Thymine glycol

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Thymine glycol
Thymine glycol.svg
Names
IUPAC name
5,6-Dihydroxy-5-methyldihydro-2,4(1H,3H)-pyrimidinedione
Other names
5,6-Dihydroxy-5,6-dihydrothymine
Identifiers
3D model (JSmol)
ChemSpider
Properties
C5H8N2O4
Molar mass 160.129 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

Thymine glycol (5,6-dihydroxy-5,6-dihydrothymine) is one of the principal DNA lesions that can be induced by oxidation and ionizing radiation. [1]

Aging, stroke

The rate at which oxidative reactions generate thymine glycol and thymidine glycol in the DNA of humans is estimated to be about 300 per cell per day. [2] Oxidized DNA bases that are excised by DNA repair processes are excreted in urine. On a body weight basis, mice excrete 18 times more thymine glycol plus thymidine glycol than humans, and monkeys four times more than humans. [2] It was proposed that rate of occurrence of oxidative DNA damages correlates with metabolic rate, and that a higher rate of oxidative damage might cause a higher rate of cellular aging. [2]

DNA Molecule that encodes the genetic instructions used in the development and functioning of all known organisms and many viruses

Deoxyribonucleic acid is a molecule composed of two chains that coil around each other to form a double helix carrying genetic instructions for the development, functioning, growth and reproduction of all known organisms and many viruses. DNA and ribonucleic acid (RNA) are nucleic acids; alongside proteins, lipids and complex carbohydrates (polysaccharides), nucleic acids are one of the four major types of macromolecules that are essential for all known forms of life.

DNA oxidation is the process of oxidative damage of deoxyribonucleic acid. As described in detail by Burrows et al., 8-oxo-2'-deoxyguanosine (8-oxo-dG) is the most common oxidative lesion observed in duplex DNA because guanine has a lower one-electron reduction potential than the other nucleosides in DNA. The one electron reduction potentials of the nucleosides are guanine 1.29, adenine 1.42, cytosine 1.6 and thymine 1.7. About 1 in 40,000 guanines in the genome are present as 8-oxo-dG under normal conditions. This means that >30,000 8-oxo-dGs may exist at any given time in the genome of a human cell. Another product of DNA oxidation is 8-oxo-dA. 8-oxo-dA occurs at about 1/3 the frequency of 8-oxo-dG. The reduction potential of guanine may be reduced by as much as 50%, depending on the particular neighboring nucleosides stacked next to it within DNA.

DNA repair Processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome

DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA damage, resulting in as many as 1 million individual molecular lesions per cell per day. Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes. Other lesions induce potentially harmful mutations in the cell's genome, which affect the survival of its daughter cells after it undergoes mitosis. As a consequence, the DNA repair process is constantly active as it responds to damage in the DNA structure. When normal repair processes fail, and when cellular apoptosis does not occur, irreparable DNA damage may occur, including double-strand breaks and DNA crosslinkages. This can eventually lead to malignant tumors, or cancer as per the two hit hypothesis.

Base excision repair is a major DNA repair pathway for removal of oxidative DNA damages. The rate of repair of thymine glycol damage in human fibroblasts was found to decrease with age. [3] Brain samples from humans who died of stroke were found to be deficient in base excision repair of thymine glycol as well as other types of oxidative damages. [4] It was suggested that impaired base excision repair is a risk factor for ischemic brain injury. [4]

Base excision repair DNA repair process

Base excision repair (BER) is a cellular mechanism, studied in the fields of biochemistry and genetics, that repairs damaged DNA throughout the cell cycle. It is responsible primarily for removing small, non-helix-distorting base lesions from the genome. The related nucleotide excision repair pathway repairs bulky helix-distorting lesions. BER is important for removing damaged bases that could otherwise cause mutations by mispairing or lead to breaks in DNA during replication. BER is initiated by DNA glycosylases, which recognize and remove specific damaged or inappropriate bases, forming AP sites. These are then cleaved by an AP endonuclease. The resulting single-strand break can then be processed by either short-patch or long-patch BER.

Fibroblast most common cell of connective tissue in animal, that synthesizes the extracellular matrix and collagen, the structural framework (stroma) for animal tissues, and plays a critical role in wound healing

A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework (stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells of connective tissue in animals.

Stroke Medical condition where poor blood flow to the brain causes cell death

A stroke is a medical condition in which poor blood flow to the brain results in cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both result in parts of the brain not functioning properly. Signs and symptoms of a stroke may include an inability to move or feel on one side of the body, problems understanding or speaking, dizziness, or loss of vision to one side. Signs and symptoms often appear soon after the stroke has occurred. If symptoms last less than one or two hours it is known as a transient ischemic attack (TIA) or mini-stroke. A hemorrhagic stroke may also be associated with a severe headache. The symptoms of a stroke can be permanent. Long-term complications may include pneumonia or loss of bladder control.


Related Research Articles

DNA glycosylases are a family of enzymes involved in base excision repair, classified under EC number EC 3.2.2. Base excision repair is the mechanism by which damaged bases in DNA are removed and replaced. DNA glycosylases catalyze the first step of this process. They remove the damaged nitrogenous base while leaving the sugar-phosphate backbone intact, creating an apurinic/apyrimidinic site, commonly referred to as an AP site. This is accomplished by flipping the damaged base out of the double helix followed by cleavage of the N-glycosidic bond.

Oxidative stress Free radical toxicity

Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal redox state of cells can cause toxic effects through the production of peroxides and free radicals that damage all components of the cell, including proteins, lipids, and DNA. Oxidative stress from oxidative metabolism causes base damage, as well as strand breaks in DNA. Base damage is mostly indirect and caused by reactive oxygen species (ROS) generated, e.g. O2 (superoxide radical), OH (hydroxyl radical) and H2O2 (hydrogen peroxide). Further, some reactive oxidative species act as cellular messengers in redox signaling. Thus, oxidative stress can cause disruptions in normal mechanisms of cellular signaling.

Cell damage is a variety of changes of stress that a cell suffers due to external as well internal environmental changes. Among other causes, this can be due to physical, chemical, infectious, biological, nutritional or immunological factors. Cell damage can be reversible or irreversible. Depending on the extent of injury, the cellular response may be adaptive and where possible, homeostasis is restored. Cell death occurs when the severity of the injury exceeds the cell’s ability to repair itself. Cell death is relative to both the length of exposure to a harmful stimulus and the severity of the damage caused. Cell death may occur by necrosis or apoptosis.

A DNA repair-deficiency disorder is a medical condition due to reduced functionality of DNA repair.

XRCC1 protein-coding gene in the species Homo sapiens

DNA repair protein XRCC1 also known as X-ray repair cross-complementing protein 1 is a protein that in humans is encoded by the XRCC1 gene. XRCC1 is involved in DNA repair where it complexes with DNA ligase III.

POLK protein-coding gene in the species Homo sapiens

DNA polymerase kappa is an DNA polymerase that in humans is encoded by the POLK gene. It is involved in translesion synthesis.

Thymine-DNA glycosylase protein-coding gene in the species Homo sapiens

G/T mismatch-specific thymine DNA glycosylase is an enzyme that in humans is encoded by the TDG gene. Several bacterial proteins have strong sequence homology with this protein.

NTHL1 protein-coding gene in the species Homo sapiens

Endonuclease III-like protein 1 is an enzyme that in humans is encoded by the NTHL1 gene.

NEIL1 protein-coding gene in the species Homo sapiens

Endonuclease VIII-like 1 is an enzyme that in humans is encoded by the NEIL1 gene.

FGF14 protein-coding gene in the species Homo sapiens

Fibroblast growth factor 14 is a protein that in humans is encoded by the FGF14 gene.

MSRA (gene) protein-coding gene in the species Homo sapiens

Peptide methionine sulfoxide reductase (Msr) is a family of enzymes that in humans is encoded by the MSRA gene.

DNA polymerase eta protein-coding gene in the species Homo sapiens

DNA polymerase eta, is a protein that in humans is encoded by the POLH gene.

The DNA damage theory of aging proposes that aging is a consequence of unrepaired accumulation of naturally occurring DNA damages. Damage in this context is a DNA alteration that has an abnormal structure. Although both mitochondrial and nuclear DNA damage can contribute to aging, nuclear DNA is the main subject of this analysis. Nuclear DNA damage can contribute to aging either indirectly or directly.

8-Oxo-2-deoxyguanosine chemical compound

8-Oxo-2'-deoxyguanosine (8-oxo-dG) is an oxidized derivative of deoxyguanosine. 8-Oxo-dG is one of the major products of DNA oxidation. Concentrations of 8-oxo-dG within a cell are a measurement of oxidative stress.

FPG IleRS zinc finger

The FPG IleRS zinc finger domain represents a zinc finger domain found at the C-terminal in both DNA glycosylase/AP lyase enzymes and in isoleucyl tRNA synthetase. In these two types of enzymes, the C-terminal domain forms a zinc finger.

Genome instability refers to a high frequency of mutations within the genome of a cellular lineage. These mutations can include changes in nucleic acid sequences, chromosomal rearrangements or aneuploidy. Genome instability does occur in bacteria. In multicellular organisms genome instability is central to carcinogenesis, and in humans it is also a factor in some neurodegenerative diseases such as amyotrophic lateral sclerosis or the neuromuscular disease myotonic dystrophy.

H2TH domain

In molecular biology, the H2TH domain is a DNA-binding domain found in DNA glycosylase/AP lyase enzymes, which are involved in base excision repair of DNA damaged by oxidation or by mutagenic agents. Most damage to bases in DNA is repaired by the base excision repair pathway. These enzymes are primarily from bacteria, and have both DNA glycosylase activity EC 3.2.2.- and AP lyase activity EC 4.2.99.18. Examples include formamidopyrimidine-DNA glycosylases and endonuclease VIII (Nei).

DNA damage is distinctly different from mutation, although both are types of error in DNA. DNA damage is an abnormal chemical structure in DNA, while a mutation is a change in the sequence of standard base pairs. DNA damages cause changes in the structure of the genetic material and prevents the replication mechanism from functioning and performing properly.

References

  1. Basu, AK; Loechler, EL; Leadon, SA; Essigmann, JM (1989). "Genetic effects of thymine glycol: site-specific mutagenesis and molecular modeling studies". Proc. Natl. Acad. Sci. U.S.A. 86: 7677–81. doi:10.1073/pnas.86.20.7677. PMC   298133 . PMID   2682618.
  2. 1 2 3 Adelman R, Saul RL, Ames BN (1988). "Oxidative damage to DNA: relation to species metabolic rate and life span". Proc. Natl. Acad. Sci. U.S.A. 85 (8): 2706–8. doi:10.1073/pnas.85.8.2706. PMC   280067 . PMID   3128794.
  3. Pons B, Belmont AS, Masson-Genteuil G, Chapuis V, Oddos T, Sauvaigo S (2010). "Age-associated modifications of Base Excision Repair activities in human skin fibroblast extracts". Mech. Ageing Dev. 131 (11–12): 661–5. doi:10.1016/j.mad.2010.09.002. PMID   20854835.
  4. 1 2 Ghosh S, Canugovi C, Yoon JS, Wilson DM, Croteau DL, Mattson MP, Bohr VA (2015). "Partial loss of the DNA repair scaffolding protein, Xrcc1, results in increased brain damage and reduced recovery from ischemic stroke in mice". Neurobiol. Aging. 36 (7): 2319–30. doi:10.1016/j.neurobiolaging.2015.04.004. PMID   25971543.