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 syn ...

isolated from ''

Streptomyces caespitosus ''Streptomyces caespitosus'' is a species of actinobacteria. It produces chemotherapeutic drug 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 ...

'' 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 Carbamoyl phosphate is an anion of biochemical significance. In land-dwelling animals, it is an intermediary metabolite in nitrogen disposal through the urea cycle and the synthesis of pyrimidines. Its enzymatic counterpart, carbamoyl phosphate syn ...

, 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 aga ...

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/m ...

(PEP) to

erythrose-4-phosphate Erythrose 4-phosphate is a phosphate of the simple sugar erythrose. It is an intermediate in the pentose phosphate pathway and the Calvin cycle. In addition, it serves as a precursor in the biosynthesis of the aromatic amino acids tyrosine, pheny ...

(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 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 breast c ...

induces competence for

transformation Transformation may refer to: Science and mathematics In biology and medicine * Metamorphosis, the biological process of changing physical form after birth or hatching * Malignant transformation, the process of cells becoming cancerous * Trans ...

. 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 ''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 make ...

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

pancreatic The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an endocr ...

and stomach cancer, 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, treatmen ...

for its potential to treat gastrointestinal

strictures A stenosis (from Ancient Greek στενός, "narrow") is an abnormal narrowing in a blood vessel or other tubular organ or structure such as foramina and canals. It is also sometimes called a stricture (as in urethral stricture). ''Stricture' ...

, 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 rem ...

surgery, corneal excimer laser surgery and endoscopic

dacryocystorhinostomy Dacryocystorhinostomy (DCR) is a surgical procedure to restore the flow of tears into the nose from the lacrimal sac when the nasolacrimal duct does not function. Process Traditional A small incision is made on the side of the nose and some bone ...

References

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