Ribozyme

A ribozyme, or RNA enzyme, is an RNA molecule that can catalyze a chemical reaction. Many natural ribozymes catalyze either their own cleavage or the cleavage of 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.

Before the discovery of ribozymes, only proteins were known to have catalytic activity. In 1967, Carl Woese, Francis Crick, and Leslie Orgel were the first to suggest that RNA could act as a catalyst based upon findings that it can form complex secondary structures. The first ribozyme was discovered in the 1980s by Thomas R. Cech, who was studying RNA splicing in the ciliated protozoan Tetrahymena thermophila. This ribozyme was found in the intron of an RNA transcript and removed itself from the transcript. Ribozymes often have divalent metal ions such as Mg²⁺ as cofactors. In 1989, Thomas R. Cech and Sydney Altman won the nobel prize in chemistry for their "discovery of catalytic properties of RNA." Nobel prize announcement (http://nobelprize.org/chemistry/laureates/1989/)

Although 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.

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.

Some known ribozymes include RNase P, Group I and Group II introns, leadzyme, hairpin ribozyme, hammerhead ribozyme, hepatitis delta virus ribozyme, and tetrahymena ribozyme.

Synthetic 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 have been produced that have good enzymatic activity. Tang and Breaker [1] (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10823936) 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.

Johnston and co-workers started with a mutated sequence of a naturally occurring ribozyme and screened approximately 1,000,000,000,000,000 mutated variants for polymerase activity [2] (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11358999). They isolated and characterized a synthetic ribozyme that has many of the properties that would be required for an RNA polymerase that could replicate pre-existing RNAs.

A synthetic ribozyme sequence that self-cleaves can be inserted upstream of an mRNA coding region, allowing upregulation of expression by introducing ribozyme activity inhibitors such as small-molecule inhibitors or Morpholino antisense oligos [3] (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15386015). Ribozymes have DNA pendants called Deoxyribozymes.

Ribozymes and deoxyribozymes have been developed that catalyze a large number of different chemical reactions including phosphoester transfer, phosphoester hydrolysis, polynucleotide ligation, polynucleotide phosphorylation, mononucleotide polymerization (akin to a protein polymerase), aminoacyl transfer (akin to aminoacylation of a transfer RNA), amide bond cleavage, amide bond formation, peptide bond formation (akin to the ribosome), N-alkylation, S-alkylation, porphyrin metallation, Diels-Alder reaction, and oxidative DNA cleavage (DNA damage). Nucleic Acid Enzymes (http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=9600881)

External links

• Ribozyme structures and mechanisms (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11441810&dopt=Abstract)
• De novo synthesis and development of an RNA enzyme (http://www.pnas.org/cgi/content/full/101/38/13750)
• Directed evolution of nucleic acid enzymes. (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15189159&query_hl=1)ja:ライボザイム