Mitomycins Explained

The mitomycins are a family of aziridine-containing natural products isolated from Streptomyces caespitosus or Streptomyces lavendulae.^{[1] [2]} 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.^[3] 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 (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 induces competence for transformation.^[4] 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.^[5] In the plant Arabidopsis thaliana, mutant strains defective in genes necessary for recombination during meiosis and mitosis are hypersensitive to killing by mitomycin C.^[6]

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.^{[7] [8]} Mitomycin C is used to treat pancreatic and stomach cancer,^[9] and is under clinical research for its potential to treat gastrointestinal strictures,^[10] wound healing from glaucoma surgery,^[11] corneal excimer laser surgery^[12] and endoscopic dacryocystorhinostomy.^[13]

Notes and References

1. Book: Bacteriophages : methods and protocols. Clokie MR, Kropinski AM . Martha Clokie . 2009. Humana Press. 9781603271646. 297169927.
2. Danshiitsoodol N, de Pinho CA, Matoba Y, Kumagai T, Sugiyama M . The mitomycin C (MMC)-binding protein from MMC-producing microorganisms protects from the lethal effect of bleomycin: crystallographic analysis to elucidate the binding mode of the antibiotic to the protein . Journal of Molecular Biology . 360 . 2 . 398–408 . July 2006 . 16756991 . 10.1016/j.jmb.2006.05.017 .
3. Mao Y, Varoglu M, Sherman DH . Molecular characterization and analysis of the biosynthetic gene cluster for the antitumor antibiotic mitomycin C from Streptomyces lavendulae NRRL 2564 . Chemistry & Biology . 6 . 4 . 251–263 . April 1999 . 10099135 . 10.1016/S1074-5521(99)80040-4 . free .
4. Charpentier X, Kay E, Schneider D, Shuman HA . Antibiotics and UV radiation induce competence for natural transformation in Legionella pneumophila . Journal of Bacteriology . 193 . 5 . 1114–1121 . March 2011 . 21169481 . 3067580 . 10.1128/JB.01146-10 .
5. Schewe MJ, Suzuki DT, Erasmus U . The genetic effects of mitomycin C in Drosophila melanogaster. II. Induced meiotic recombination . Mutation Research . 12 . 3 . 269–279 . July 1971 . 5563942 . 10.1016/0027-5107(71)90015-7 .
6. Bleuyard JY, Gallego ME, Savigny F, White CI . Differing requirements for the Arabidopsis Rad51 paralogs in meiosis and DNA repair . The Plant Journal . 41 . 4 . 533–545 . February 2005 . 15686518 . 10.1111/j.1365-313X.2004.02318.x .
7. Feng J, Shi W, Zhang S, Zhang Y . Identification of new compounds with high activity against stationary phase Borrelia burgdorferi from the NCI compound collection . Emerging Microbes & Infections . 4 . 6 . e31 . June 2015 . 26954881 . 5176177 . 10.1038/emi.2015.31 .
8. Sharma B, Brown AV, Matluck NE, Hu LT, Lewis K . Borrelia burgdorferi, the Causative Agent of Lyme Disease, Forms Drug-Tolerant Persister Cells . Antimicrobial Agents and Chemotherapy . 59 . 8 . 4616–4624 . August 2015 . 26014929 . 4505243 . 10.1128/AAC.00864-15 .
9. Web site: Mitomycin. Drugs.com. 2017. 11 November 2017.
10. Rustagi T, Aslanian HR, Laine L . Treatment of Refractory Gastrointestinal Strictures With Mitomycin C: A Systematic Review . Journal of Clinical Gastroenterology . 49 . 10 . 837–847 . 2015 . 25626632 . 10.1097/MCG.0000000000000295 . 5867992 .
11. Cabourne E, Clarke JC, Schlottmann PG, Evans JR . Mitomycin C versus 5-Fluorouracil for wound healing in glaucoma surgery . The Cochrane Database of Systematic Reviews . 2015 . 11 . CD006259 . November 2015 . 26545176 . 8763343 . 10.1002/14651858.CD006259.pub2 .
12. Majmudar PA, Forstot SL, Dennis RF, Nirankari VS, Damiano RE, Brenart R, Epstein RJ . Topical mitomycin-C for subepithelial fibrosis after refractive corneal surgery . Ophthalmology . 107 . 1 . 89–94 . January 2000 . 10647725 . 10.1016/s0161-6420(99)00019-6 .
13. Cheng SM, Feng YF, Xu L, Li Y, Huang JH . Efficacy of mitomycin C in endoscopic dacryocystorhinostomy: a systematic review and meta-analysis . PLOS ONE . 8 . 5 . e62737 . 2013 . 23675423 . 3652813 . 10.1371/journal.pone.0062737 . free . 2013PLoSO...862737C .