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BIOSYNTHETIC KEY STEPS OF ANGUCYCLINE ANTITUMOR DRUGS

安古环素抗肿瘤药物的生物合成关键步骤

基本信息

批准号：
7845298
负责人：
Jurgen T Rohr
金额：
$ 0.74万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2009-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7845298
关键词：
Address Amino Acids Anabolism Antifungal Antibiotics Antineoplastic Agents Architecture Binding Biological Brain Brain Neoplasms C-glycoside Colon Coumarins DNA DNA Sequence Rearrangement Development Elements Enzymatic Biochemistry Enzymes Family Figs - dietary Foundations Gene Cluster Generations Genes Genetic Recombination Goals Histones Investigation Knowledge Lead Lung Malignant Neoplasms Malignant neoplasm of prostate Methods Modeling Modification Molecular Multienzyme Complexes Oxygenases Pathway interactions Pharmaceutical Preparations Production Property Prostate Reaction Research Route Side Skin Streptomyces Streptomyces lividans Structure Substrate Interaction Substrate Specificity Toxic effect Ultraviolet Rays alpha benzopyrone analog anticancer activity antineoplastic antibiotics antitumor drug base combinatorial drug biological activity gilvocarcin V glycosylation glycosyltransferase improved interest jadomycin B leukemia mutant novel polyketide synthase

项目摘要

DESCRIPTION (provided by applicant): Gilvocarcins and jadomycins are angucyclin-derived anticancer drugs/antibiotics possessing unique molecular frames, whose common biosynthetic key step is an oxidative rearrangement catalyzed by a closely related set of enzymes. The gilvocarcins, produced by various Streptomyces strains including Streptomyces griseoflavus Go 3592, represent a distinct family of interesting aryl C-glycoside antitumor drugs with a coumarin-based aromatic core that promote specific DNA interactions when photoactivated by near UV light. This class of anticancer drugs shows excellent antitumor activity and remarkably low toxicity. Its unprecedented molecular architecture in conjunction with its unique biological activity makes the gilvocarcins an excellent target for biosynthetic studies and the development of novel, photoactivatable anticancer drugs through combinatorial biosynthesis. The drugs may be useful for the treatment of special cancers, such as brain tumors, colon, skin, lung, and prostate cancers or leukemia. The jadomycins are antibiotics/antifungals, whose structure is characterized by an unusual insertion of an amino acid building block after an oxidative bond breakage. Previous biosynthetic studies suggest for both, gilvocarcins and jadomycins, a pathway dominated by a type-2 polyketide synthase (PKS), leading initially to an angucycline type drug intermediate, which then oxidatively rearranges into the final molecular frame. Selected intriguing post-PKS tailoring steps, namely the oxidative rearrangement (gilvocarcin and jadomycin biosynthesis), the unusual C-glycosylation step (gilvocarcin biosynthesis), and the formation of the vinyl group side chain of gilvocarcin V, are key biosynthetic features responsible for the generation of structural elements, which are essential for the unique biological activity of the gilvocarcin drugs. The investigation of these cascades of post-PKS tailoring biosynthetic key reactions, found in both the jadomycin and gilvocarcin biosyntheses, is a main goal of the research, since it as an interesting model for post-PKS enzyme complexes, their mechanisms, interactions, substrate binding/passing modes etc. This topic has never been studied in detail despite the importance of such tailoring steps for the biological activity of polyketide drugs. The understanding of these biosynthetic steps, and the enzymes responsible for their execution will ultimately pave the way for the generation of more potential and more selective drugs through combinatorial biosynthetic methods. The following specific aims will be addressed: (1) Characterization of the late steps of the gilvocarcin and jadomycin biosynthesis; (2) Generation of new gilvocarcin analogues by inactivation and recombination of selected post-PKS tailoring genes; (3) Characterization of key enzymes of the gilvocarcin and the related jadomycin biosynthetic pathway to understand their mechanism-of-action and substrate specificity range, their interaction; and (4) assessment of the antitumor activity of gilvocarcin and newly generated analogues from specific aim 2. The long-term goal of this research is to develop improved anticancer drugs for the treatment of special cancers.

描述（申请人提供）：Gilvocacins和jadomycins是安古环素衍生的抗癌药物/抗生素，具有独特的分子框架，其共同的生物合成关键步骤是由一组密切相关的酶催化的氧化重排。 gilvocarcins 由包括 Streptomyces griseoflavus Go 3592 在内的各种链霉菌菌株产生，代表了一个独特的芳基 C-糖苷抗肿瘤药物家族，其具有基于香豆素的芳香核心，当被近紫外光光激活时，可促进特定的 DNA 相互作用。此类抗癌药物显示出优异的抗肿瘤活性和极低的毒性。其前所未有的分子结构及其独特的生物活性使 gilvocacin 成为生物合成研究和通过组合生物合成开发新型光活化抗癌药物的绝佳靶标。这些药物可用于治疗特殊癌症，例如脑肿瘤、结肠癌、皮肤癌、肺癌、前列腺癌或白血病。贾多霉素是抗生素/抗真菌药，其结构特征是氧化键断裂后异常插入氨基酸结构单元。先前的生物合成研究表明，对于吉沃卡星和贾多霉素来说，一条由2型聚酮合酶（PKS）主导的途径，最初产生安古环素型药物中间体，然后氧化重排成最终的分子框架。选定的有趣的 PKS 后剪裁步骤，即氧化重排（gilvocacin 和 jadomycin 生物合成）、不寻常的 C-糖基化步骤（gilvocacin 生物合成）以及 gilvocacin V 乙烯基侧链的形成，是负责生成结构元件的关键生物合成特征，这些元件对于 gilvocacin 药物具有独特的生物活性。研究在 Jadomycin 和 gilvocacin 生物合成中发现的 PKS 后定制生物合成关键反应的级联是本研究的主要目标，因为它作为 PKS 后酶复合物、其机制、相互作用、底物结合/传递模式等的有趣模型。尽管此类定制步骤对于聚酮类药物。对这些生物合成步骤以及负责其执行的酶的理解最终将为通过组合生物合成方法生成更具潜力和更具选择性的药物铺平道路。将解决以下具体目标：（1）吉沃卡星和贾多霉素生物合成后期步骤的表征； (2) 通过选定的 PKS 后剪裁基因的失活和重组产生新的吉沃卡星类似物； (3) 吉沃卡星及相关贾多霉素生物合成途径关键酶的表征，以了解其作用机制、底物特异性范围、相互作用； (4)评估gilvocacin和特定目标2新生成的类似物的抗肿瘤活性。这项研究的长期目标是开发改进的抗癌药物来治疗特殊癌症。

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

GilR, an unusual lactone-forming enzyme involved in gilvocarcin biosynthesis.

DOI：
10.1002/cbic.200900130
发表时间：
2009-05-25
期刊：
CHEMBIOCHEM
影响因子：
3.2
作者：
Kharel, Madan Kumar;Pahari, Pallab;Lian, Hui;Rohr, Juergen
通讯作者：
Rohr, Juergen

Moromycins A and B, isolation and structure elucidation of C-glycosylangucycline-type antibiotics from Streptomyces sp. KY002.

DOI：
10.1021/np800281f
发表时间：
2008-09
期刊：
JOURNAL OF NATURAL PRODUCTS
影响因子：
5.1
作者：
Abdelfattah, Mohamed S.;Kharel, Madan Kumar;Hitron, John Andrew;Baig, Irfan;Rohr, Juergen
通讯作者：
Rohr, Juergen

Elucidation of oxygenation steps during oviedomycin biosynthesis and generation of derivatives with increased antitumor activity.

DOI：
10.1002/cbic.200800425
发表时间：
2009-01-26
期刊：
CHEMBIOCHEM
影响因子：
3.2
作者：
Lombo, Felipe;Abdelfattah, Mohamed S.;Brana, Alfredo F.;Salas, Jose A.;Rohr, Juergen;Mendez, Carmen
通讯作者：
Mendez, Carmen

11-Deoxylandomycinone and landomycins X-Z, new cytotoxic angucyclin(on)es from a Streptomyces cyanogenus K62 mutant strain.