Who introduced the term nucleic acid?
Nucleic acids are macromolecules made up of individual building blocks, the nucleotides. Alternating simple sugars and phosphoric acid esters form a chain, with a nucleic base attached to each sugar.
In addition to proteins, carbohydrates and fats, nucleic acids form the fourth large group of biomolecules. Its best-known representative is deoxyribonucleic acid (DNA), the store of genetic information. In addition to their function as information stores, nucleic acids can also serve as signal transmitters or catalyze biochemical reactions.
The nucleic acid was first described by the Swiss physician Friedrich Miescher in 1869. After he gave up his research on proteins because they were too complex and diverse, he turned to the study of cell nuclei. Their function was completely unknown at the time. He isolated a substance from the nuclei of white blood cells that differed significantly from proteins because of its high phosphorus content. He called her Nuclein after the Latin word nucleus (Core). Although Miescher of the function of Nuclein came very close, he ultimately did not believe that a single substance could be responsible for heredity.
"If we (...) wanted to assume that a single substance (...) is in some way (...) the specific cause of fertilization, one would undoubtedly have to think primarily of the nucleus."
- Friedrich Miescher (1874)
Albrecht Kossel discovered that Nuclein is made up of four building blocks and sugar molecules. Finally, in 1889, Richard Altmann, who was the first to find nucleic acids in plant cells, named the Nuclein due to its chemical properties in nucleic acid around. It was not until 1929 that Phoebus Levene recognized that the nucleic acid (here the deoxyribonucleic acid) consists of deoxyribose, phosphoric acid residues and the four organic bases adenine, guanine, cytosine and thymine. He coined the term 'nucleotide' for these building blocks of the nucleic acid. In 1944, Oswald Avery, Colin McLeod and Maclyn McCarty were able to prove that nucleic acids are the stores of genetic information and not proteins, as previously assumed.
In 1977 Frederick Sanger, Allan Maxam and Walter Gilbert developed a method with which the order of the nucleotide building blocks, the sequence, could be determined. This chain termination method is now used in automated processes to sequence DNA.
The chemical structure
Nucleic acids are chains with nucleotides as links. The central part of a nucleotide is the ring-shaped sugar molecule (in the picture in red: the ribose). If the carbon atoms of this sugar are numbered clockwise from 1-5, a nucleic base (Fig. 1: yellow) is attached to C1 via a glycosidic bond. At C3, a phosphate residue of the following nucleotide (blue) has formed an ester bond with the OH group of the sugar. A phosphate residue is also bound to the C5 of the sugar via a phosphodiester bond.
In its unbound state, phosphoric acid has three acid groups (three OH groups that can split off protons). In a nucleic acid, two of these three acid groups are esterified and can therefore no longer release any protons. The third unbound acid function is responsible for the acidic character that gave the nucleic acid its name. It can act as a proton donor or is deprotonated in the cell (negative charge on O). Under physiological conditions (pH 7), the nucleic acid is a large anion overall due to this negatively charged oxygen atom. When separating nucleic acids according to their size, an electric field can therefore be used, in which nucleic acids generally migrate to the anode (see agarose gel electrophoresis).
Their structure gives the nucleic acid polarity. It has a 5 'end (read: 5-line end, named after the C5 atom of the sugar) to which a phosphate residue is bound and a 3' end to which the free OH group on the C3 atom the chain completes. Usually, one writes down sequences, i.e. nucleotide sequences, starting with the 5 'end towards the 3' end. Polarity is very important in organisms. For example, there are DNA polymerases that can only build up a DNA strand in the 5 '→ 3' direction and still others correct incorrectly incorporated nucleotides only in the 3 '→ 5' direction.
The spatial structure
The spatial alignment of nucleic acids is called secondary structure. While the primary structure (the sequence) stores the information, the secondary structure determines the size, durability and also access to the stored information.
The simplest spatial structure is the double strand. Here two nucleic acid chains are facing each other in opposite directions. They are connected to one another via hydrogen bonds between the nucleobases. A pyrimidine base is paired with a purine base, the type of pair determining the stability of the double strand. Three hydrogen bonds are formed between guanine and cytosine, while adenine and thymine are only connected by two hydrogen bonds (see Figure 2). The higher the GC content (proportion of guanine-cytosine pairs), the more stable the double strand and the more energy (heat) has to be expended to split it into single strands. A double strand can consist of two different nucleic acid molecules or just a single molecule. At the end of the double strand, a loop is formed in which the chain 'reverses' so that the opposite orientation is created.
In DNA, as a result of the many different bond angles, the double strand winds around its own axis and forms a double helix. There are both left and right handed helices. This double strand, which is wound around itself, can then be twisted even further and wrap itself around other structures such as histones (special proteins). The point of this further tangling is to save space. Untwisted and stretched out, the DNA of a single human chromosome would be about 4 cm long.
Natural nucleic acids
Nucleic acids are found in all living organisms. Their task is, among other things, to save the genetic information, the blueprint of the respective organism, to exchange it with others of its kind and to pass it on to subsequent generations. In most organisms, this is what DNA does. Only some viruses (retroviruses such as HIV) use the less stable RNA as a storage medium.
- see main article deoxyribonucleic acid
DNA has deoxyribose as a sugar component (hence the name Deoxyribonucleic acid), which differs from ribose only in the lack of an OH group on the C2 atom. The reduction of the OH group to a simple H does not take place until the end of the nucleotide synthesis. Deoxyribonucleotides thus arise from the ribonucleotides, the RNA building blocks. The difference, however, makes DNA chemically much more stable than RNA (justification see section RNA) and so stable that it can be detected dissolved in seawater (1 ppb) and estuaries (up to 44 ppb). The nucleobases adenine, cytosine, guanine and thymine occur in DNA, the latter being specific for DNA. Despite the small number of four different basic modules, a lot of information can be stored.
- Sample calculation:
- A piece of DNA made up of 4 possible basic building blocks with a total length of 10 base pairs results in 410 = 1,048,576 possible combinations
- The genome of the E. coli bacterium is approximately 4 x 10 in size6 Base pairs. Since there are 4 possibilities (A, C, G or T) for a base pair, it corresponds to 2 bits (22 = 4). This means that the entire genome has an information content of 1 megabyte.
The DNA is in the form of a double strand that is wound around itself to form a double helix. Of the three helix types identified by X-ray structure analysis, only the B-DNA has so far been detected in vivo. It is a right-handed helix with a pitch (length of the helix for a complete turn) of 3.54 nm and 10 base pairs and a diameter of 2.37 nm , 55 nm) and the more elongated Z-helix (pitch 4.56 nm; diameter 1.84 nm). If a gene encoded in the DNA is to be read or if the DNA itself is to be doubled in the course of cell division, the helix is untwisted on a section by enzymes (topoisomerases) and the double strand is split into single strands (helicases).
In bacteria, the DNA is present as a ring-shaped molecule, while in eukaryotes it has free ends, the so-called telomeres. The nature of the DNA replication mechanism means that linear DNA molecules are shortened by a few base pairs each time they are doubled. The more often a cell divides, the shorter the DNA becomes. This has no consequences with limited cell division, since at the end of such a strand there are short sequences that are repeated several thousand times. So no genetic information is lost. The shortening is partly compensated for by the enzyme telomerase (only in stem cells and cancer cells). If the length of the repetitive sequences at the end of the strand falls below a certain length, the cell no longer divides. This is one of the reasons for a limited lifespan. Because bacteria have a circular DNA molecule, the strand does not shorten.
- see main article ribonucleic acid
As already indicated in the upper section, the OH group on the C2 atom of the ribose is responsible for the lower stability of the RNA. This is because, like the OH group on the C3 atom for normal chain formation, it can form a link with the phosphate residue. If such a transesterification occurs spontaneously, the nucleic acid chain is interrupted.
Another difference is that thymine is used in DNA, while uracil is used in RNA. Nucleic bases within the DNA can be chemically changed by oxidative conditions or other influences. Occasionally, deamination occurs (elimination of an NH2-Group, an O = group is created instead). In a double strand, the sites for hydrogen bonds of the opposite nucleic bases no longer fit together and a partial split occurs. Enzymes can cut out and replace or repair altered nucleobases. To do this, use the second, unchanged nucleobase as a template. If such deamination occurs with cytosine, uracil is formed. If uracil were also commonly found in DNA, an enzyme could no longer distinguish whether the uracil is the wrong nucleobase or the opposite guanine (which was previously paired with cytosine). In this case, important information could be changed and a mutation could occur. In order to avoid this confusion, thymine is not used in the DNA. Uracil is recognized and removed in the DNA by specific enzymes, the uracil glycosylases. Enzymes can recognize this perfectly thanks to its additional methyl group and so it is clear that every uracil in the DNA is a broken cytosine. In RNA, this risk of information corruption is not serious, since information is only stored here for a short time and there are not just one RNA molecule of the respective type, but hundreds. If some of them are defective, this does not have any serious effects on the entire organism, as there are enough replacements.
Synthetic nucleic acids
A nucleic acid of interest to biotechnology that does not occur naturally is peptide nucleic acid (abbreviated to PNA, from English Peptide Nucleic Acid).
In addition, numerous nucleic acid variants have been developed, the building blocks of which at first glance no longer appear as ribo- (in the case of RNA) or deoxyribonucleotides (in the case of DNA) are recognizable:
- Phosphorothioate deoxyribonucleic acid
- Cyclohexene nucleic acids (CeNA)
- N3'-P5'-phosphoramidates (NP)
- Locked nucleic acid (LNA)
- Tricyclo-Deoxyribonucleic Acids (tcDNA)
- Morpholino-Phosphoramidate (MF)
- Hans Beyer and Wolfgang Walter: Organic Chemistry Textbook, 23rd edition, Hirzel Stuttgart (1998), ISBN 3-7776-0808-4
- Lubert Stryer: biochemistry, 5th edition, Spektrum Verlag (2003), ISBN 3827413036
- R. Dahm: The molecule from the castle kitchen, Max Planck Research (2004/1), pages 50-55 (online version)
Category: nucleic acid
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