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Threose nucleic acid (TNA) is an artificial genetic
polymer A polymer () is a chemical substance, substance or material that consists of very large molecules, or macromolecules, that are constituted by many repeat unit, repeating subunits derived from one or more species of monomers. Due to their br ...
in which the natural five-carbon ribose sugar found in
RNA Ribonucleic acid (RNA) is a polymeric molecule that is essential for most biological functions, either by performing the function itself (non-coding RNA) or by forming a template for the production of proteins (messenger RNA). RNA and deoxyrib ...
has been replaced by an unnatural four-carbon
threose Threose is a four-carbon monosaccharide with molecular formula C4H8O4. It has a terminal aldehyde group, rather than a ketone, in its linear chain and so is considered part of the aldose family of monosaccharides. The threose name can be used to ...
sugar.Schöning, K. U. ''et al.'' Chemical etiology of nucleic acid structure: the a-threofuranosyl-(3'-->2') oligonucleotide system. ''Science'' 290, 1347-1351, (2000) Invented by Albert Eschenmoser as part of his quest to explore the chemical
etiology Etiology (; alternatively spelled aetiology or ætiology) is the study of causation or origination. The word is derived from the Greek word ''()'', meaning "giving a reason for" (). More completely, etiology is the study of the causes, origins ...
of RNA, TNA has become an important synthetic genetic polymer ( XNA) due to its ability to efficiently
base pair A base pair (bp) is a fundamental unit of double-stranded nucleic acids consisting of two nucleobases bound to each other by hydrogen bonds. They form the building blocks of the DNA double helix and contribute to the folded structure of both DNA ...
with complementary sequences of
DNA Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...
and RNA. The main difference between TNA and DNA/RNA is their backbones. DNA and RNA have their phosphate backbones attached to the 5' carbon of the deoxyribose or ribose sugar ring, respectively. TNA, on the other hand, has its phosphate backbone directly attached to the 3' carbon in the ring, since it does not have a 5' carbon. This modified backbone makes TNA, unlike DNA and RNA, completely refractory to
nuclease In biochemistry, a nuclease (also archaically known as nucleodepolymerase or polynucleotidase) is an enzyme capable of cleaving the phosphodiester bonds that link nucleotides together to form nucleic acids. Nucleases variously affect single and ...
digestion, making it a promising nucleic acid analog for therapeutic and diagnostic applications. TNA oligonucleotides were first constructed by automated solid-phase synthesis using phosphoramidite chemistry. Methods for chemically synthesized TNA monomers (phosphoramidites and nucleoside triphosphates) have been heavily optimized to support
synthetic biology Synthetic biology (SynBio) is a multidisciplinary field of science that focuses on living systems and organisms. It applies engineering principles to develop new biological parts, devices, and systems or to redesign existing systems found in nat ...
projects aimed at advancing TNA research. More recently, polymerase engineering efforts have identified TNA
polymerase In biochemistry, a polymerase is an enzyme (Enzyme Commission number, EC 2.7.7.6/7/19/48/49) that synthesizes long chains of polymers or nucleic acids. DNA polymerase and RNA polymerase are used to assemble DNA and RNA molecules, respectively, by ...
s that can copy genetic information back and forth between DNA and TNA. TNA replication occurs through a process that mimics RNA replication. In these systems, TNA is reverse transcribed into DNA, the DNA is amplified by the
polymerase chain reaction The polymerase chain reaction (PCR) is a method widely used to make millions to billions of copies of a specific DNA sample rapidly, allowing scientists to amplify a very small sample of DNA (or a part of it) sufficiently to enable detailed st ...
, and then forward transcribed back into TNA. The availability of TNA polymerases have enabled the in vitro selection of biologically stable TNA aptamers to both small molecule and protein targets.Yu, H., Zhang, S. & Chaput, J. C. Darwinian evolution of an alternative genetic system provides support for TNA as an RNA progenitor. ''Nat. Chem.'' 4, 183-187, (2012). Such experiments demonstrate that the properties of heredity and evolution are not limited to the natural genetic polymers of DNA and RNA. The high biological stability of TNA relative to other nucleic acid systems that are capable of undergoing Darwinian evolution, suggests that TNA is a strong candidate for the development of next-generation therapeutic aptamers. The mechanism of TNA synthesis by a laboratory evolved TNA polymerase has been studied using X-ray crystallography to capture the five major steps of nucleotide addition. These structures demonstrate imperfect recognition of the incoming TNA nucleotide triphosphate and support the need for further directed evolution experiments to create TNA polymerases with improved activity. The binary structure of a TNA reverse transcriptase has also been solved by X-ray crystallography, revealing the importance of structural plasticity as a possible mechanism for template recognition.


Pre DNA system

John Chaput, a professor in the department of Pharmaceutical Sciences at the
University of California, Irvine The University of California, Irvine (UCI or UC Irvine) is a Public university, public Land-grant university, land-grant research university in Irvine, California, United States. One of the ten campuses of the University of California system, U ...
, has theorized that issues concerning the prebiotic synthesis of ribose sugars and the non-enzymatic replication of RNA may provide circumstantial evidence of an earlier genetic system more readily produced under primitive earth conditions. TNA could have been an early genetic system and a precursor to RNA. TNA is simpler than RNA and can be synthesized from a single starting material. TNA is able to transfer back and forth information with RNA and with strands of itself that are complementary to the RNA. TNA has been shown to fold into tertiary structures with discrete ligand-binding properties.


Commercial applications

Although TNA research is still in its infancy, practical applications are already apparent. Its ability to undergo Darwinian evolution, coupled with its nuclease resistance, make TNA a promising candidate for the development of diagnostic and therapeutic applications that require high biological stability. This would include the evolution of TNA aptamers that can bind to specific small molecule and protein targets, as well as the development of TNA enzymes (threozymes) that can catalyze a chemical reaction. In addition, TNA is a promising candidate for RNA therapeutics that involve gene silencing technology. For example, TNA has been evaluated in a model system for antisense technology.Liu, L. S. ''et al.'' alpha-l-Threose Nucleic Acids as Biocompatible Antisense Oligonucleotides for Suppressing Gene Expression in Living Cells. ''ACS Appl Mater Interfaces'' 10, 9736-9743, (2018).


See also

*
Abiogenesis Abiogenesis is the natural process by which life arises from non-living matter, such as simple organic compounds. The prevailing scientific hypothesis is that the transition from non-living to living entities on Earth was not a single even ...
* Glycol nucleic acid * Oligonucleotide synthesis *
Peptide nucleic acid Peptide nucleic acid (PNA) is an artificially synthesized polymer similar to DNA or RNA. Synthetic peptide nucleic acid oligomers have been used in recent years in molecular biology procedures, diagnostic assays, and antisense therapies. Due to ...
*
Synthetic biology Synthetic biology (SynBio) is a multidisciplinary field of science that focuses on living systems and organisms. It applies engineering principles to develop new biological parts, devices, and systems or to redesign existing systems found in nat ...
* Xeno nucleic acid * Xenobiology


References


Further reading

* * This works is describes in: *


External links


Was simple TNA the first nucleic acid on Earth to carry a genetic code?
New Scientist ''New Scientist'' is a popular science magazine covering all aspects of science and technology. Based in London, it publishes weekly English-language editions in the United Kingdom, the United States and Australia. An editorially separate organ ...
(behind paywall)
ORIGIN OF LIFE: A Simpler Nucleic Acid
Leslie Orgel {{Nucleic_acids Nucleic acids Polymers