The Structures of Mitomycins A, B and C and Porfiromycin--Part I

The biosynthesis of 3-amino-5-hydroxybenzoic acid (AHBA), the precursor of mC7N units in ansamycin and mitomycin antibiotics: a review

“…3,4 This so-called mC 7 N unit was the only part of the structural core not derived from acetate/propionate units. Such mC 7 N units were also found in ansamycins of the 'benzenic' type, such as geldanamycin 5 and the maytansinoids, 6 and in the unrelated family of the mitomycin antibiotics ( Figure 1).…”

“…Such mC 7 N units were also found in ansamycins of the 'benzenic' type, such as geldanamycin 5 and the maytansinoids, 6 and in the unrelated family of the mitomycin antibiotics ( Figure 1). 7 A number of other compounds also seemed to contain mC 7 N units, such as validamycin 8 and acarbose, 9 pactamycin, 10 as well as asukamycin 11 and the manumycins, 12 and were proposed to have a similar biosynthetic origin. 11,13 However, subsequent work has shown their origins to be different.…”

“…11,13 However, subsequent work has shown their origins to be different. The mC 7 N unit of validamycin and acarbose arises from 2-epi-5-epi-valiolone, a product of the cyclization of seduheptulose 7-phosphate, 14 that of pactamycin from the shikimate pathway via 3-aminobenzoic acid, 15 and those of asukamycin and manumycin from 3-amino-4-hydroxybenzoic acid, which arises from the condensation of a triose phosphate and a C 4 -dicarboxylic acid. 16 The incorporation patterns of labeled precursors into several ansamycins and into mitomycins, 13,[17][18][19] as well as mutant complementation studies 20 all suggested a shikimate pathway origin of the mC 7 N unit, but attempts to incorporate labeled shikimic acid, quinic acid or 3-dehydroquinic acid were unsuccessful.…”

“…The cells of the rifamycin producer Amycolatopsis mediterranei are indeed impermeable for shikimic acid. 20 But this explanation as the general reason for the nonincorporation of shikimic acid was ruled out when in the case of ansatrienin (mycotrienin) it was shown that the producer organism, Streptomyces collinus, incorporated labeled shikimic acid into the cyclohexane moiety of the antibiotic, but not into its mC 7 N unit. 24 Hence, the formation of the mC 7 N unit must branch off from the shikimate pathway before dehydroquinic acid, a conclusion also reached by mutant studies on rifamycin formation.…”

Cloning and analysis of a locus (mcr) involved in mitomycin C resistance in Streptomyces lavendulae

“…Its unique structural properties and biological activity have motivated numerous studies to determine its cellular target sites and mechanism of action. Complete characterization of MMC (29,30) has been followed by studies examining the basis of its selectivity against mammalian tumor cells and the mechanisms that render mammalian tumor cells MMC resistant (5,14,18,22,26,27). However, the molecular basis for MMC resistance in the producing organism, S. lavendulae, has not been established.…”