The aureolic acid family of antitumor compounds: structure, mode of action, biosynthesis, and novel derivatives

Abstract

Members of the aureolic acid family are tricyclic polyketides with antitumor activity which are produced by different streptomycete species. These members are glycosylated compounds with two oligosaccharide chains of variable sugar length. They interact with the DNA minor groove in high-GC-content regions in a nonintercalative way and with a requirement for magnesium ions. Mithramycin and chromomycins are the most representative members of the family, mithramycin being used as a chemotherapeutic agent for the treatment of several cancer diseases. For chromomycin and durhamycin A, antiviral activity has also been reported. The biosynthesis gene clusters for mithramycin and chromomycin A(3) have been studied in detail by gene sequencing, insertional inactivation, and gene expression. Most of the biosynthetic intermediates in these pathways have been isolated and characterized. Some of these compounds showed an increase in antitumor activity in comparison with the parent compounds. A common step in the biosynthesis of all members of the family is the formation of the tetracyclic intermediate premithramycinone. Further biosynthetic steps (glycosylation, methylations, acylations) proceed through tetracyclic intermediates which are finally converted into tricyclic compounds by the action of a monooxygenase, a key event for the biological activity. Heterologous expression of biosynthetic genes from other aromatic polyketide pathways in the mithramycin producer (or some mutants) led to the isolation of novel hybrid compounds.

Pomalidomide and Lenalidomide Induce p21WAF-1 Expression in Both Lymphoma and Multiple Myeloma through a LSD1-Mediated Epigenetic Mechanism

“…Sp1 is known to interact with GC-rich promoter sequences and to have its binding inhibited by MTM (31). The treatment of Namalwa cells by MTM abolished both the upregulation of p21 WAF-1 RNA expression (Fig.…”

“…This is suggested by the fact that the treatment of Namalwa cells by MTM, which inhibits all transcription factors binding to GC-rich regions (37), abolished the up-regulation of p21 WAF-1 . Sp1, whose binding to DNA is inhibited by MTM (31), is involved in the up-regulation of p21 WAF-1 in several cell types (14,38), as well as in the repression of this gene (39)(40)(41)(42). In addition, Sp3, Egr1, and Egr2 bind GC-rich regions and have been Figure 5.…”

Oxytetracycline Biosynthesis

“…The oxy cluster contains a ZhuC homolog, OxyP, and there are indications that it may serve a similar role in suppressing acetate priming and reducing the level of 2-acetyl-2-decarboxamido-OTC (ADOTC). 4 Reduction of the ADOTC:OTC ratio is desirable, as ADOTC has greatly reduced antibiotic activity compared with OTC and is difficult to remove from fermentation broths (51). Unlike the R1128 pathway, which produces only acetate-primed polyketides in the absence of the proofreading activities of ZhuC, the oxy PKS does not require OxyP to incorporate the malonamate starter unit.…”

“…Type II polyketides, also known as bacterial aromatic polyketides, are a group of compounds produced naturally in bacteria from a poly-␤-ketone intermediate that is tailored to form a polycyclic product containing at least one aromatic ring (1,2). This class of metabolites includes many important bioactive compounds such as anticancer agents doxorubicin (3) and mithramycin (4), the antiviral and antifungal pradimicin (5), and the antibiotic tetracyclines (6). The biosynthetic machinery responsible for the synthesis of these compounds is structurally and biochemically similar to that for type II fatty acid synthases, leading to the classification type II polyketide synthases.…”

Transcriptional regulation of mithramycin biosynthesis in Streptomyces argillaceus: dual role as activator and repressor of the PadR-like regulator MtrY

“…The mithramycin gene cluster of Streptomyces argillaceus has been cloned and characterized (Lombó et al, 2006). In addition, using combinatorial biosynthesis strategies, several new derivatives have been generated, some of which showed higher antitumour activity and/or less toxicity than the parental compound (Albertini et al, 2006;García et al, 2011;Nú ñez et al, 2012;Pérez et al, 2008;Remsing et al, 2003).…”