In general, the biosynthesis of all mitomycins proceeds via combination of 3-amino-5-hydroxybenzoic acid (AHBA),D-glucosamine, andcarbamoyl 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 asrifamycin and ansamycin.
Specifically, the biosynthesis begins with the addition ofphosphoenolpyruvate (PEP) toerythrose-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 andD-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
In the bacteriumLegionella pneumophila,mitomycin C inducescompetence fortransformation.[4]Natural transformation is a process of DNA transfer between cells, and is regarded as a form of bacterial sexual interaction. In the fruit flyDrosophila melanogaster, exposure to mitomycin C increases recombination during meiosis, a key stage of the sexual cycle.[5] In the plantArabidopsis thaliana, mutant strains defective in genes necessary for recombination during meiosis and mitosis are hypersensitive to killing by mitomycin C.[6]
^Danshiitsoodol N, de Pinho CA, Matoba Y, Kumagai T, Sugiyama M (July 2006). "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.doi:10.1016/j.jmb.2006.05.017.PMID16756991.
^Schewe MJ, Suzuki DT, Erasmus U (July 1971). "The genetic effects of mitomycin C in Drosophila melanogaster. II. Induced meiotic recombination".Mutation Research.12 (3):269–279.doi:10.1016/0027-5107(71)90015-7.PMID5563942.
^Bleuyard JY, Gallego ME, Savigny F, White CI (February 2005). "Differing requirements for the Arabidopsis Rad51 paralogs in meiosis and DNA repair".The Plant Journal.41 (4):533–545.doi:10.1111/j.1365-313X.2004.02318.x.PMID15686518.
^"Mitomycin". Drugs.com. 2017. Retrieved11 November 2017.
^Rustagi T, Aslanian HR, Laine L (2015). "Treatment of Refractory Gastrointestinal Strictures With Mitomycin C: A Systematic Review".Journal of Clinical Gastroenterology.49 (10):837–847.doi:10.1097/MCG.0000000000000295.PMID25626632.S2CID5867992.
