Chemical Factor of Mutation
What is a mutation?
Any changes in the DNA gene sequence in such a way as to alter the genetic message carried by that gene sequence.
What is mutagen?
Any biological, physical or chemical agent that changes the genetic material, usually DNA of an organism is called mutagen.
What is mutagenesis?
It is a process by which genetic information of an organism is changed resulting in a mutation
The interaction of chemical compound and cell metabolism resulting in a change in DNA structure that mutate one or more genes this chemically induced mutation is called chemical mutagenesis.
Image Source: CK-12
Chemical mutagens (Chemical Factor of Mutation)
A substance that can alter a base that has already been incorporated into DNA and change its hydrogen bonding specificity. It includes:
- Base analogues
- Chemicals changing the specificity of hydrogen bonding
- Alkylating agents
- Intercalating agents
A chemical compound similar to purines and pyrimidines of DNA.
May be incorporated into a growing polynucleotide chain in place of normal bases when normal replication process occurs.
Replace the bases and cause mutation
Analogue of thymine(T) and pair with adenine
Thymine has a methyl group while 5-bU has Br-atom instead of the methyl group.
Mutate 5-bU is used in chemotherapy of virus and cancer in the drug industry
- It is a purine analogue paired with thymine it is able to form single H-bond with cytosine resulting in the transition of AT to GC.
Cause transition and a frameshift mutation in Escherichia coli.
Chemical changing the specificity of H-bonding
- Chemicals after incorporation into DNA change the specificity of H-bonding.
These chemical includes :
- Nitrous oxide
- Deamination of adenine
- Deamination of guanine
- Deamination of cytosine
- Convert amino group of bases into keto group alter base pairing of cytosine and guanine
- Order of frequency of deamination is
- Adenine ˃Cytosine ˃Guanine
- Cause mutation in DNA affecting protein synthesis.
- Use in the chemical industry for the production of Diazonium compounds which are further used in making azo-dyes.
- Used as a dental and surgical anesthetic for over 150 years.
Deamination of adenine:
- It results in the formation of hypoxanthine.
- It paired with cytosine instead of thymine.
- Replacing A-T pairing by G-C pairing.
Deamination of guanine:
- It results in the formation of xanthine
- Xanthine behaves like guanine and pairs with cytosine.
- Later xanthine is not mutagenic
- Therefore, G-C pairing replaced by X-C pairing
Deamination of cytosine
- Results in the formation of uracil by replacing the amine group into a hydroxyl group.
- G-C pairing replaced by U-A pairing.
- Break the ring of uracil and cytosine from pyrazoline and 3-aminopyrasole.
- With DNA, produce apyrimidinic acid.
- With RNA, produce ribo-apyrimidinic acid.
- Use in the industry as reducing agent, agriculture as pesticide and medicine in hydralazine i.e. anti-tubercular drug.
- Agents which have one or more alkyl groups can be transferred to DNA or other molecules.
- Use methyl and ethyl group in the DNA base and result in specific mispairing.
Some of the widely used alkylating agents:
- Nitrogen mustard
- Methyl nitrosoguanine
- Dimethyl sulfate (DMS)
- Ethyl-ethane sulphonate (EES)
Use as a component of poison gases in world war
- Highly electrophilic and react with a nucleophile such as proteins and N7 guanine base of DNA.
- Used in chemotherapy
- Carcinogen and mutagen
- Add alkyl group to O6 of guanine and O4 of thymine lead to transition mutation between G-C and A-T.
- Use in anti-neoplastic agents
- Use as a component of poison gases in world war
- Use for manufacturing organic chemicals in industry
Ethyl ethane sulphonate:
- Alkyl group is linked to sulphonate functionally as ethyl.
- It is used in the pharmaceutical industry.
- Intercalating agents:
- Intercalating agents:
- Flat, multiple ring molecules that may insert itself between bases in DNA, causing frameshift mutation during replication.
- Acridine orange
- Ethidium bromide
- A fluorescent dye that intercalate between DNA double helix.
- Cause insertion or deletion of one or more bases and causes frameshift mutation.
- Planer tricyclic system.
- Used as a topical antibacterial agent in the second world war.
- Targets bacterial DNA.
- Used as antiseptic.
- Used in microbiology labs for techniques i.e. agarose gel electrophoresis as a fluorescent dye.
- It stacks between the bases of DNA causes distortion.
- EtBr gets intercalated between the bases.
- It is a mutagen and a carcinogen.
- You can see the DNA bands in a gel if you stain the gel after or before running your sample.
- Detection is achieved when using UV light.
AGENTS ALTERING DNA STRUCTURE
This is a catch-all category that includes a variety of different kinds of agents. These may be large molecules that bind to bases in DNA referred to as “bulky lesions”. Agents causing intra-strand and inter-strand crosslinks.
ii. Poly Aromatic hydrocarbons
iii. Reactive Oxygen Species (RSO)
iv. Aromatic Amines
- This occurs naturally in plants (figs, celery, all citrus fruits).
Mechanism: Intercalate in DNA and for Thymine adduct upon activation by UV.
- Monoadducts mostly formed in higher proportions. So, absorb the second UV-photon and form diadduct or crosslink.
Uses: In the treatment of skin problems and in photochemotherapy.
Poly Aromatic Hydrocarbons:
- Such hydrocarbons that contain C and H only in their multiple aromatic rings.
Mechanism: undergo metabolic activation to diol-epoxides which bind covalently to guanine and adenine on DNA. Then form adducts and cause mutation.
Examples: Anthracene, Pyrene, Phenanthrene.
- Anthracene => manufacture of dyes and pigments.
- Pyrene => manufacture of pigments.
- Phenanthrene => manufacture of pesticides.
Reactive Oxygen Species:
Are chemically reactive species containing oxygen.
Mechanism: modification in bases. DNA deoxyribose oxidation, DNA strand break, and Proteins cross-links.
Examples: hydrogen peroxides, superoxide, hydroxyl radical.
Used as an oxygen source in chemical oxygen generators like in space shuttles and submarines.
- Hydrogen peroxide
Used for paper and pulp bleaching. Used in bleaches in detergents, as a disinfectant , for sterilization, in the cosmetic industry.
- Hydroxyl radical
Used in oxidative destruction of pollutants.
- Aromatic Amines:
Sources: cigarette smoke, diesel, exhaust, coal, cooked food.
Mechanism: requires metabolic activation by P450 monooxygenase and form adducts at the C8 position of guanine.
Examples: 2-aminoacridine, 2-Aminoflourene, N-acetyl-2-Aminoflourene.