Mitomycins

{{Short description|Group of antibiotics}} {{About|mitomycins as a family of natural products|its use as a medication|Mitomycin C}} [[File:Mitomycin.svg|thumb|right|Chemical structure of mitomycin C]] The '''mitomycins''' are a family of aziridine-containing natural products isolated from ''Streptomyces caespitosus'' or ''Streptomyces lavendulae.''<ref>{{Cite book|title=Bacteriophages: methods and protocols| vauthors = Clokie MR, Kropinski AM |author-link1=Martha Clokie |date=2009|publisher=Humana Press|isbn=978-1-60327-164-6|oclc=297169927}}</ref><ref>{{cite journal | vauthors = Danshiitsoodol N, de Pinho CA, Matoba Y, Kumagai T, Sugiyama M | title = 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 = Journal of Molecular Biology | volume = 360 | issue = 2 | pages = 398–408 | date = July 2006 | pmid = 16756991 | doi = 10.1016/j.jmb.2006.05.017 }}</ref> 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.<ref name=Sherman>{{cite journal | vauthors = Mao Y, Varoglu M, Sherman DH | title = Molecular characterization and analysis of the biosynthetic gene cluster for the antitumor antibiotic mitomycin C from Streptomyces lavendulae NRRL 2564 | journal = Chemistry & Biology | volume = 6 | issue = 4 | pages = 251–263 | date = April 1999 | pmid = 10099135 | doi = 10.1016/S1074-5521(99)80040-4 | doi-access = free }}</ref> 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.

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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

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==Biological effects== In the bacterium ''Legionella pneumophila'', mitomycin C induces competence for transformation.<ref>{{cite journal | vauthors = Charpentier X, Kay E, Schneider D, Shuman HA | title = Antibiotics and UV radiation induce competence for natural transformation in Legionella pneumophila | journal = Journal of Bacteriology | volume = 193 | issue = 5 | pages = 1114–1121 | date = March 2011 | pmid = 21169481 | pmc = 3067580 | doi = 10.1128/JB.01146-10 }}</ref> 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.<ref>{{cite journal | vauthors = Schewe MJ, Suzuki DT, Erasmus U | title = The genetic effects of mitomycin C in Drosophila melanogaster. II. Induced meiotic recombination | journal = Mutation Research | volume = 12 | issue = 3 | pages = 269–279 | date = July 1971 | pmid = 5563942 | doi = 10.1016/0027-5107(71)90015-7 }}</ref> In the plant ''Arabidopsis thaliana'', mutant strains defective in genes necessary for recombination during meiosis and mitosis are hypersensitive to killing by mitomycin C.<ref>{{cite journal | vauthors = Bleuyard JY, Gallego ME, Savigny F, White CI | title = Differing requirements for the Arabidopsis Rad51 paralogs in meiosis and DNA repair | journal = The Plant Journal | volume = 41 | issue = 4 | pages = 533–545 | date = February 2005 | pmid = 15686518 | doi = 10.1111/j.1365-313X.2004.02318.x | doi-access = }}</ref>

==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.<ref>{{cite journal | vauthors = Feng J, Shi W, Zhang S, Zhang Y | title = Identification of new compounds with high activity against stationary phase Borrelia burgdorferi from the NCI compound collection | journal = Emerging Microbes & Infections | volume = 4 | issue = 6 | article-number = e31 | date = June 2015 | pmid = 26954881 | pmc = 5176177 | doi = 10.1038/emi.2015.31 }}</ref><ref>{{cite journal | vauthors = Sharma B, Brown AV, Matluck NE, Hu LT, Lewis K | title = Borrelia burgdorferi, the Causative Agent of Lyme Disease, Forms Drug-Tolerant Persister Cells | journal = Antimicrobial Agents and Chemotherapy | volume = 59 | issue = 8 | pages = 4616–4624 | date = August 2015 | pmid = 26014929 | pmc = 4505243 | doi = 10.1128/AAC.00864-15 }}</ref> Mitomycin C is used to treat pancreatic and stomach cancer,<ref>{{cite web|url=https://www.drugs.com/mtm/mitomycin.html|title=Mitomycin|publisher=Drugs.com|date=2017|access-date=11 November 2017}}</ref> and is under clinical research for its potential to treat gastrointestinal strictures,<ref>{{cite journal | vauthors = Rustagi T, Aslanian HR, Laine L | title = Treatment of Refractory Gastrointestinal Strictures With Mitomycin C: A Systematic Review | journal = Journal of Clinical Gastroenterology | volume = 49 | issue = 10 | pages = 837–847 | year = 2015 | pmid = 25626632 | doi = 10.1097/MCG.0000000000000295 | s2cid = 5867992 }}</ref> wound healing from glaucoma surgery,<ref>{{cite journal | vauthors = Cabourne E, Clarke JC, Schlottmann PG, Evans JR | title = Mitomycin C versus 5-Fluorouracil for wound healing in glaucoma surgery | journal = The Cochrane Database of Systematic Reviews | volume = 2015 | issue = 11 | article-number = CD006259 | date = November 2015 | pmid = 26545176 | pmc = 8763343 | doi = 10.1002/14651858.CD006259.pub2 }}</ref> corneal excimer laser surgery<ref>{{cite journal | vauthors = Majmudar PA, Forstot SL, Dennis RF, Nirankari VS, Damiano RE, Brenart R, Epstein RJ | title = Topical mitomycin-C for subepithelial fibrosis after refractive corneal surgery | journal = Ophthalmology | volume = 107 | issue = 1 | pages = 89–94 | date = January 2000 | pmid = 10647725 | doi = 10.1016/s0161-6420(99)00019-6 }}</ref> and endoscopic dacryocystorhinostomy.<ref>{{cite journal | vauthors = Cheng SM, Feng YF, Xu L, Li Y, Huang JH | title = Efficacy of mitomycin C in endoscopic dacryocystorhinostomy: a systematic review and meta-analysis | journal = PLOS ONE | volume = 8 | issue = 5 | article-number = e62737 | year = 2013 | pmid = 23675423 | pmc = 3652813 | doi = 10.1371/journal.pone.0062737 | doi-access = free | bibcode = 2013PLoSO...862737C }}</ref>

== References == {{Reflist|30em}}

Category:Mitomycins Category:DNA replication inhibitors Category:IARC Group 2B carcinogens Category:Quinones Category:Carbamates Category:Ethers Category:Aziridines Category:Nitrogen heterocycles Category:Heterocyclic compounds with 4 rings Category:Enones Category:Methoxy compounds