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Mitomycin C

Page history last edited by PBworks 12 years, 6 months ago

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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