The mitomycins are a family of aziridine-containing natural products isolated from ''

Streptomyces caespitosus ''Streptomyces caespitosus'' is a species of Actinomycetota, actinobacteria. It produces chemotherapeutic medication, drug mitomycin C. References

Streptomyces, caespitosus {{Streptomyces-stub ...

'' 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 The rifamycins are a group of antibiotics that are synthesized either naturally by the bacterium ''Amycolatopsis rifamycinica'' or artificially. They are a subclass of the larger family of ansamycins. Rifamycins are particularly effective again ...

and ansamycin. Specifically, the biosynthesis begins with the addition of phosphoenolpyruvate (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 ''Legionella pneumophila'' is a thin, aerobic, pleomorphic, flagellated, non-spore-forming, Gram-negative bacterium of the genus ''Legionella''. ''L. pneumophila'' is the primary human pathogenic bacterium in this group and is the causative age ...

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

'', 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'', a factor in lyme disease. Mitomycin C is used to treat

pancreatic The pancreas is an Organ (anatomy), organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdominal cavity, abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine ...

and

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

, and is under clinical research for its potential to treat gastrointestinal strictures, wound healing from glaucoma 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