Thymineless death
Encyclopedia
Thymineless death is the phenomenon by which bacteria, yeasts and mammalian cells undergo irreversible cell death when they are starved of thymidine triphosphate
(dTTP), an essential precursor for DNA replication
. This phenomenon underlies the mechanism of action of several antibacterial, antimalarial and anticancer agents, such as Trimethoprim
, Sulfamethoxazole
, Methotrexate
and Fluorouracil
.
when thymine requiring mutants of the bacterium lost viability when grown in a medium lacking thymine
but containing other essential nutrients. Subsequently, this discovery led to the development of or explained the mechanism of action of several pyrimidine
analogs that targeted thymine metabolism in bacteria and tumor cells. The phenomenon was commonly attributed to "unbalanced growth" wherein cells continued fundamental processes of RNA transcription, protein synthesis and metabolism
in the absence of DNA replication. However, nutrient starvation generally do not kill cells to the extent as observed in cells that lack thymine. The molecular mechanism of thymineless death remains unknown; it has been proposed that this process is mediated through an addiction module which is responsible for cell death.
Thymidine triphosphate
5-Methyluridine triphosphate or m5UTP is one of five nucleoside triphosphates. It is the ribonucleoside triphosphate of thymidine, but the 5-methyluridine nomenclature is used because the term thymidine triphosphate is used for the deoxyribonucleoside by convention.-References:...
(dTTP), an essential precursor for DNA replication
DNA replication
DNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule...
. This phenomenon underlies the mechanism of action of several antibacterial, antimalarial and anticancer agents, such as Trimethoprim
Trimethoprim
Trimethoprim is a bacteriostatic antibiotic mainly used in the prophylaxis and treatment of urinary tract infections.It belongs to the class of chemotherapeutic agents known as dihydrofolate reductase inhibitors...
, Sulfamethoxazole
Sulfamethoxazole
Sulfamethoxazole is a sulfonamide bacteriostatic antibiotic.It is most often used as part of a synergistic combination with trimethoprim in a 5:1 ratio in co-trimoxazole , also known under trade names such as Bactrim, Septrin, or Septra; in Eastern Europe it is marketed as Biseptol...
, Methotrexate
Methotrexate
Methotrexate , abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug. It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions. It acts by inhibiting the metabolism of folic acid. Methotrexate...
and Fluorouracil
Fluorouracil
Fluorouracil is a drug that is a pyrimidine analog which is used in the treatment of cancer. It is a suicide inhibitor and works through irreversible inhibition of thymidylate synthase. It belongs to the family of drugs called antimetabolites...
.
History
The phenomenon was first reported in 1954 by Hazel D. Barner and Seymour S. Cohen in Escherichia coliEscherichia coli
Escherichia coli is a Gram-negative, rod-shaped bacterium that is commonly found in the lower intestine of warm-blooded organisms . Most E. coli strains are harmless, but some serotypes can cause serious food poisoning in humans, and are occasionally responsible for product recalls...
when thymine requiring mutants of the bacterium lost viability when grown in a medium lacking thymine
Thymine
Thymine is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The others are adenine, guanine, and cytosine. Thymine is also known as 5-methyluracil, a pyrimidine nucleobase. As the name suggests, thymine may be derived by methylation of uracil at...
but containing other essential nutrients. Subsequently, this discovery led to the development of or explained the mechanism of action of several pyrimidine
Pyrimidine
Pyrimidine is a heterocyclic aromatic organic compound similar to benzene and pyridine, containing two nitrogen atoms at positions 1 and 3 of the six-member ring...
analogs that targeted thymine metabolism in bacteria and tumor cells. The phenomenon was commonly attributed to "unbalanced growth" wherein cells continued fundamental processes of RNA transcription, protein synthesis and metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
in the absence of DNA replication. However, nutrient starvation generally do not kill cells to the extent as observed in cells that lack thymine. The molecular mechanism of thymineless death remains unknown; it has been proposed that this process is mediated through an addiction module which is responsible for cell death.