonucleotides in RNA. That, plus the recent discovery that ribosomal RNA catalyzes the addition of amino acids to the growing peptide chain in protein biosynthesis, takes care of the most serious deficiencies in the RNA World model by providing precedents for the catalysis of biological processes by RNA. 

Ribozyme (Section 28.11) A polynucleotide that has catalytic activity. 

Several features of these RNA enzymes, or ribozymes, lead to the realization that their biological efficiency does not challenge that achieved by proteins. First, RNA enzymes often do not fulfill the criterion of catalysis in vivo because they act only once in intramolecular events such as self-splicing. Second, the catalytic rates achieved by RNA enzymes in vivo and in vitro are... 

Cate, J. H., et al., 1996. Crystal structure of a group I ribozyme domain Principles of RNA packing. Science 273 1678. 

Cecil, T. R., et al., 1992. RNA catalysis by a group I ribozyme Developing a model for transition-state stabilization. Journal of Biological Chemistry... 

Scott, W. G., and King, A., 1996. Ribozymes Structure and mechanism in RNA catalysis. Trends in Biochemical Sciences 21 220-224. 

Zhang, B., and Cecil, T. R., 1997. Peptide bond formation by in vitro selected ribozymes. Nature 59 99- 99. 

Cagnon, L., and Rossi, J. J. (2000). Down regulation of the CCRS beta-chemokine receptor and inhibition of HIV-1 infection by stable VAl-ribozyme chimeric transcripts. Antisen. Nuc. A. Drug Dev. 10 251—261. 

Ribozymes that are small RNA molecules with endoribonuclease activity and exhibit catalytic sequence-specific cleavage of the target. 

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. 

Antisense Oligonucleotides. Table 1 Malignant disorders as potential targets for ribozyme gene therapy... 

Target gene Gene product Ribozyme-induced change of function... 

Angiozyme is a ribozyme that specifically recognizes the mRNA for FLT-1, one of the most important VEGF... 

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