Lombó Felipe, Menéndez Nuria, Salas José A, Méndez Carmen
Departamento de Biología Funcional e Instituto Universitario de Oncología del Principado de Asturias (I.U.O.P.A), Universidad de Oviedo, 33006, Oviedo, Spain.
Appl Microbiol Biotechnol. 2006 Nov;73(1):1-14. doi: 10.1007/s00253-006-0511-6. Epub 2006 Sep 30.
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.
金霉素酸家族的成员是具有抗肿瘤活性的三环聚酮化合物，由不同的链霉菌物种产生。这些成员是具有两条糖长度可变的寡糖链的糖基化化合物。它们以非嵌入方式与高GC含量区域的DNA小沟相互作用，并且需要镁离子。光辉霉素和色霉素是该家族最具代表性的成员，光辉霉素被用作治疗多种癌症疾病的化疗药物。对于色霉素和达勒霉素A，也有抗病毒活性的报道。通过基因测序、插入失活和基因表达，对光辉霉素和色霉素A(3)的生物合成基因簇进行了详细研究。这些途径中的大多数生物合成中间体已被分离和表征。与母体化合物相比，其中一些化合物的抗肿瘤活性有所增加。该家族所有成员生物合成的一个共同步骤是四环中间体前光辉霉素酮的形成。进一步的生物合成步骤（糖基化、甲基化、酰化）通过四环中间体进行，这些中间体最终通过单加氧酶的作用转化为三环化合物，这是生物活性的关键事件。在光辉霉素产生菌（或一些突变体）中异源表达来自其他芳香族聚酮途径的生物合成基因，导致了新型杂合化合物的分离。
