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]
References
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