Free radical damage to DNA

Last updated

Free radical damage to DNA can occur as a result of exposure to ionizing radiation or to radiomimetic [1] compounds. Damage to DNA as a result of free radical attack is called indirect DNA damage because the radicals formed can diffuse throughout the body and affect other organs. Malignant melanoma can be caused by indirect DNA damage because it is found in parts of the body not exposed to sunlight. DNA is vulnerable to radical attack because of the very labile hydrogens that can be abstracted and the prevalence of double bonds in the DNA bases that free radicals can easily add to. [2]

Contents

Damage via radiation exposure

Radiolysis of intracellular water by ionizing radiation creates peroxides, which are relatively stable precursors to hydroxyl radicals. 60%–70% of cellular DNA damage is caused by hydroxyl radicals, [3] yet hydroxyl radicals are so reactive that they can only diffuse one or two molecular diameters before reacting with cellular components. Thus, hydroxyl radicals must be formed immediately adjacent to nucleic acids in order to react. Radiolysis of water creates peroxides that can act as diffusable, latent forms of hydroxyl radicals. Some metal ions in the vicinity of DNA generate the hydroxyl radicals from peroxide. [4]

H2O + hν → H2O+ + e−
H2O + e− → H2O−
H2O+ → H+ + OH·
H2O− → OH− + H·
2 OH· →H2O2

Free radical damage to DNA is thought to cause mutations that may lead to some cancers.

The Fenton reaction

The Fenton reaction results in the creation of hydroxyl radicals from hydrogen peroxide and an Iron (II) catalyst. Iron(III) is regenerated via the Haber–Weiss reaction. Transition metals with a free coordination site are capable of reducing peroxides to hydroxyl radicals. [1] Iron is believed to be the metal responsible for the creation of hydroxyl radicals because it exists at the highest concentration of any transition metal in most living organisms. [5] The Fenton reaction is possible because transition metals can exist in more than one oxidation state and their valence electrons may be unpaired, allowing them to participate in one-electron redox reactions.

Fe2+ + H2O2 → Fe3+ + OH· + OH−

The creation of hydroxyl radicals by iron(II) catalysis is important because iron(II) can be found coordinated with, and therefore in close proximity to, DNA. This reaction allows for hydrogen peroxide created by radiolysis of water to diffuse to the nucleus and react with Iron (II) to produce hydroxyl radicals, which in turn react with DNA. The location and binding of Iron (II) to DNA may play an important role in determining the substrate and nature of the radical attack on the DNA. The Fenton reaction generates two types of oxidants, Type I and Type II. Type I oxidants are moderately sensitive to peroxides and ethanol. [5] Type I and Type II oxidants preferentially cleave at the specific sequences. [5]

Radical hydroxyl attack

Radical hydroxyl attacks can form baseless sites Radical hydroxyl attacks can form baseless sites.jpg
Radical hydroxyl attacks can form baseless sites

Hydroxyl radicals can attack the deoxyribose DNA backbone and bases, potentially causing a plethora of lesions that can be cytotoxic or mutagenic. Cells have developed complex and efficient repair mechanisms to fix the lesions. In the case of free radical attack on DNA, base-excision repair is the repair mechanism used. Hydroxyl radical reactions with the deoxyribose sugar backbone are initiated by hydrogen abstraction from a deoxyribose carbon, and the predominant consequence is eventual strand breakage and base release. The hydroxyl radical reacts with the various hydrogen atoms of the deoxyribose in the order 5′ H > 4′ H > 3′ H ≈ 2′ H ≈ 1′ H. This order of reactivity parallels the exposure to solvent of the deoxyribose hydrogens. [6]

Hydroxyl radicals react with DNA bases via addition to the electron-rich, pi bonds. These pi bonds in the bases are located between C5-C6 of pyrimidines and N7-C8 in purines. [7] Upon addition of the hydroxyl radical, many stable products can be formed. In general, radical hydroxyl attacks on base moieties do not cause altered sugars or strand breaks except when the modifications labilize the N-glycosyl bond, allowing the formation of baseless sites that are subject to beta-elimination.

Abasic sites

Route of deoxyribonolactone formation ABASICS.svg
Route of deoxyribonolactone formation

Hydrogen abstraction from the 1’-deoxyribose carbon by the hydroxyl radical creates a 1 ‘-deoxyribosyl radical. The radical can then react with molecular oxygen, creating a peroxyl radical which can be reduced and dehydrated to yield a 2’-deoxyribonolactone and free base. A deoxyribonolactone is mutagenic and resistant to repair enzymes. Thus, an abasic site is created. [8]

Radical damage through radiomimetic compounds

Radical damage to DNA can also occur through the interaction of DNA with certain natural products known as radiomimetic compounds, molecular compounds which affect DNA in similar ways to radiation exposure. Radiomimetic compounds induce double-strand breaks in DNA via highly specific, concerted free-radical attacks on the deoxyribose moieties in both strands of DNA.

General mechanism

Many radiomimetic compounds are enediynes, which undergo the Bergman cyclization reaction to produce a 1,4-didehydrobenzene diradical. The 1,4-didehydrobenzene diradical is highly reactive, and will abstract hydrogens from any possible hydrogen-donor.

Para-benzyne generation.png

In the presence of DNA, the 1,4-didehydrobenzene diradical abstracts hydrogens from the deoxyribose sugar backbone, predominantly at the C-1’, C-4’ and C-5’ positions. Hydrogen abstraction causes radical formation at the reacted carbon. The carbon radical reacts with molecular oxygen, which leads to a strand break in the DNA through a variety of mechanisms. [9] 1,4-Didehydrobenzene is able to position itself in such a way that it can abstract proximal hydrogens from both strands of DNA. [10] This produces a double-strand break in the DNA, which can lead to cellular apoptosis if not repaired.

Different mechanisms of DNA cleavage by p-benzyne.png

Enediynes generally undergo the Bergman cyclization at temperatures exceeding 200 °C. However, incorporating the enediyne into a 10-membered cyclic hydrocarbon makes the reaction more thermodynamically favorable by releasing the ring strain of the reactants. This allows for the Bergman cyclization to occur at 37 °C, the biological temperature of humans. Molecules which incorporate enediynes into these larger ring structures have been found to be extremely cytotoxic. [11]

Natural products

Enediynes are present in many complicated natural products. They were originally discovered in the early 1980s during a search for new anticancer products produced by microorganisms. [10] Calicheamicin was one of the first such products identified and was originally found in a soil sample taken from Kerrville, Texas. These compounds are synthesized by bacteria as defense mechanisms due to their ability to cleave DNA through the formation of 1,4-didehydrobenzene from the enediyne component of the molecule.

Calicheamicin.png

Calicheamicin and other related compounds share several common characteristics. The extended structures attached to the enediyne allow the compound to specifically bind DNA, [12] in most cases to the minor groove of the double helix. Additionally, part of the molecule is known as the “trigger” which, under specific physiological conditions, activates the enediyne, known as the “warhead” and 1,4-didehydrobenzene is generated.

Three classes of enediynes have since been identified: calicheamicin, dynemicin, and chromoprotein-based products.

The calicheamicin types are defined by a methyl trisulfide group that is involved in triggering the molecule by the following mechanism. [10]

Calicheamicin cleavage of DNA.png

Calicheamicin and the closely related esperamicin have been used as anticancer drugs due to their high toxicity and specificity. [10]

Dynemicin and its relatives are characterized by the presence of an anthraquinone and enediyne core. The anthraquinone component allows for specific binding of DNA at the 3’ side of purine bases through intercalation, a site that is different from calicheamicin. Its ability to cleave DNA is greatly increased in the presence of NADPH and thiol compounds. [13] This compound has also found prominence as an antitumor agent. [13]

Dynemicin A.svg

Chromoprotein enediynes are characterized by an unstable chromophore enediyne bound to an apoprotein.

C-1027 mechanism.png

The chromophore is unreactive when bound to the apoprotein. Upon its release, it reacts to form 1,4-didehydrobenzene and subsequently cleaves DNA.

Antitumor ability

Most enediynes, including the ones listed above, have been used as potent antitumor antibiotics due to their ability to efficiently cleave DNA. Calicheamicin and esperamicin are the two most commonly used types due to their high specificity when binding to DNA, which minimizes unfavorable side reactions. [12] They have been shown to be especially useful for treating acute myeloid leukemia. [14]

Additionally, calicheamicin is able to cleave DNA at low concentrations, proving to be up to 1000 times more effective than adriamycin at combating certain types of tumors. [15] In all cases, cells lack the ability to repair double-stranded DNA breaks, making these compounds especially effective for treating tumor cells.

The free radical mechanism to treat certain types of cancers extends beyond enediynes. Tirapazamine generates a free radical under anoxic conditions instead of the trigger mechanism of an enediyne. The free radical then continues on to cleave DNA in a similar manner to 1,4-didehydrobenzene in order to treat cancerous cells. It is currently in Phase III trials.

Related Research Articles

Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals. This can lead to polymerization and other chain reactions. They are frequently added to industrial products, such as fuels and lubricants, to prevent oxidation, and to foods to prevent spoilage, in particular the rancidification of oils and fats. In cells, antioxidants such as glutathione, mycothiol or bacillithiol, and enzyme systems like superoxide dismutase, can prevent damage from oxidative stress.

<span class="mw-page-title-main">Reactive oxygen species</span> Highly reactive molecules formed from diatomic oxygen (O2)

In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen. Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen.

<span class="mw-page-title-main">Molecular lesion</span> Damage to the structure of a biological molecule

A molecular lesion or point lesion is damage to the structure of a biological molecule such as DNA, RNA, or protein. This damage may result in the reduction or absence of normal function, and in rare cases the gain of a new function. Lesions in DNA may consist of breaks or other changes in chemical structure of the helix, ultimately preventing transcription. Meanwhile, lesions in proteins consist of both broken bonds and improper folding of the amino acid chain. While many nucleic acid lesions are general across DNA and RNA, some are specific to one, such as thymine dimers being found exclusively in DNA. Several cellular repair mechanisms exist, ranging from global to specific, in order to prevent lasting damage resulting from lesions.

<span class="mw-page-title-main">Lipid peroxidation</span>

Lipid peroxidation is the chain of reactions of oxidative degradation of lipids. It is the process in which free radicals "steal" electrons from the lipids in cell membranes, resulting in cell damage. This process proceeds by a free radical chain reaction mechanism. It most often affects polyunsaturated fatty acids, because they contain multiple double bonds in between which lie methylene bridges (-CH2-) that possess especially reactive hydrogen atoms. As with any radical reaction, the reaction consists of three major steps: initiation, propagation, and termination. The chemical products of this oxidation are known as lipid peroxides or lipid oxidation products (LOPs).

<span class="mw-page-title-main">AP site</span> Biochemical site of damaged DNA or RNA

In biochemistry and molecular genetics, an AP site, also known as an abasic site, is a location in DNA that has neither a purine nor a pyrimidine base, either spontaneously or due to DNA damage. It has been estimated that under physiological conditions 10,000 apurinic sites and 500 apyrimidinic may be generated in a cell daily.

<span class="mw-page-title-main">Oxidative stress</span> 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 the reactive oxygen species 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.

Radiation chemistry is a subdivision of nuclear chemistry which is the study of the chemical effects of radiation on matter; this is very different from radiochemistry as no radioactivity needs to be present in the material which is being chemically changed by the radiation. An example is the conversion of water into hydrogen gas and hydrogen peroxide.

<span class="mw-page-title-main">Bergman cyclization</span>

The Masamune-Bergman cyclization or Masamune-Bergman reaction or Masamune-Bergman cycloaromatization is an organic reaction and more specifically a rearrangement reaction taking place when an enediyne is heated in presence of a suitable hydrogen donor. It is the most famous and well-studied member of the general class of cycloaromatization reactions. It is named for Japanese-American chemist Satoru Masamune and American chemist Robert G. Bergman. The reaction product is a derivative of benzene.

<span class="mw-page-title-main">Calicheamicin</span> Chemical compound

The calicheamicins are a class of enediyne antitumor antibiotics derived from the bacterium Micromonospora echinospora, with calicheamicin γ1 being the most notable. It was isolated originally in the mid-1980s from the chalky soil, or "caliche pits", located in Kerrville, Texas. The sample was collected by a scientist working for Lederle Labs. It is extremely toxic to all cells and, in 2000, a CD33 antigen-targeted immunoconjugate N-acetyl dimethyl hydrazide calicheamicin was developed and marketed as targeted therapy against the non-solid tumor cancer acute myeloid leukemia (AML). A second calicheamicin-linked monoclonal antibody, inotuzumab ozogamicin an anti-CD22-directed antibody-drug conjugate, was approved by the U.S. Food and Drug Administration on August 17, 2017, for use in the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Calicheamicin γ1 and the related enediyne esperamicin are the two of the most potent antitumor agents known.

Pro-oxidants are chemicals that induce oxidative stress, either by generating reactive oxygen species or by inhibiting antioxidant systems. The oxidative stress produced by these chemicals can damage cells and tissues, for example an overdose of the analgesic paracetamol (acetaminophen) can fatally damage the liver, partly through its production of reactive oxygen species.

Advanced oxidation processes (AOPs), in a broad sense, are a set of chemical treatment procedures designed to remove organic (and sometimes inorganic) materials in water and wastewater by oxidation through reactions with hydroxyl radicals (·OH). In real-world applications of wastewater treatment, however, this term usually refers more specifically to a subset of such chemical processes that employ ozone (O3), hydrogen peroxide (H2O2) and/or UV light. One such type of process is called in situ chemical oxidation.

<span class="mw-page-title-main">Esperamicin</span> Chemical compound

The esperamicins are chromoprotein enediyne antitumor antibiotics of bacterial origin. Esperamicin A1 is the most well studied compound in this class. Esperamcin A1 and the related enediyne calicheamicin are the two most potent antitumor agents known. The esperamicins are extremely toxic DNA splicing compounds.

<span class="mw-page-title-main">Enediyne</span> Any organic compound containing one double and two triple bonds

In organic chemistry, enediynes are organic compounds containing two triple bonds and one double bond.

<span class="mw-page-title-main">Dynemicin A</span> Anti-cancer drug

Dynemicin A is an anti-cancer enediyne drug. It displays properties which illustrate promise for cancer treatments, but still requires further research.

All living cells produce reactive oxygen species (ROS) as a byproduct of metabolism. ROS are reduced oxygen intermediates that include the superoxide radical (O2−) and the hydroxyl radical (OH•), as well as the non-radical species hydrogen peroxide (H2O2). These ROS are important in the normal functioning of cells, playing a role in signal transduction and the expression of transcription factors. However, when present in excess, ROS can cause damage to proteins, lipids and DNA by reacting with these biomolecules to modify or destroy their intended function. As an example, the occurrence of ROS have been linked to the aging process in humans, as well as several other diseases including Alzheimer's, rheumatoid arthritis, Parkinson's, and some cancers. Their potential for damage also makes reactive oxygen species useful in direct protection from invading pathogens, as a defense response to physical injury, and as a mechanism for stopping the spread of bacteria and viruses by inducing programmed cell death.

<span class="mw-page-title-main">Kedarcidin</span> Chemical compound

Kedarcidin is a chromoprotein antitumor antibiotic first isolated from an Actinomycete in 1992, comprising an ansa-bridged enediyne chromophore (shown) as well as an apoprotein that serves to stabilize the toxin in the Actinomycete. Like other members of the enediyne class of drugs—so named for the nine-or-ten-membered core structure bearing an alkene directly attached to two alkynyl appendages—kedarcidin was likely evolved to kill bacteria that compete with the producing organism. Because it achieves this by causing DNA damage, however, kedarcidin is capable of harming tumor cells, as well. Kedarcidin is thus the subject of scientific research, both for its structural complexity as well as its anticancer properties.

<span class="mw-page-title-main">Galactose oxidase</span>

Galactose oxidase is an enzyme that catalyzes the oxidation of D-galactose in some species of fungi.

<span class="mw-page-title-main">C-1027</span> Chemical compound

C-1027 or Lidamycin is an antitumor antibiotic consisting of a complex of an enediyne chromophore and an apoprotein. It shows antibiotic activity against most Gram-positive bacteria. It is one of the most potent cytotoxic molecules known, due to its induction of a higher ratio of DNA double-strand breaks than single-strand breaks.

<span class="mw-page-title-main">Shishijimicin A</span> Chemical compound

Shishijimicin A is an enediyne antibiotic isolated from Didemnum proliferum. Isolated in 2003 it is part of the family of 10 member ringed enediyne antitumor antibiotic agents, which includes: namenamicin, esperamicin and, calicheamicin. Due to its high potency from cytotoxicity, Shishjimicin A is currently undergoing testing as a possible Antibody-antibiotic Conjugate (ADCs) cancer treatment. Laboratory tests indicate it to be “more than 1,000 times as toxic to cancer cells as the anticancer drug taxol”, also known as Paclitaxel, a prevalent chemotherapy medication. As such, theoretically, only an administration of a minuscule dose of the molecule would be necessary per each treatment. As shishjimicin A supply is scarce and the full extent of its side effects is not yet established, there is still a need for further biological and clinical studies.

<span class="mw-page-title-main">Metalloenediynes</span>

Metalloenediynes are a family of compounds composed of an enediyne-containing ligand complexed to a transition metal that have potential use as anti-tumor therapeutics. Enediynes naturally undergo the Bergman cyclization to produce a 1,4-didehydrobenzene intermediate, whose thermal activation energy is stabilized by chelation of the ligand to a metal center, allowing for temperature regulation of this diradical formation.

References

  1. 1 2 Barbusinski K (2009). "Fenton Reaction – Controversy Concerning the Chemistry". Ecological Chemistry and Engineering. 16 (3).
  2. ↑ Greenberg MM (2016). "Reactivity of Nucleic Acid Radicals". Advances in Physical Organic Chemistry. Elsevier. 50: 119–202. doi:10.1016/bs.apoc.2016.02.001. ISBN   978-0-12-804716-3. PMC   5435387 . PMID   28529390.
  3. ↑ Ward JF (1988). DNA damage produced by ionizing radiation in mammalian cells: identities, mechanisms of formation, and reparability. Progress in Nucleic Acid Research and Molecular Biology. Vol. 35. pp. 95–125. doi:10.1016/s0079-6603(08)60611-x. ISBN   9780125400350. PMID   3065826.
  4. ↑ Henle ES, Linn S (August 1997). "Formation, prevention, and repair of DNA damage by iron/hydrogen peroxide". The Journal of Biological Chemistry. 272 (31): 19095–8. doi: 10.1074/jbc.272.31.19095 . PMID   9235895. S2CID   11016259.
  5. 1 2 3 Pogozelski WK, Tullius TD (May 1998). "Oxidative Strand Scission of Nucleic Acids: Routes Initiated by Hydrogen Abstraction from the Sugar Moiety". Chemical Reviews. 98 (3): 1089–1108. doi:10.1021/cr960437i. PMID   11848926.
  6. ↑ Balasubramanian B, Pogozelski WK, Tullius TD (August 1998). "DNA strand breaking by the hydroxyl radical is governed by the accessible surface areas of the hydrogen atoms of the DNA backbone". Proceedings of the National Academy of Sciences of the United States of America. 95 (17): 9738–43. Bibcode:1998PNAS...95.9738B. doi: 10.1073/pnas.95.17.9738 . PMC   21406 . PMID   9707545.
  7. ↑ Steenken S (1989). "Purine bases, nuclesides and nucleotides: aqueous solution redox chemistry and transformation reactions of their radical cations and e- and OH adducts". Chem. Rev. 89 (3): 503–529. doi:10.1021/cr00093a003.
  8. ↑ Lhomme J, Constant JF, Demeunynck M (1999). "Abasic DNA structure, reactivity, and recognition". Biopolymers. 52 (2): 65–83. doi:10.1002/1097-0282(1999)52:2<65::aid-bip1>3.3.co;2-l. PMID   10898853.
  9. ↑ Povirk LF (1996). "DNA damage and mutagenesis by radiomimetic DNA-cleaving agents: Bleomycin, neocarzinostatin and other enediynes". Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis. 355 (1–2): 71–89. doi:10.1016/0027-5107(96)00023-1. PMID   8781578.
  10. 1 2 3 4 Kraka E, Cremer D (2000). "Computer design of anticancer drugs. A new enediyne warhead". J. Am. Chem. Soc. 122 (34): 8245–8264. doi:10.1021/ja001017k.
  11. ↑ Zhen YS, Ming XY, Yu B, Otani T, Saito H, Yamada Y (August 1989). "A new macromolecular antitumor antibiotic, C-1027. III. Antitumor activity". The Journal of Antibiotics. 42 (8): 1294–8. doi: 10.7164/antibiotics.42.1294 . PMID   2759910.
  12. 1 2 Ellestad GA (September 2011). "Structural and conformational features relevant to the anti-tumor activity of calicheamicin γ 1I". Chirality. 23 (8): 660–71. doi:10.1002/chir.20990. PMID   21800378.
  13. 1 2 Sugiura Y, Shiraki T, Konishi M, Oki T (May 1990). "DNA intercalation and cleavage of an antitumor antibiotic dynemicin that contains anthracycline and enediyne cores". Proceedings of the National Academy of Sciences of the United States of America. 87 (10): 3831–5. Bibcode:1990PNAS...87.3831S. doi: 10.1073/pnas.87.10.3831 . PMC   53997 . PMID   2339123.
  14. ↑ Sievers EL, Appelbaum FR, Spielberger RT, Forman SJ, Flowers D, Smith FO, Shannon-Dorcy K, Berger MS, Bernstein ID (June 1999). "Selective ablation of acute myeloid leukemia using antibody-targeted chemotherapy: a phase I study of an anti-CD33 calicheamicin immunoconjugate". Blood. 93 (11): 3678–84. doi:10.1182/blood.V93.11.3678. PMID   10339474.
  15. ↑ Zein N, Sinha AM, McGahren WJ, Ellestad GA (May 1988). "Calicheamicin gamma 1I: an antitumor antibiotic that cleaves double-stranded DNA site specifically". Science. 240 (4856): 1198–201. Bibcode:1988Sci...240.1198Z. doi:10.1126/science.3240341. PMID   3240341.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.