Martín Juan F, Ramos Angelina, Liras Paloma
Area de Microbiología, Departmento de Biología Molecular, Universidad de León, 24071 León, Spain.
Instituto de Biotecnología (INBIOTEC). Av. Real 1, 24006 León, Spain.
Antibiotics (Basel). 2019 Jun 30;8(3):87. doi: 10.3390/antibiotics8030087.
Geldanamycin and the closely related herbimycins A, B, and C are benzoquinone-type ansamycins with antitumoral activity. They are produced by var. , and among other strains. Geldanamycins interact with the Hsp-90 chaperone, a protein that has a key role in tumorigenesis of human cells. Geldanamycin is a polyketide antibiotic and the polyketide synthase contain seven modules organized in three geldanamycin synthases genes named , , and . The loading domain of GdmI activates AHBA, and also related hydroxybenzoic acid derivatives, forming geldanamycin analogues. Three regulatory genes, , , and were found associated with the geldanamycin gene cluster in strains. GdmRI and GdmRII are LAL-type (large ATP binding regulators of the LuxR family) transcriptional regulators, while GdmRIII belongs to the TetR-family. All three are positive regulators of geldanamycin biosynthesis and are strictly required for expression of the geldanamycin polyketide synthases. In the regulates geldanamycin biosynthesis and also expression of genes in the elaiophylin gene cluster, an unrelated macrodiolide antibiotic. The biosynthesis of geldanamycin is very sensitive to the inorganic phosphate concentration in the medium. This regulation is exerted through the two components system PhoR-PhoP. The genes of are linked to encoding a transcriptional modulator. The gene was deleted in var and the mutant was unable to grow in SPG medium unless supplemented with 5 mM phosphate. Also, the gene involved in the high affinity phosphate transport was cloned, and PhoP binding sequences (PHO boxes), were found upstream of , , and ; sequences were confirmed by EMSA and nuclease footprinting protection assays. The PhoP binding sequence consists of 11 nucleotide direct repeat units that are similar to those found in and other species. The available genetic information provides interesting tools for modification of the biosynthetic and regulatory mechanisms in order to increase geldanamycin production and to obtain new geldanamycin analogues with better antitumor properties.
格尔德霉素以及与之密切相关的赫比霉素A、B和C是具有抗肿瘤活性的苯醌型安莎霉素。它们由 变种、 和 等菌株产生。格尔德霉素与热休克蛋白90（Hsp-90）伴侣蛋白相互作用，该蛋白在人类细胞肿瘤发生中起关键作用。格尔德霉素是一种聚酮类抗生素，聚酮合酶包含七个模块，由三个名为 、 和 的格尔德霉素合酶基因组成。GdmI的负载结构域激活AHBA以及相关的羟基苯甲酸衍生物，形成格尔德霉素类似物。在 菌株中发现三个调控基因 、 和 与格尔德霉素基因簇相关。GdmRI和GdmRII是LAL型（LuxR家族的大型ATP结合调节因子）转录调节因子，而GdmRIII属于TetR家族。这三者都是格尔德霉素生物合成的正调控因子，是格尔德霉素聚酮合酶表达所严格必需的。在 中， 调节格尔德霉素生物合成以及伊来霉素基因簇中基因的表达，伊来霉素是一种不相关的大环二醇类抗生素。格尔德霉素的生物合成对培养基中的无机磷酸盐浓度非常敏感。这种调节是通过双组分系统PhoR-PhoP进行的。 的 基因与编码转录调节因子的 相连。 在 变种中被删除，该突变体在SPG培养基中无法生长，除非补充5 mM磷酸盐。此外，克隆了参与高亲和力磷酸盐转运的 基因，并在 、 和 的上游发现了PhoP结合序列（PHO框）；通过电泳迁移率变动分析（EMSA）和核酸酶足迹保护试验证实了这些序列。PhoP结合序列由11个核苷酸直接重复单元组成，与 在 和其他 物种中发现的序列相似。现有的遗传信息为修饰生物合成和调控机制提供了有趣的工具，以提高格尔德霉素的产量并获得具有更好抗肿瘤特性的新格尔德霉素类似物。
