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ribozyme

 
Dictionary: ri·bo·zyme   ('bə-zīm') pronunciation
n.
An RNA segment that has the ability to catalyze the cleavage and formation of covalent bonds in RNA strands at specific sites.

[RIBO(NUCLEIC ACID) + (EN)ZYME.]


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Sci-Tech Encyclopedia: Ribozyme
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A ribonucleic acid (RNA) molecule that, like a protein, can catalyze specific biochemical reactions. Examples include self-splicing rRNA and RNase P, both involved in catalyzing RNA processing reactions (that is, the biochemical reactions that convert a newly synthesized RNA molecule to its mature form). Different ribozyme structures catalyze quite distinct RNA processing reactions, just as protein enzyme families that are composed of different structures catalyze different types of biochemical reactions.

Ribozymes share many similarities with protein enzymes, as assessed by two parameters that are used to describe a biological catalyst. The Michaelis-Menten constant Km relates to the affinity that the catalyst has for its substrate, and ribozymes possess Km values which are comparable to Km values of protein enzymes. The catalytic rate constant describes how efficiently a catalyst converts substrate into product. The values of this constant for ribozymes are markedly lower than those values observed for protein enzymes. Nevertheless, ribozymes accelerate the rate of chemical reaction with specific substrates by 1011 compared with the rate observed for the corresponding uncatalyzed, spontaneous reaction. Therefore, ribozymes and protein enzymes are capable of lowering to similar extents the activation energy for chemical reaction. See also Enzyme; Protein; Ribonucleic acid (RNA).


Genetics Encyclopedia: Ribozyme
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Ribozymes are RNA molecules that catalyze chemical reactions. Most biological processes do not happen spontaneously. For example, the cleavage of a molecule into two parts or the linkage of two molecules into one larger molecule requires catalysts, that is, helper molecules that make a reaction go faster. The majority of biological catalysts are proteins called enzymes. For many years scientists assumed that proteins alone had the structural complexity needed to serve as specific catalysts in cells, but around 1980 the research groups of Tom Cech and Sidney Altman independently discovered that some biological catalysts are made of RNA. These two scientists were honored with the Nobel Prize in chemistry in 1989 for their discovery.

Structure and Function

The RNA catalysts called ribozymes are found in the nucleus, mitochondria, and chloroplasts of eukaryotic organisms. Some viruses, including several bacterial viruses, also have ribozymes. The ribozymes discovered to date can be grouped into different chemical types, but in all cases the RNA is associated with metal ions, such as magnesium (Mg2+) or potassium (K+), that play important roles during the catalysis. Almost all ribozymes are involved in processing RNA. They act either as molecular scissors to cleave precursor RNA chains (the chains that form the basis of a new RNA chain) or as "molecular staplers" that ligate two RNA molecules together. Although most ribozyme targets are RNA, there is now very strong evidence that the linkage of amino acids into proteins, which occurs at the ribosome during translation, is also catalyzed by RNA. Thus, the ribosomal RNA is itself also a ribozyme.

In some ribozyme-catalyzed reactions, the RNA cleavage and ligation processes are linked. In this case, an RNA chain is cleaved in two places and the middle piece (called the intron) is discarded, while the two flanking RNA pieces (called exons) are ligated together. This reaction is called splicing. Besides ribozyme-mediated splicing, which involves RNA alone, there are some splicing reactions that involve RNA-protein complexes. These complexes are called small nucleus ribonucleoprotein particles, abbreviated as snRNPs. This class of splicing is a very common feature of messenger RNA (mRNA) processing in "higher" eukaryotes such as humans. It is not yet known if snRNP-mediated splicing is catalyzed by the RNA components. Note also that some RNA splicing reactions are catalyzed by enzymes made of only protein.

Some precursor RNA molecules have a ribozyme built into their own intron, and this ribozyme is responsible for removal of the intron in which it is found. These are called self-splicing RNAs. After the splicing reaction is complete, the intron, including the ribozyme, is degraded. In these cases, each ribozyme works only once, unlike protein enzymes that catalyze a reaction repeatedly. Examples of self-spliced RNAs include the ribosomal RNAs of ciliated protozoa and certain mRNAs of yeast mitochondria.

Some RNA viruses, such as the hepatitis delta virus, also include a ribozyme as part of their inherited RNA molecule. During replication of the viral RNA, long strands containing repeats of the RNA genome (viral genetic information) are synthesized. The ribozyme then cleaves the long multimeric molecules into pieces that contain one genome copy, and fits that RNA piece into a virus particle.

Other ribozymes work on other RNA molecules. One ribozyme of this type is RNase P, which consists of one RNA chain and one or more proteins (depending on the organism). The catalytic mechanism of RNase P has been especially well-studied in bacteria. This ribozyme processes precursor transfer RNA (tRNA) by removing an extension from the 5-prime end, to create the 5-prime end of the "mature" tRNA (the two ends of an RNA molecule are chemically distinct and are called the 5-prime and 3-prime ends, referring to specific carbons in the sugar moiety of the terminal nucleotides). When the RNA molecule from bacterial RNase P is purified away from its protein, it can still cleave its precursor tRNA target, albeit at a very slow rate, proving that the RNA is the catalyst. Nevertheless, the protein(s) in RNase P also has important functions, such as maintenance of the proper conformation of the RNase P RNA and interaction with the precursor tRNA.

Relics of an "Rna World"

Many biologists hypothesize that ribozymes are vestiges of an ancient, prebiotic world that predated the evolution of proteins. In this "RNA world," RNAs were the catalysts of such functions as replication, cleavage, and ligation of RNA molecules. Proteins are hypothesized to have evolved later, and as they evolved they took over functions previously performed by RNA molecules. This may have happened because proteins are more versatile and efficient in their catalytic functions.

In today's world, most processing of precursor tRNA is performed by the ribozyme RNase P, as described above, but in some chloroplasts, this function is performed by a protein that apparently contains no RNA. This may be an example of the evolution of protein enzymes that replace ribozymes.

Intensive studies of ribozymes have provided rules for how they recognize their targets. Based on these rules, it has been possible to alter ribozymes to recognize and cleave new targets in RNA molecules that are normally not subject to ribozyme cleavage. These results raise the exciting possibility of using ribozymes for human therapy. For example, the abundance of disease-causing RNA molecules such as HIV, the cause of AIDS, could be reduced with artificial ribozymes. Considerable success has been achieved in testing these ribozymes in model cells. However, the biggest question remaining to be solved is how these potential "disease-fighting" ribozymes can be introduced into a patient and taken up by the appropriate cells.

Bibliography

Cech, T. R. "RNA as an Enzyme." Scientific American 255 (1986): 64-75.

Karp, Gerald. Cell and Molecular Biology, 3rd ed. New York: John Wiley & Sons, 2002.

—Lasse Lindahl

Biology Q&A: What are ribozymes?
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Ribozymes are often referred to as "molecular scissors" that cut RNA. They were discovered in the early 1980s by Sidney Altman (1939-) and Thomas Cech (1947-), who won the Nobel Prize in Chemistry for their work in 1989. The ability of ribozymes to recognize and cut specific sequences of RNA allows certain genes to be turned off. Ribozymes are now being used in human genetic studies.

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Veterinary Dictionary: ribozyme
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Enzyme whose catalytic function is carried out by an RNA subunit; of the four known classes, three carry out self processing reactions while the fourth, ribonuclease P (RNase P), is a true catalyst; discovered in the context of RNA splicing.

Wikipedia: Ribozyme
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Structure of hammerhead ribozyme

A ribozyme (from ribonucleic acid enzyme, also called RNA enzyme or catalytic RNA) is an RNA molecule that catalyzes a chemical reaction. Many natural ribozymes catalyze either the hydrolysis of one of their own phosphodiester bonds, or the hydrolysis of bonds in other RNAs, but they have also been found to catalyze the aminotransferase activity of the ribosome.

Investigators studying the origin of life have produced ribozymes in the laboratory that are capable of catalyzing their own synthesis under very specific conditions, such as an RNA polymerase ribozyme.[1] Mutagenesis and selection has been performed resulting in isolation of improved variants of the "Round-18" polymerase ribozyme from 2001. "B6.61" is able to add up to 20 nucleotides to a primer template in 24 hours, until it decomposes by hydrolysis of its phosphodiester bonds.[2]

Some ribozymes may play an important role as therapeutic agents, as enzymes which tailor defined RNA sequences, as biosensors, and for applications in functional genomics and gene discovery.[3]

Contents

Discovery

Schematic showing ribozyme cleavage of RNA.

Before the discovery of ribozymes, enzymes, which are defined as catalytic proteins,[4] were the only known biological catalysts. In 1967, Carl Woese, Francis Crick, and Leslie Orgel were the first to suggest that RNA could act as a catalyst. This idea was based upon the discovery that RNA can form complex secondary structures.[5] The first ribozymes were discovered in the 1980s by Thomas R. Cech, who was studying RNA splicing in the ciliated protozoan Tetrahymena thermophila and Sidney Altman, who was working on the bacterial RNase P complex. These ribozymes were found in the intron of an RNA transcript, which removed itself from the transcript, as well as in the RNA component of the RNase P complex, which is involved in the maturation of pre-tRNAs. In 1989, Thomas R. Cech and Sidney Altman won the Nobel Prize in chemistry for their "discovery of catalytic properties of RNA."[6] The term ribozyme was first introduced by Kelly Kruger et al. in 1982 in a paper published in Cell.

It had been a firmly established belief in biology that catalysis was reserved for proteins. In retrospect, catalytic RNA makes a lot of sense. This is based on the old question regarding the origin of life: Which comes first, enzymes that do the work of the cell or nucleic acids that carry the information required to produce the enzymes? Nucleic acids as catalysts circumvents this problem.[7]

In the 1970s Thomas Cech, at the University of Colorado at Boulder, was studying the excision of introns in a ribosomal RNA gene in Tetrahymena thermophila. While trying to purify the enzyme responsible for splicing reaction, he found that intron could be spliced out in the absence of any added cell extract. Much as they tried, Cech and his colleagues could not identify any protein associated with the splicing reaction. After much work, Cech proposed that the intron sequence portion of the RNA could break and reform phosphodiester bonds. At about the same time, Sidney Altman, who is a Professor at Yale University, was studying the way tRNA molecules are processed in the cell when he and his colleagues isolated an enzyme called RNase-P, which is responsible for conversion of a precursor tRNA into the active tRNA. Much to their surprise, they found that RNase-P contained RNA in addition to protein and that RNA was an essential component of the active enzyme. This was such a foreign idea that they had difficulty publishing their findings. The following year, Altman demonstrated that RNA can act as a catalyst by showing that the RNase-P RNA subunit could catalyze the cleavage of precursor tRNA into active tRNA in the absence of any protein component.

Since Cech's and Altman's discovery, other investigators have discovered other examples of self-cleaving RNA or catalytic RNA molecules. Many ribozymes have either a hairpin – or hammerhead – shaped active center and a unique secondary structure that allows them to cleave other RNA molecules at specific sequences. It is now possible to make ribozymes that will specifically cleave any RNA molecule. These RNA catalysts may have pharmaceutical applications. For example, a ribozyme has been designed to cleave the RNA of HIV. If such a ribozyme was made by a cell, all incoming virus particles would have their RNA genome cleaved by the ribozyme, which would prevent infection.

Activity

Although most ribozymes are quite rare in the cell, their roles are sometimes essential to life. For example, the functional part of the ribosome, the molecular machine that translates RNA into proteins, is fundamentally a ribozyme. Ribozymes often have divalent metal ions such as Mg2+ as cofactors.

RNA can also act as a hereditary molecule, which encouraged Walter Gilbert to propose that in the past, the cell used RNA as both the genetic material and the structural and catalytic molecule, rather than dividing these functions between DNA and protein as they are today. This hypothesis became known as the "RNA world hypothesis" of the origin of life.

If ribozymes were the first molecular machines used by early life, then today's remaining ribozymes -- such as the ribosome machinery -- could be considered living fossils of a life based primarily on nucleic acids.

A recent test-tube study of prion folding suggests that an RNA may catalyze the pathological protein conformation in the manner of a chaperone enzyme.[8]

Known ribozymes

Naturally occurring ribozymes include:

Artificial ribozymes

Since the discovery of ribozymes that exist in living organisms, there has been interest in the study of new synthetic ribozymes made in the laboratory. For example, artificially-produced self-cleaving RNAs that have good enzymatic activity have been produced. Tang and Breaker[10] isolated self-cleaving RNAs by in vitro selection of RNAs originating from random-sequence RNAs. Some of the synthetic ribozymes that were produced had novel structures, while some were similar to the naturally occurring hammerhead ribozyme.

The techniques used to discover artificial ribozymes involve Darwinian evolution. This approach takes advantage of RNA's dual nature as both a catalyst and an informational polymer, making it easy for an investigator to produce vast populations of RNA catalysts using polymerase enzymes. The ribozymes are mutated by reverse transcribing them with reverse transcriptase into various cDNA and amplified with mutagenic PCR. The selection parameters in these experiments often differ. One approach for selecting a ligase ribozyme involves using biotin tags, which are covalently linked to the substrate. If a molecule possesses the desired ligase activity, a streptavidin matrix can be used to recover the active molecules.

Lincoln and Joyce developed an RNA enzyme system capable of self replication in about an hour. By utilizing molecular competition (in vitro evolution) of a candidate enzyme mixture, a pair of RNA enzymes emerged, in which each synthesizes the other from synthetic oligonucleotides, with no protein present.[11]

See also

References

  1. ^ Johnston W, Unrau P, Lawrence M, Glasner M, Bartel D (2001). "RNA-catalyzed RNA polymerization: accurate and general RNA-templated primer extension" (PDF). Science 292 (5520): 1319–25. doi:10.1126/science.1060786. PMID 11358999. http://web.wi.mit.edu/bartel/pub/publication_reprints/Johnston_Science01.pdf. 
  2. ^ Zaher HS, Unrau P (2007). "Selection of an improved RNA polymerase ribozyme with superior extension and fidelity". RNA 13 (7): 1017–26. doi:10.1261/rna.548807. PMID 17586759. http://www.ncbi.nlm.nih.gov/sites/entrez?db=PubMed&cmd=Retrieve&list_uids=17586759. 
  3. ^ Hean J and Weinberg MS (2008). "The Hammerhead Ribozyme Revisited: New Biological Insights for the Development of Therapeutic Agents and for Reverse Genomics Applications". RNA and the Regulation of Gene Expression: A Hidden Layer of Complexity. Caister Academic Press. ISBN 978-1-904455-25-7. http://www.horizonpress.com/rnareg. 
  4. ^ Enzyme definition Dictionary.com Accessed 6 April 2007
  5. ^ Carl Woese, The Genetic Code (New York: Harper and Row, 1967).
  6. ^ The Nobel Prize in Chemistry 1989 was awarded to Thomas R. Cech and Sidney Altman "for their discovery of catalytic properties of RNA".
  7. ^ RNA Catalysis (January 2007). "http://adsabs.harvard.edu/abs/1984OrLi...14..291V". http://adsabs.harvard.edu/abs/1984OrLi...14..291V. Retrieved 2007-08-04. 
  8. ^ "Prion protein conversion in vitro" by S. Supattapone (2004) in Journal of Molecular Medicine Volume 82, pages 348-356. Entrez Pubmed 15014886
  9. ^ Nielsen H, Westhof E, Johansen S (2005). "An mRNA is capped by a 2', 5' lariat catalyzed by a group I-like ribozyme". Science 309 (5740): 1584–7. doi:10.1126/science.1113645. PMID 16141078. 
  10. ^ Jin Tang and Ronald R. Breaker (1997). "Structural diversity of self-cleaving ribozymes". Proceedings of the National Academy of Sciences 97 (11): 5784–5789. doi:10.1073/pnas.97.11.5784. PMID 10823936. http://www.pnas.org/cgi/content/full/97/11/5784. 
  11. ^ Lincoln, Tracey A.; Joyce, Gerald F. (January 8, 2009). "Self-Sustained Replication of an RNA Enzyme". Science (New York: American Association for the Advancement of Science) 323: 1229. doi:10.1126/science.1167856. PMID 19131595. http://www.sciencemag.org/cgi/content/abstract/1167856. Retrieved 2009-01-14. Lay summary – ScienceDaily (January 10, 2009). 

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Dictionary. The American Heritage® Dictionary of the English Language, Fourth Edition Copyright © 2007, 2000 by Houghton Mifflin Company. Updated in 2009. Published by Houghton Mifflin Company. All rights reserved.  Read more
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