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20-September-2008 09:29:09 - acid analogues Not to be confused with degenerate bases. For phosphoramidite synthesis of nucleic acids, see Oligonucleotide synthesis. RNA with its nucleobases to the left and DNA to the right. RNA with its nucleobases to the left and DNA to the right. Nucleic acid analogues are compounds structurally similar analog to naturally occurring RNA and DNA, used in medicine and in molecular biology research. Nucleic acids are chains of nucleotides, which are composed of three parts: a phosphate backbone, a pucker-shaped pentose sugar, either ribose or deoxyribose, and one of four nucleobases. An analogue may have any of these altered, typically the analogue nucleobases confer, among other things, different base pairing and base stacking proprieties such as universal bases, which can pair with all four canon bases, while the phosphate-sugar backbone analogues affect the properties of the chain, such as PNA which whose secondary structure differs significantly and may form a triplex a triple stranded helix. 1 Contents 1 Medicine 2 Molecular biology 3 backbone analogues 3.1 Hydrolysis resistant RNA-analogues 3.2 Other notable analogues used as tools 3.3 precursors to the RNA-world 4 Base analogues 4.1 Nucleobase structure and nomeclature 4.2 Fluorophores 4.3 Natural non-canon bases 4.4 Base-pairing 5 See also 6 References Medicine Main article: Nucleoside analogues Several nucleoside analogues are used as antiviral or anticancer agents. The viral polymerase incorporates these compounds with non-canon bases. These compounds are activated in the cells by being converted into nucleotides, they are administered as nucleosides since charged nucleotides cannot easily cross cell membranes. Molecular biology Common changes in nucleotide analogues Common changes in nucleotide analogues Nucleic acid analogues are used in molecular biology for several purposes: As a tool to detect particular sequences As a tool with resistance to RNA hydrolysis As a tool for another purpose, such as sequencing Naturally occurring, such as in tRNA Investigation of the mechanisms used by enzyme, such as an Enzyme inhibitor Investigation of possible scenarios of the origin of life Investigation of the structural features of nucleic acids Investigation of the possible alternatives to the natural system in Synthetic biology backbone analogues Hydrolysis resistant RNA-analogues Chemical structure of Morpholino Chemical structure of Morpholino To overcome the fact that ribose's 2' hydroxy group that reacts with the phosphate linked 3' hydroxy group RNA is too unstable to be used or synthesised reliably, a ribose anologue is used. The most common RNA analogues are locked nucleic acid LNA, morpholino, peptide nucleic acid PNA. These oligonucleotides differ as they have a different backbone sugar but still bind according to Watson and Crick pairing with RNA or DNA, but are immune to nuclease activity They generally cannot be enzymatically synthesised and can only be produced synthetically. Other notable analogues used as tools In sequencing dideoxynucleotides are used. These nucleotide triphosphates possess a non-canon sugar, dideoxyribose which lacks 3' hydroxyl group which accepts the phosphate and therefore cannot bond with the next base, terminating the chain as the DNA polymerases mistake it for a regular deoxyribonucleotide. The nucleoside analogue with a ribose lacking both 2' and 3' is called cordycepin, an anticancer drug. Another analogue in sequencing is a nucleobase analogue, 7-deaza-GTP and is used to sequence CG rich regions, instead 7-deaza-ATP is called tubercidin, an antibiotic. precursors to the RNA-world Main article: RNA world hypothesis RNA may be too complex to be the first nucleic acid, so before the RNA world there may have been one of these several candidate original nucleic acids which differ in the backbone, such as TNA and GNA and PNA. Base analogues Nucleobase structure and nomeclature Main article: Nucleobase Natural bases are divided into two classes depending on their structure: pyrimidine an heterocyclic aromatic six-membered ring with nitrogen atoms in position 1 and 3 and purine a pyrimidine numeration inverted fused with an imidazole ring, a five-membered ring with 2 nitrogen atoms separated by one carbon meta, 7,9. Their main proprieties are base pairing, resulting form 2 or 3 hydrogen bonds between keto and amino functional groups, and base stacking, caused by the attraction of the delocalized pi electron clouds of the aromatic ring structure. size size Purine Pyrimidine For structures of the analogues that may be mentioned in the literature, see Simple aromatic ring. Fluorophores Main article: Fluorophore Structure of aminoallyl-uridine Structure of aminoallyl-uridine Commonly fluorophores such as rhodamine or fluorescein are linked to the ring linked to the sugar in para via a flexible arm, presumably extruding form the major groove of the helix. Due to taq polymerases low processivity of the nucleotides linked to bulky adducts such as florophores, the sequence is typically copied using a nucleotide with an arm and later coupled with a reactive fluorophore indirect labelling: amine reactive: Aminoallyl nucleotide contain a primary amine group on a linker that reacts with the amino-reactive dye such as a cyanine or Alexa Fluor dyes, which contain a reactive leaving group, such as a succinimidyl ester NHS. base pairing amino groups are not affected. thiol reactive: thiol containing nucleotides reacts with the fluorophore linked to a reactive leaving group, such as a maleimide. biotin linked nucleotides rely on the same indirect labelling principle + fluorescent streptavidin and are used in Affymetrix DNAchips. Fluorophores find a variety of uses in medicine and biochemistry. Natural non-canon bases In a cell, there are several noncanon bases present: CpG islands in DNA are often methylated, all eukaryotic mRNA capped with a methyl-7-guanosine, and several bases of rRNAs are methylated. Often, tRNAs are heavily modified postranscriptionally in order to improve their conformation or base pairing in particular in/near the anticodon: inosine can base pair with C, U, and even with A, whereas thiouridine with A is more specific than uracil with a purine. Other common tRNA base modifications are pseudorindine which gives its name to the TΨC loop, dihydrouridine which does not stack as it is not aromatic, queosine, wyosine and so forth. Nevertheless these are all modifications to normal bases and are not placed by a polymerase. Base-pairing Canonical bases may have either a keto or amino group on the carbons surrounding the nitrogen atom furthest away from the glycosidic bond, which allows them to base pair Watson-Crick base pairing via hydrogen bonds amine with keto, purine with pyrimidine. A and T are amine only and keto only, while C and G are mixed inverted in respect to each other. Natural basepairs A GC basepair: purine keto/amine forms three intermolecular hydrogen bonds with pyrimidine amine/keto An AT basepair: purine amine/- forms two intermolecular hydrogen bonds with pyrimidine keto/keto The precise reason why there are only four nucleotides is debated, but they are several unused possibilities. Furthermore adenine is not the most stable choice for base pairing: in Cyanophage S-2L diaminopurine DAP is used instead of adenine host evasion. Diaminopurine basepairs perfectly with thymine as it is identical to adenine but has an amine group at position 2 forming 3 intramolecular hydrogen bonds, eliminating the major difference between the two types of basepairs Weak:A-T and Strong:C-G. This improved stability affects protein binding ineractions which rely on those differences. Other combination include, isoguanosine and isocytosine, which are have their amino and keto inverted, not used probably as tautomers are problematic for base pairing, but isoG and isoG can be amplified correctly with PCR even in the presence of the 4 canon bases 2 diaminopyrimidine and a xanthine not used as xanthine is a deamination product Unused basepair arrangements A DAP-T base: purine amine/amine forms three intermolecular hydrogen bonds with pyrimidine keto/keto An X-DAY base: purine keto/keto forms three intermolecular hydrogen bonds with pyrimidine amine/amine A iG-iC base: purine amine/keto forms three intermolecular hydrogen bonds with pyrimidine keto/amine However correct DNA structure can form even when the bases are not paired via hydrogen bonding, as studies have shown using DNA isosteres analogues with same number of atoms, such as the thymine analogue 2,4-difluorotoluene F or the adenine analogue 4-methylbenzimidazole Z. Other noteworthy basepairs: Several fluorescent bases have also been made, such as the 2-amino-6-2-thienylpurine and pyrrole-2-carbaldehyde base pair. 3 Metal coordinated bases, such as two 2,6-bisethylthiomethylpyridine SPy with a silver ion or pyridine-2,6-dicarboxamide Dipam and a mondentate pyridine Py with a copper ion 4. Universal bases may pair indiscriminately with any other base, but generally lower the melting temperature of the sequence considerably, examples include 2'-deoxyinosine derivatives, nitroazole analogues and hydrophobic aromatic non-hydrogen bonding bases strong stacking effects. These are used as proof of concept and are not generally utilised in degenerate primers which are a mixture of primers. The numbers of possible base pairs is doubled when xDNA is considered. xDNA contains expanded bases, in which a benzine ring has been added, which may pair with canon bases, resulting in four possible base-pairs 8 bases:xA-T,xT-A,xC-G,xG-C, 16 bases if the unused arrangements are used. Another form of benzine added bases is yDNA, in which the base is widened by the benzine5. Novel basepairs with special proprieties A F-Z base: methylbenzimidazole does not form intermolecular hydrogen bonds with toluene F/F An S-Pa base: purine thienyl/amine forms three intermolecular hydrogen bonds with pyrrole -/carbaldehyde An xA-T base: same bonding as A-T See also Molecular biology Genetics synthetic biology Oligonucleotide synthesis Nucleobase, nucleoside, nucleotide, and nucleic acid Biotin, fluorophore and dark quencher ribozyme v d e Types of nucleic acids Constituents Nucleobases | Nucleosides | Nucleotides | Deoxynucleotides Ribonucleic acids RNA | mRNA pre-mRNA/hnRNA | tRNA | rRNA | aRNA | gRNA | miRNA | ncRNA | piRNA | shRNA | siRNA | snRNA | snoRNA | stRNA | ta-siRNA | tmRNA Deoxyribonucleic acids DNA | cDNA | gDNA | msDNA | mtDNA Nucleic acid analogues GNA | LNA | PNA | TNA | morpholino Cloning vectors phagemid | plasmid | lambda phage | cosmid | P1 phage | fosmid | BAC | YAC | HAC Major families of biochemicals Saccharides | Carbohydrates | Glycosides | | Amino acids | Peptides | Proteins | Glycoproteins | | Lipids | Terpenes | Steroids | Carotenoids Alkaloids | Nucleobases | Nucleic acids | | Enzyme cofactors | Flavonoids | Polyketides | Tetrapyrroles References ^ Petersson B et al. Crystal structure of a partly self-complementary peptide nucleic acid PNA oligomer showing a duplex-triplex network. J Am Chem Soc. 2005 Feb 9;1275:1424-30. ^ Johnson SC et al. A third base pair for the polymerase chain reaction: inserting isoC and isoG. Nucleic Acids Res. 2004 Mar 29;326:1937-41. ^ Kimoto M et al. Fluorescent probing for RNA molecules by an unnatural base-pair system. Nucleic Acids Res. 2007;3516:5360-9. ^ Zimmermann N et al. A second-generation copperII-mediated metallo-DNA-base pair. Bioorg Chem. 2004 Feb;321:13-25. ^ Liu H et al ET Kool Lab1. A four-base paired genetic helix with expanded size. Science. 2003 Oct 31;3025646:868-71 Retrieved from http://en..org/wiki/Nucleic_acid_analogues Categories: Molecular genetics | Nucleic acids | Nucleotides | RNA | RNA interference | Gene expression Views Article Discussion this page History Personal tools Log in / create account Navigation Main page Contents Featured content Current events Random article Search Go Search Interaction Community portal Recent changes Contact Donate to Help Toolbox What links here Related changes Upload file Special pages Printable version Permanent link Cite this page This page was last modified on 8 August 2008, at 02:44
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