Biosynthesis of cytotoxic sesquiterpenoids by higher basidiomycetes

高等担子菌生物合成细胞毒性倍半萜类化合物

基本信息

批准号：
8085831
负责人：
CLAUDIA SCHMIDT-DANNERT
金额：
$ 28.33万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-22 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8085831
关键词：
Agaricales Anabolism Anti-Bacterial Agents Antibiotics Attention Basidiomycota Biological Factors Complementary DNA Coprinus Cosmids Cyclization Cyclobutanes Cyclopropanes Cytochrome P450 Cytostatics Data Enzymes Exhibits Fruit Genes Goals Human Investigation Label Libraries Literature Metabolic Pathway Microbe Mixed Function Oxygenases Modification Multi-Drug Resistance Oligonucleotide Primers Oligonucleotide Probes Pharmaceutical Preparations Phase I/II Trial Plants Property Reaction Recombinants Reporting Research Resources Saccharomyces cerevisiae Screening procedure Sesquiterpenes Skeleton Solid Neoplasm Structure Therapeutic Therapeutic Index Traditional Medicine Tumor Cell Line acylfulvene analog antitumor drug base cyclopropane cytotoxic farnesyl pyrophosphate feeding fungus illudin M improved isoprenoid neoplastic cell novel oxidation scaffold substance R tumor

项目摘要

DESCRIPTION (provided by applicant): Higher basidiomycetes, commonly referred to as mushrooms, have been used for centuries in traditional medicine and are known to synthesize an array of biologically active natural products. It is thought that mushrooms are among the greatest unexplored resources for the discovery of novel biologically active compounds. Despite the extremely rich chemodiversity of higher basidiomycetes and the prospects for the discovery of new drugs, mushrooms have only recently caught the attention of medicinal chemists and biochemists. Mushrooms are known to produce a variety of sesquiterpenes with unique skeletons not found in microbes or plants. One class of sesquiterpenoids, the illudanes, has received considerable attention because of their potent antitumor and antibacterial activity. Illudins M and S produced by the Jack O'Lantern mushroom Omphalotus olearius exhibit cytotoxic and cytostatic properties at nanomolar concentrations in several human tumor cell lines, including multiple drug resistant tumors. Semi-synthetic illudin analogues irofulvene and acylfulvene with improved therapeutic indexes and remarkable antitumor activities have been synthesized and are currently under investigation in several phase I and II trials against several solid tumor types. The biosynthesis, however, of this class of illudane sesquiterpenoids is not known. The proposed research will be the first biosynthetic investigation of this important and unique class higher fungal sesquiterpene natural products. The specific hypotheses of this proposal are that: (1) Illudins are derived via a protoilludane skeleton synthesized by a new type of cyclase and (2) installment of the reactive cyclopropane ring in illudins occurs after the initial cyclization reaction presumably via a P450 monooxygenase catalyzed reaction. It is proposed to (1) identify and characterize the cyclase responsible for formation of the protoilludane scaffold, (2) identify and characterize additional illudin biosynthetic genes and (3) probe the substrate range of protoilludane scaffold modifying enzymes. The long-term goal of this research is to investigate biosynthesis of different protoilludane-type sesquiterpenoids in higher fungi with the goal of using the identified biosynthetic enzymes to explore synthesis of new functionalized sesquiterpenoids with potent antitumor properties and improved therapeutic properties. It is thought that mushrooms are among the greatest unexplored resources for the discovery of novel biologically active compounds; but despite the extremely rich chemodiversity of higher basidiomycetes and the prospects for the discovery of new drugs, mushrooms have only recently caught the attention of medicinal chemists and biochemists. One class of sesquiterpenoids, the illudanes, produced by the Jack O'Lantern mushroom Omphalotus olearius exhibit potent cytotoxic and cytostatic properties in several human tumor cell lines, including multiple drug resistant tumors. The goal of this research is to investigate biosynthesis of illudane sesquiterpenoids in mushrooms with the goal of using the identified biosynthetic enzymes to explore synthesis of new sesquiterpenoid structures with potent antitumor properties and improved therapeutic properties.

描述（由申请人提供）：较高的基本菌（通常称为蘑菇）已在传统医学中使用了几个世纪，并且已知可以合成一系列具有生物活性的天然产品。人们认为，蘑菇是发现新型生物活性化合物的最大未开发资源之一。尽管较高的基础菌菌具有极丰富的化学多样性以及发现新药的前景，但蘑菇直到最近才引起了药物化学家和生物化学家的注意。众所周知，蘑菇会产生各种在微生物或植物中发现的独特骨骼的倍半萜。一类倍半萜类化合物（illudanes）由于其有效的抗肿瘤和抗菌活性而受到了相当大的关注。杰克·奥兰特·蘑菇元素Olearius产生的illudins M和S在几种人类肿瘤细胞系中，在包括多种耐药性肿瘤（包括多种耐药性肿瘤）中，在纳摩尔浓度下表现出细胞毒性和细胞抑制性能。半合成的Illudin类似物Irofulvene和Acylvene具有改进的治疗指数和显着的抗肿瘤活性，目前正在针对几种实体瘤类型的几个I期和II期试验中进行研究。然而，这类菌根倍半萜类化合物的生物合成尚不清楚。拟议的研究将是对这种重要和独特的较高真菌倍烯烯天然产品的首次生物合成研究。该提议的具体假设是：（1）illudins是通过新型环酶合成的原菌骨架来得出的，（2）（2）在初始环化反应中发生了反应性环丙烷环在illudins中发生，这可能是通过P450单一型酶催化的催化的。反应。提议（1）识别和表征负责原始支架形成的环化酶，（2）识别和表征其他illudin Biosynthetic基因，（3）探测原始硅烷基修饰酶的底物范围。这项研究的长期目标是研究较高真菌中不同原始型倍半萜类化合物的生物合成，目的是使用已鉴定的生物合成酶探索具有有效抗肿瘤特性的新功能化倍半萜类化合物的合成，并提高了抗肿瘤的特性和改善的特性。人们认为，蘑菇是发现新型生物活性化合物的最大未开发资源之一。但是，尽管较高的基础菌菌具有极丰富的化学多样性以及发现新药的前景，但蘑菇直到最近才引起了药物化学家和生物化学家的关注。一类由杰克·奥兰特蘑菇Omphalotus Olearius生产的倍半萜类化合物在包括多种耐药性肿瘤在内的几种人肿瘤细胞系中具有有效的细胞毒性和细胞抑制性能。这项研究的目的是研究蘑菇中illudane倍半萜类化合物的生物合成，目的是使用已鉴定的生物合成酶探索具有有效抗肿瘤特性的新倍半萜结构的合成，并改善了治疗特性。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Engineering of biocatalysts - from evolution to creation.

生物催化剂工程 - 从进化到创造。

DOI：
10.1021/cs200217t
发表时间：
2011-09-02
期刊：
ACS CATALYSIS
影响因子：
12.9
作者：
Quin, Maureen B.;Schmidt-Dannert, Claudia
通讯作者：
Schmidt-Dannert, Claudia

Designer microbes for biosynthesis.

DOI：
10.1016/j.copbio.2014.02.014
发表时间：
2014-10
期刊：
CURRENT OPINION IN BIOTECHNOLOGY
影响因子：
7.7
作者：
Quin, Maureen B.;Schmidt-Dannert, Claudia
通讯作者：
Schmidt-Dannert, Claudia

Purification, crystallization and preliminary X-ray diffraction analysis of Omp6, a protoilludene synthase from Omphalotus olearius.

Omp6（一种来自 Omphalotus olearius 的原伊鲁烯合酶）的纯化、结晶和初步 X 射线衍射分析。

DOI：
10.1107/s1744309113010749
发表时间：
2013
期刊：
Acta crystallographica. Section F, Structural biology and crystallization communications
影响因子：
0
作者：
Quin,MaureenB;Wawrzyn,Grayson;Schmidt-Dannert,Claudia
通讯作者：
Schmidt-Dannert,Claudia

Biosynthesis of terpenoid natural products in fungi.