The mitomycins are a family of aziridine-containing

natural products A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical sy ...

isolated from '' Streptomyces caespitosus'' or ''

Streptomyces lavendulae ''Streptomyces lavendulae'' is a species of bacteria from the genus ''Streptomyces''. It is isolated from soils globally and is known for its production of medically useful biologically active metabolites. To see a photo of this organism clic ...

.'' They include mitomycin A, mitomycin B, and mitomycin C. When the name mitomycin occurs alone, it usually refers to mitomycin C, its international nonproprietary name. Mitomycin C is used as a medicine for treating various disorders associated with the growth and spread of cells.

Biosynthesis

In general, the biosynthesis of all mitomycins proceeds via combination of 3-amino-5-hydroxybenzoic acid (AHBA), D-glucosamine, and carbamoyl phosphate, to form the mitosane core, followed by specific tailoring steps. The key intermediate, AHBA, is a common precursor to other anticancer drugs, such as rifamycin and ansamycin. Specifically, the biosynthesis begins with the addition of

phosphoenolpyruvate Phosphoenolpyruvate (2-phosphoenolpyruvate, PEP) is the ester derived from the enol of pyruvate and phosphate. It exists as an anion. PEP is an important intermediate in biochemistry. It has the highest-energy phosphate bond found (−61.9 kJ/ ...

(PEP) to erythrose-4-phosphate (E4P) with a yet undiscovered enzyme, which is then ammoniated to give 4-amino-3-deoxy-D-arabino heptulosonic acid-7-phosphate (aminoDHAP). Next, DHQ synthase catalyzes a ring closure to give 4-amino3-dehydroquinate (aminoDHQ), which then undergoes a double oxidation via aminoDHQ dehydratase to give 4-amino-dehydroshikimate (aminoDHS). The key intermediate, 3-amino-5-hydroxybenzoic acid (AHBA), is made via aromatization by AHBA synthase. Synthesis of the key intermediate, 3-amino-5-hydroxy-benzoic acid. The mitosane core is synthesized as shown below via condensation of AHBA and D-glucosamine, although no specific enzyme has been characterized that mediates this transformation. Once this condensation has occurred, the mitosane core is tailored by a variety of enzymes. Both the sequence and the identity of these steps are yet to be determined. *Complete reduction of C-6 – Likely via F420-dependent tetrahydromethanopterin (H4MPT) reductase and H4MPT:CoM methyltransferase *Hydroxylation of C-5, C-7 (followed by transamination), and C-9a. – Likely via cytochrome P450 monooxygenase or benzoate hydroxylase *O-Methylation at C-9a – Likely via SAM dependent methyltransferase *Oxidation at C-5 and C8 – Unknown *Intramolecular amination to form aziridine – Unknown *Carbamoylation at C-10 – Carbamoyl transferase, with carbamoyl phosphate (C4P) being derived from L-citrulline or L-arginine

Biological effects

In the bacterium '' Legionella pneumophila'',

mitomycin C Mitomycin C is a mitomycin that is used as a chemotherapeutic agent by virtue of its antitumour activity. Medical uses It is given intravenously to treat upper gastro-intestinal cancers (e.g. esophageal carcinoma), anal cancers, and breas ...

induces

competence Competence may refer to: *Competence (geology), the resistance of a rock against deformation or plastic flow. *Competence (human resources), a standardized requirement for an individual to properly perform a specific job *Competence (law), the me ...

for transformation.

Natural transformation In category theory, a branch of mathematics, a natural transformation provides a way of transforming one functor into another while respecting the internal structure (i.e., the composition of morphisms) of the categories involved. Hence, a na ...

is a process of DNA transfer between cells, and is regarded as a form of bacterial sexual interaction. In the fruit fly ''

Drosophila melanogaster ''Drosophila melanogaster'' is a species of fly (the taxonomic order Diptera) in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the " vinegar fly" or " pomace fly". Starting with ...

'', exposure to mitomycin C increases recombination during meiosis, a key stage of the sexual cycle. In the plant ''

Arabidopsis thaliana ''Arabidopsis thaliana'', the thale cress, mouse-ear cress or arabidopsis, is a small flowering plant native to Eurasia and Africa. ''A. thaliana'' is considered a weed; it is found along the shoulders of roads and in disturbed land. A winter ...

'', mutant strains defective in genes necessary for recombination during meiosis and mitosis are hypersensitive to killing by mitomycin C.

Medicinal uses and research

Mitomycin C has been shown to have activity against stationary phase persisters caused by ''

Borrelia burgdorferi ''Borrelia burgdorferi'' is a bacterial species of the spirochete class in the genus '' Borrelia'', and is one of the causative agents of Lyme disease in humans. Along with a few similar genospecies, some of which also cause Lyme disease, it ...

'', a factor in

lyme disease Lyme disease, also known as Lyme borreliosis, is a vector-borne disease caused by the '' Borrelia'' bacterium, which is spread by ticks in the genus '' Ixodes''. The most common sign of infection is an expanding red rash, known as erythema ...

. Mitomycin C is used to treat pancreatic and

stomach cancer Stomach cancer, also known as gastric cancer, is a cancer that develops from the Gastric mucosa, lining of the stomach. Most cases of stomach cancers are gastric carcinomas, which can be divided into a number of subtypes, including gastric adenoca ...

, and is under

clinical research Clinical research is a branch of healthcare science that determines the safety and effectiveness ( efficacy) of medications, devices, diagnostic products and treatment regimens intended for human use. These may be used for prevention, treat ...

for its potential to treat

gastrointestinal The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...

strictures, wound healing from

glaucoma Glaucoma is a group of eye diseases that result in damage to the optic nerve (or retina) and cause vision loss. The most common type is open-angle (wide angle, chronic simple) glaucoma, in which the drainage angle for fluid within the eye re ...

surgery, corneal excimer laser surgery and endoscopic dacryocystorhinostomy.

References

{{Chemotherapeutic agents DNA replication inhibitors IARC Group 2B carcinogens Quinones Carbamates Ethers Aziridines Nitrogen heterocycles Heterocyclic compounds with 4 rings Enones