Mechanism of Action
Mitomycin C fucntions by crosslinking DNA. A single crosslink per genome has shown to be effective in killing bacteria. This is accomplished by reductive activation, followed, by a doulbe alkyation. This process is very selective in that the first alkylation is at a guanine nucleoside in the sequence 5'-CpG-3' followed by a second alkylation at a site on the complimentary straand with the same sequence.
Biosythesis
I general the biosynthesis of all mitomycins proceed via combination of 3-amino-5-hydroxybenzoic acid (AHBA), D-glucosamine, and carbamoyl phosphate, 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 and ansamycin.
Specifially, 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 is 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.
Figure 1. Synthesis of the key intermediate, 3-amino-5-hydroxy-benzoic acid.
The mitosane core is synthesized 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. Unfortunately, both the sequence and the identity of these steps are yet to be determined.
· Complete reduction of C-6
o Likely via F420-dependent tetrahydromethanopterin (H4MPT)) reductase and H4MPT:CoM methyltransferase
· Hydroxylation of C-5, C-7 (followed by transamination), and C-9a.
o Likely via cytochrome P450 monooxygenase or benzoate hydroxylase
· O-Methylation at C-9a
o Likely via SAM dependent methyltransferase
· Oxidation at C-5 and C8
o Unknown
· Intramolecular amination to form aziridine
o Unknown
· Carbamoylation at C-10
o Carbamoyl transferrase, with carbamoyl phosphate (C4P) being derived from L-citrulline or L-arginine
Figure 2. Formatoin of mitosane core followed by tailoring specific to Mitomycin C.
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