Catalysis ribozymes

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. 

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... 

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. 

The hypothesis that our biological world built on the DNA-RNA-protein central dogma was preceded by an RNA world in which RNA molecules carried both the genetic information and executed the gene functions (through ribozyme activity) is now widely accepted [130]. However, it is also well recognized that RNA due to its vulnerability to hydrolysis - especially as a result of catalysis by divalent metal ions - would not have been able to evolve in a harsh pre-biotic environment Also the formation of RNA under presumed pre-biotic conditions is extremely inefficient It is not so far-fetched to propose that a peptide nucleic acid-like molecule may have been able to function as a form of pre-biotic genetic material since it... 

UNRAVELING THE MECHANISMS OF RIBOZYME CATALYSIS WITH MULTISCALE SIMULATIONS... 

Keywords Ribozyme catalysis, multiscale simulation, linear-scaling method, QM/MM, DFT... 

Case Study Chemical Steps of Catalysis in Hairpin Ribozyme... 

In contrast, the hairpin ribozyme (HPR) [107, 108], which catalyzes the reversible, site-specific phosphodiester bond cleavage of an RNA substrate, is unique in that the chemical steps of the reaction do not require involvement of a divalent metal ion [107-111]. This lack of an explicit metal ion requirement [112] makes the hairpin ribozyme an ideal target for theoretical studies aimed to characterize the contribution of generalized solvation provided by the solvated ribozyme on catalysis. 

Case Study Role of Divalent Metal Ions in Hammerhead Ribozyme Catalysis... 

Lilley DM (2008) Ribozymes and RNA Catalysis, chap. The Hairpin and Varkud Satellite Ribozymes, 66-91, RSC Biomolecular Series, RSC Publishing, Cambridge. 

There are three mechanistic possibilities for catalysis by two-metal ion sites (Fig. 10). The first of these is the classic two-metal ion catalysis in which one metal plays the dominant role in activating the substrate toward nucleophilic attack, while the other metal ion furnishes the bound hydroxide as the nucleophile (Fig. 10 a). Upon substrate binding, the previously bridged hydroxide shifts to coordinate predominately with one metal ion. Enzymes believed to function through such a mechanism include a purple acid phosphatase [79], DNA polymerase I [80], inositol monophosphatase [81],fructose-1,6-bisphosphatase [82], Bam HI [83], and ribozymes [63]. 

Ribozymes, 17 614,, 20 447, 618—619 catalysis by, 17 619 Ricard-Allenet four-column sequence, 8 832... 

The peptidyl transferase centre of the ribosome is located in the 50S subunit, in a protein-free environment (there is no protein within 15 A of the active site), supporting biochemical evidence that the ribosomal RNA, rather than the ribosomal proteins, plays a key role in the catalysis of peptide bond formation. This confirms that the ribosome is the largest known RNA catalyst (ribozyme) and, to date, the only one with synthetic activity. Adjacent to the peptidyl transferase centre is the entrance to the protein exit tunnel, through which the growing polypeptide chain moves out of the ribosome. 

The discovery of self-splicing introns showed that RNA could catalyse chemical reactions. Yet, unlike proteins, RNA has no functional groups with pKa values and chemical properties similar to those considered to be important in protein-based enzymes. Steitz and Steitz (1993) postulated that two metal ions were essential for catalysis by ribozymes using a mechanism similar to DNA cleavage, in which a free 3 OH is produced. They proposed,... 

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