Creating natural product diversity via the fabrication of a hybrid fatty acid-nonribosomal peptide synthetase
通过制造杂合脂肪酸-非核糖体肽合成酶创造天然产物多样性
基本信息
- 批准号:10339399
- 负责人:
- 金额:$ 1.99万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-01-01 至 2022-04-29
- 项目状态:已结题
- 来源:
- 关键词:AchievementAddressAmino AcidsAnabolismAntibioticsAntifungal AgentsBerryBiochemistryBiomedical EngineeringCarrier ProteinsChemicalsClinicComplexComputational BiologyComputer ModelsComputing MethodologiesCouplingDaptomycinDataDevelopmentDrug TargetingEngineeringEnzymesEscherichia coliFatty AcidsFatty-acid synthaseFutureGoalsHybridsImmunosuppressive AgentsIn VitroKnowledgeMethodologyMethodsMicrobeModelingModernizationModificationMolecularMonitorMovementMultiple PartnersMutagenesisNatural ProductsNatureOrganismPathway interactionsPeptide BiosynthesisPeptidesPharmaceutical PreparationsPrevalenceProdigiosinProductionProductivityProteinsRoleSpecificityStructureSystemTherapeuticTrainingWorkX-Ray Crystallographyantimicrobialclinically relevantcombinatorialdesigngenetic technologygenome sequencingholo-(acyl-carrier-protein) synthasein vivomethicillin resistant Staphylococcus aureusmicrobialnovelpeptide synthasepolyketide synthasepractical applicationprogramsprotein complexprotein protein interactionrational designscaffoldsimulationstructural biologysuccesstool
项目摘要
Abstract: Natural products and derivatives/mimics of natural products make up the majority of modern
therapeutic drugs due to their unique complex organic scaffolds that contribute to their wide range of bioactivities.
These natural products are synthesized by the fatty acid synthase (FAS), the nonribosomal peptide synthetase
(NRPS) or the polyketide synthase (PKS). This program studies the role of protein•protein interactions in the
modular synthases responsible for the formation of clinically relevant fatty acids and nonribosomal peptides for
the long-term goal of re-designing and completely controlling the biosynthetic assembly lines. An example of a
natural product therapeutic in the clinic is the antimicrobial daptomycin, which is a lipopeptide synthesized from
a hybrid fatty acid synthase (FAS) and nonribosomal peptide synthetase (NRPS) that is used to treat methicillin-
resistant Staphylococcus aureus. Thus, the hybrid FAS/NRPS are valuable systems to study and control so we
may diversify natural products with new or enhanced bioactivities. Over the last three decades, true control over
the biosynthetic assembly lines has remained elusive; the lack of a fundamental understanding on how the mega-
synthase’s protein•protein interactions govern natural product biosynthesis has hindered this promising advance.
In order to control and develop a hybrid FAS/NRPS biosynthetic pathway, first we must understand the
fundamentals that guides the related biosynthetic machinery. Both FASs and NRPSs are dependent on the
carrier protein (CP); the CP shuttles the growing substrate between multiple partner proteins (PP) for
functionalization and incorporation into the natural product. The modular nature of fatty acid and nonribosomal
peptide biosynthesis is conserved among organisms, however, the mechanism of CP•PP recognition in each
pathway is distinct. Thus, to re-design these biosynthetic assembly lines, this project focuses on studying the
molecular details of the CP•PP interface. We aim to 1) Characterize NRPS CP•PP interactions via X-ray
crystallography, 2) establish a computational methodology to design a hybrid NRPS/FAS interaction, and 3)
explore the cross-pathway productivity of the hybrid NRPS/FAS interaction. The results from these studies will
be integral to the future bioengineering of these modular synthases.
翻译后摘要:天然产物和天然产物的衍生物/模拟物构成了现代的大部分,
由于其独特的复杂的有机支架,有助于其广泛的生物活性,治疗药物。
这些天然产物是由脂肪酸合成酶(FAS),即非核糖体肽合成酶合成的
(NRPS)或聚酮合酶(PKS)。该计划研究蛋白质·蛋白质相互作用在蛋白质中的作用。
负责形成临床相关脂肪酸和非核糖体肽的模块化脂肪酶,
重新设计和完全控制生物合成装配线的长期目标。的示例
临床上的天然产物治疗剂是抗微生物达托霉素,其是由以下合成的脂肽:
一种用于治疗甲氧西林的杂合脂肪酸合成酶(FAS)和非核糖体肽合成酶(NRPS),
耐药金黄色葡萄球菌因此,混合FAS/NRPS是值得研究和控制的系统,
可能使天然产品多样化,具有新的或增强的生物活性。在过去的三十年里,真正控制
生物合成装配线仍然难以捉摸;缺乏对大型生物合成如何进行的基本理解,
合成酶的蛋白质-蛋白质相互作用控制天然产物的生物合成,阻碍了这一有前途的进展。
为了控制和开发杂交FAS/NRPS生物合成途径,首先我们必须了解
指导相关生物合成机制的基本原理。FAS和NRPS都依赖于
载体蛋白(CP); CP在多个伴侣蛋白(PP)之间穿梭生长底物,
功能化和掺入天然产物中。脂肪酸和非核糖体的模块性质
肽的生物合成在生物体中是保守的,然而,CP·PP在每个生物体中的识别机制是不同的。
路是不同的。因此,为了重新设计这些生物合成装配线,本项目重点研究了
CP·PP界面的分子细节。我们的目标是:1)通过X射线表征NRPS CP·PP相互作用
晶体学,2)建立计算方法来设计杂化NRPS/FAS相互作用,以及3)
探索杂合NRPS/FAS相互作用的跨途径生产力。这些研究的结果将
成为这些模块化酶的未来生物工程的组成部分。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Protein-protein interface analysis of the non-ribosomal peptide synthetase peptidyl carrier protein and enzymatic domains.
- DOI:10.1016/j.synbio.2022.02.006
- 发表时间:2022-06
- 期刊:
- 影响因子:4.8
- 作者:Corpuz JC;Sanlley JO;Burkart MD
- 通讯作者:Burkart MD
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Joshua Catungal Corpuz其他文献
Joshua Catungal Corpuz的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 1.99万 - 项目类别:
Fellowship
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 1.99万 - 项目类别:
Continuing Grant
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 1.99万 - 项目类别:
Research Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 1.99万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 1.99万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 1.99万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 1.99万 - 项目类别:
EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 1.99万 - 项目类别:
Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 1.99万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 1.99万 - 项目类别:
Research Grant