In recent years rare Actinobacteria have become increasingly recognised as a rich source of novel bioactive metabolites. Actinomadura are Gram-positive bacteria that occupy a wide range of ecological niches. This review highlights about 230 secondary metabolites produced by Actinomadura spp., reported until the end of 2022, including their bioactivities and selected biosynthetic pathways. Notably, the bioactive compounds produced by Actinomadura spp. demonstrate a wide range of activities, including antimicrobial, antitumor and anticoccidial effects, highlighting their potential in various fields.
覆盖范围:至 2022 年底
{"title":"Chemistry and biology of specialized metabolites produced by Actinomadura","authors":"Yousef Dashti , Jeff Errington","doi":"10.1039/d3np00047h","DOIUrl":"10.1039/d3np00047h","url":null,"abstract":"<div><p>Covering: up to the end of 2022</p></div><div><p>In recent years rare Actinobacteria have become increasingly recognised as a rich source of novel bioactive metabolites. <em>Actinomadura</em> are Gram-positive bacteria that occupy a wide range of ecological niches. This review highlights about 230 secondary metabolites produced by <em>Actinomadura</em> spp., reported until the end of 2022, including their bioactivities and selected biosynthetic pathways. Notably, the bioactive compounds produced by <em>Actinomadura</em> spp. demonstrate a wide range of activities, including antimicrobial, antitumor and anticoccidial effects, highlighting their potential in various fields.</p></div>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":null,"pages":null},"PeriodicalIF":11.9,"publicationDate":"2024-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138681480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Martin Baunach , Arthur Guljamow , María Miguel-Gordo , Elke Dittmann
Covering: 2000 to 2023
Cyanobacteria produce a variety of bioactive natural products that can pose a threat to humans and animals as environmental toxins, but also have potential for or inspire pharmaceutical use. As oxygenic phototrophs, cyanobacteria furthermore hold great promise for sustainable biotechnology. Yet, the necessary tools for exploiting their biotechnological potential have so far been established only for a few model strains of cyanobacteria, while large untapped biosynthetic resources are hidden in slow-growing cyanobacterial genera that are difficult to access by genetic techniques. In recent years, several approaches have been developed to circumvent the bottlenecks in cyanobacterial natural product research. Here, we summarize current progress that has been made in unlocking or characterizing cryptic metabolic pathways using integrated omics techniques, orphan gene cluster activation, use of genetic approaches in original producers, heterologous expression and chemo-enzymatic techniques. We are mainly highlighting genomic mining concepts and strategies towards high-titer production of cyanobacterial natural products from the last 10 years and discuss the need for further research developments in this field.
覆盖范围:2000 年至 2023 年
{"title":"Harnessing the potential: advances in cyanobacterial natural product research and biotechnology†","authors":"Martin Baunach , Arthur Guljamow , María Miguel-Gordo , Elke Dittmann","doi":"10.1039/d3np00045a","DOIUrl":"10.1039/d3np00045a","url":null,"abstract":"<div><p>Covering: 2000 to 2023</p></div><div><p>Cyanobacteria produce a variety of bioactive natural products that can pose a threat to humans and animals as environmental toxins, but also have potential for or inspire pharmaceutical use. As oxygenic phototrophs, cyanobacteria furthermore hold great promise for sustainable biotechnology. Yet, the necessary tools for exploiting their biotechnological potential have so far been established only for a few model strains of cyanobacteria, while large untapped biosynthetic resources are hidden in slow-growing cyanobacterial genera that are difficult to access by genetic techniques. In recent years, several approaches have been developed to circumvent the bottlenecks in cyanobacterial natural product research. Here, we summarize current progress that has been made in unlocking or characterizing cryptic metabolic pathways using integrated omics techniques, orphan gene cluster activation, use of genetic approaches in original producers, heterologous expression and chemo-enzymatic techniques. We are mainly highlighting genomic mining concepts and strategies towards high-titer production of cyanobacterial natural products from the last 10 years and discuss the need for further research developments in this field.</p></div>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":null,"pages":null},"PeriodicalIF":11.9,"publicationDate":"2024-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138581239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Terpene cyclases (TCs) catalyze some of the most complicated reactions in nature and are responsible for creating the skeletons of more than 95 000 terpenoid natural products. The canonical TCs are divided into two classes according to their structures, functions, and mechanisms. The class II TCs mediate acid–base-initiated cyclization reactions of isoprenoid diphosphates, terpenes without diphosphates (e.g., squalene or oxidosqualene), and prenyl moieties on meroterpenes. The past twenty years witnessed the emergence of many class II TCs, their reactions and their roles in biosynthesis. Class II TCs often act as one of the first steps in the biosynthesis of biologically active natural products including the gibberellin family of phytohormones and fungal meroterpenoids. Due to their mechanisms and biocatalytic potential, TCs elicit fervent attention in the biosynthetic and organic communities and provide great enthusiasm for enzyme engineering to construct novel and bioactive molecules. To engineer and expand the structural diversities of terpenoids, it is imperative to fully understand how these enzymes generate, precisely control, and quench the reactive carbocation intermediates. In this review, we summarize class II TCs from nature, including sesquiterpene, diterpene, triterpene, and meroterpenoid cyclases as well as noncanonical class II TCs and inspect their sequences, structures, mechanisms, and structure-guided engineering studies.
覆盖范围:至 2023 年 7 月
{"title":"Class II terpene cyclases: structures, mechanisms, and engineering","authors":"Xingming Pan , Jeffrey D. Rudolf , Liao-Bin Dong","doi":"10.1039/d3np00033h","DOIUrl":"10.1039/d3np00033h","url":null,"abstract":"<div><p>Covering: up to July 2023</p></div><div><p>Terpene cyclases (TCs) catalyze some of the most complicated reactions in nature and are responsible for creating the skeletons of more than 95 000 terpenoid natural products. The canonical TCs are divided into two classes according to their structures, functions, and mechanisms. The class II TCs mediate acid–base-initiated cyclization reactions of isoprenoid diphosphates, terpenes without diphosphates (<em>e.g.</em>, squalene or oxidosqualene), and prenyl moieties on meroterpenes. The past twenty years witnessed the emergence of many class II TCs, their reactions and their roles in biosynthesis. Class II TCs often act as one of the first steps in the biosynthesis of biologically active natural products including the gibberellin family of phytohormones and fungal meroterpenoids. Due to their mechanisms and biocatalytic potential, TCs elicit fervent attention in the biosynthetic and organic communities and provide great enthusiasm for enzyme engineering to construct novel and bioactive molecules. To engineer and expand the structural diversities of terpenoids, it is imperative to fully understand how these enzymes generate, precisely control, and quench the reactive carbocation intermediates. In this review, we summarize class II TCs from nature, including sesquiterpene, diterpene, triterpene, and meroterpenoid cyclases as well as noncanonical class II TCs and inspect their sequences, structures, mechanisms, and structure-guided engineering studies.</p></div>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":null,"pages":null},"PeriodicalIF":11.9,"publicationDate":"2024-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138743634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Fernando Baquero , Konstantinos Beis , David J. Craik , Yanyan Li , A. James Link , Sylvie Rebuffat , Raúl Salomón , Konstantin Severinov , Séverine Zirah , Julian D. Hegemann
Covering: 1992 up to 2023
Since their discovery, lasso peptides went from peculiarities to be recognized as a major family of ribosomally synthesized and post-translationally modified peptide (RiPP) natural products that were shown to be spread throughout the bacterial kingdom. Microcin J25 was first described in 1992, making it one of the earliest known lasso peptides. No other lasso peptide has since then been studied to such an extent as microcin J25, yet, previous review articles merely skimmed over all the research done on this exceptional lasso peptide. Therefore, to commemorate the 30th anniversary of its first report, we give a comprehensive overview of all literature related to microcin J25. This review article spans the early work towards the discovery of microcin J25, its biosynthetic gene cluster, and the elucidation of its three-dimensional, threaded lasso structure. Furthermore, the current knowledge about the biosynthesis of microcin J25 and lasso peptides in general is summarized and a detailed overview is given on the biological activities associated with microcin J25, including means of self-immunity, uptake into target bacteria, inhibition of the Gram-negative RNA polymerase, and the effects of microcin J25 on mitochondria. The in vitro and in vivo models used to study the potential utility of microcin J25 in a (veterinary) medicine context are discussed and the efforts that went into employing the microcin J25 scaffold in bioengineering contexts are summed up.
{"title":"The pearl jubilee of microcin J25: thirty years of research on an exceptional lasso peptide","authors":"Fernando Baquero , Konstantinos Beis , David J. Craik , Yanyan Li , A. James Link , Sylvie Rebuffat , Raúl Salomón , Konstantin Severinov , Séverine Zirah , Julian D. Hegemann","doi":"10.1039/d3np00046j","DOIUrl":"10.1039/d3np00046j","url":null,"abstract":"<div><p>Covering: 1992 up to 2023</p></div><div><p>Since their discovery, lasso peptides went from peculiarities to be recognized as a major family of ribosomally synthesized and post-translationally modified peptide (RiPP) natural products that were shown to be spread throughout the bacterial kingdom. Microcin J25 was first described in 1992, making it one of the earliest known lasso peptides. No other lasso peptide has since then been studied to such an extent as microcin J25, yet, previous review articles merely skimmed over all the research done on this exceptional lasso peptide. Therefore, to commemorate the 30th anniversary of its first report, we give a comprehensive overview of all literature related to microcin J25. This review article spans the early work towards the discovery of microcin J25, its biosynthetic gene cluster, and the elucidation of its three-dimensional, threaded lasso structure. Furthermore, the current knowledge about the biosynthesis of microcin J25 and lasso peptides in general is summarized and a detailed overview is given on the biological activities associated with microcin J25, including means of self-immunity, uptake into target bacteria, inhibition of the Gram-negative RNA polymerase, and the effects of microcin J25 on mitochondria. The <em>in vitro</em> and <em>in vivo</em> models used to study the potential utility of microcin J25 in a (veterinary) medicine context are discussed and the efforts that went into employing the microcin J25 scaffold in bioengineering contexts are summed up.</p></div>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":null,"pages":null},"PeriodicalIF":11.9,"publicationDate":"2024-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139072689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This review presents the exceptional story of ophiobolin A (OphA) and sphaeropsidin A (SphA), a sesterterpene and a diterpene, respectively, which were initially isolated as fungal phytotoxins and subsequently shown to possess other interesting biological activities, including promising anticancer activities. Ophiobolin A is a phytotoxin produced by different fungal pathogens, all belonging to the Bipolaris genus. Initially, it was only known as a very dangerous phytotoxin produced by fungi attacking essential cereals, such as rice and barley. However, extensive and interesting studies were carried out to define its original carbon skeleton, which is characterized by a typical 5 : 8 : 5 ring system and shared with fusicoccins and cotylenins, and its phytotoxic activity on host and non-host plants. The biosynthesis of OphA was also defined by describing the different steps starting from mevalonate and through the rearrangement of the acyclic C-25 precursor lead the toxin is obtained. OphA was also produced as a bioherbicide from Drechslera gigantea and proposed for the biocontrol of the widespread and dangerous weed Digitaria sanguinaria. To date, more than sixty ophiobolins have been isolated from different fungi and their biological activities and structure–activity relationship investigated, which were also described using their hemisynthetic derivatives. In the last two decades, thorough studies have been performed on the potential anticancer activity of OphA and its original mode of action, attracting great interest from scientists. Sphaeropsidin A has a similar story. It was isolated as the main phytotoxin from Diplodia cupressi, the causal agent of Italian cypress canker disease, resulting in the loss of millions of plants in a few years in the Mediterranean basin. The damage to the forest, environment and ornamental heritage are noteworthy and economic losses are also suffered by tree nurseries and the wood industry. Six natural analogues of SphA were isolated and several interesting hemisynthetic derivatives were prepared to study its structure–activity relationship. Surprisingly, sphaeropsidin A showed other interesting biological activities, including antibiotic, antifungal, and antiviral. In the last decade, extensive studies have focused on the anticancer activity and original mode of action of SphA. Furthermore, specific hemisynthetic studies enable the preparation of derivatives of SphA, preserving its chromophore, which showed a noteworthy increase in anticancer activity. It has been demonstrated that ophiobolin A and sphaeropsidin A are promising natural products showing potent activity against some malignant cancers, such as brain glioblastoma and different melanomas.
本综述介绍了ophiobolin A(OphA)和sphaeropsidin A(SphA)的非凡故事,它们分别是一种酯萜和一种二萜,最初作为真菌植物毒素被分离出来,随后被证明具有其他有趣的生物活性,包括有希望的抗癌活性。Ophiobolin A 是一种由不同真菌病原体产生的植物毒素,这些病原体都属于双孢蘑菇属。最初,人们只知道它是由侵袭大米和大麦等重要谷物的真菌产生的一种非常危险的植物毒素。然而,为了确定它的原始碳骨架,人们进行了大量有趣的研究,其特点是典型的 5 : 8 :5 环系统的特点,以及它对寄主植物和非寄主植物的植物毒性活性。通过描述从甲羟戊酸开始的不同步骤,以及通过无环 C-25 前体的重排获得毒素的过程,还对 OphA 的生物合成进行了定义。OphA 还作为一种生物除草剂从 Drechslera gigantea 中生产出来,并建议用于对广泛分布的危险杂草 Digitaria sanguinaria 进行生物防治。迄今为止,已从不同真菌中分离出六十多种ophiobolins,并对其生物活性和结构-活性关系进行了研究,还利用其半合成衍生物对其进行了描述。近二十年来,人们对 OphA 的潜在抗癌活性及其原始作用模式进行了深入研究,引起了科学家们的极大兴趣。Sphaeropsidin A 也有类似的故事。它是从意大利柏树腐烂病的病原体 Diplodia cupressi 中分离出来的主要植物毒素,导致地中海盆地在几年内损失了数百万株植物。对森林、环境和观赏遗产造成的破坏值得注意,苗圃和木材工业也蒙受了经济损失。为了研究 SphA 的结构-活性关系,我们分离了六种 SphA 天然类似物,并制备了几种有趣的半合成衍生物。令人惊讶的是,Sphaeropsidin A 还具有其他有趣的生物活性,包括抗生素、抗真菌和抗病毒。近十年来,人们对 SphA 的抗癌活性和原始作用模式进行了广泛的研究。此外,通过特定的半合成研究,可以制备出 SphA 的衍生物,但保留了其发色团,从而显著提高了抗癌活性。研究表明,ophiobolin A 和 sphaeropsidin A 是很有前途的天然产品,对一些恶性癌症,如脑胶质母细胞瘤和不同的黑色素瘤有很强的抗癌活性。
{"title":"The incredible story of ophiobolin A and sphaeropsidin A: two fungal terpenes from wilt-inducing phytotoxins to promising anticancer compounds†‡","authors":"Antonio Evidente","doi":"10.1039/d3np00035d","DOIUrl":"10.1039/d3np00035d","url":null,"abstract":"<div><p>Covering: 2000 to 2023</p></div><div><p>This review presents the exceptional story of ophiobolin A (OphA) and sphaeropsidin A (SphA), a sesterterpene and a diterpene, respectively, which were initially isolated as fungal phytotoxins and subsequently shown to possess other interesting biological activities, including promising anticancer activities. Ophiobolin A is a phytotoxin produced by different fungal pathogens, all belonging to the <em>Bipolaris</em> genus. Initially, it was only known as a very dangerous phytotoxin produced by fungi attacking essential cereals, such as rice and barley. However, extensive and interesting studies were carried out to define its original carbon skeleton, which is characterized by a typical 5 : 8 : 5 ring system and shared with fusicoccins and cotylenins, and its phytotoxic activity on host and non-host plants. The biosynthesis of OphA was also defined by describing the different steps starting from mevalonate and through the rearrangement of the acyclic C-25 precursor lead the toxin is obtained. OphA was also produced as a bioherbicide from <em>Drechslera gigantea</em> and proposed for the biocontrol of the widespread and dangerous weed <em>Digitaria sanguinaria</em>. To date, more than sixty ophiobolins have been isolated from different fungi and their biological activities and structure–activity relationship investigated, which were also described using their hemisynthetic derivatives. In the last two decades, thorough studies have been performed on the potential anticancer activity of OphA and its original mode of action, attracting great interest from scientists. Sphaeropsidin A has a similar story. It was isolated as the main phytotoxin from <em>Diplodia cupressi</em>, the causal agent of Italian cypress canker disease, resulting in the loss of millions of plants in a few years in the Mediterranean basin. The damage to the forest, environment and ornamental heritage are noteworthy and economic losses are also suffered by tree nurseries and the wood industry. Six natural analogues of SphA were isolated and several interesting hemisynthetic derivatives were prepared to study its structure–activity relationship. Surprisingly, sphaeropsidin A showed other interesting biological activities, including antibiotic, antifungal, and antiviral. In the last decade, extensive studies have focused on the anticancer activity and original mode of action of SphA. Furthermore, specific hemisynthetic studies enable the preparation of derivatives of SphA, preserving its chromophore, which showed a noteworthy increase in anticancer activity. It has been demonstrated that ophiobolin A and sphaeropsidin A are promising natural products showing potent activity against some malignant cancers, such as brain glioblastoma and different melanomas.</p></div>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":null,"pages":null},"PeriodicalIF":11.9,"publicationDate":"2024-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138827258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Covering: up to the end of 2023Type I modular polyketide synthases construct polyketide natural products in an assembly line-like fashion, where the growing polyketide chain attached to an acyl carrier protein is passed from catalytic domain to catalytic domain. These enzymes have immense potential in drug development since they can be engineered to produce non-natural polyketides by strategically adding, exchanging, and deleting individual catalytic domains. In practice, however, this approach frequently results in complete failures or dramatically reduced product yields. A comprehensive understanding of modular polyketide synthase architecture is expected to resolve these issues. We summarize the three-dimensional structures and the proposed mechanisms of three full-length modular polyketide synthases, Lsd14, DEBS module 1, and PikAIII. We also describe the advantages and limitations of using X-ray crystallography, cryo-electron microscopy, and AlphaFold2 to study intact type I polyketide synthases.
覆盖范围:截至 2023 年底I 型模块化多酮合成酶以类似流水线的方式构建多酮天然产物,其中附着在酰基载体蛋白上的不断生长的多酮链从一个催化结构域传递到另一个催化结构域。这些酶在药物开发方面具有巨大的潜力,因为它们可以通过战略性地添加、交换和删除单个催化结构域来生产非天然的多酮苷。但在实践中,这种方法经常会导致完全失败或产品产量急剧下降。全面了解模块化聚酮酸酯合成酶的结构有望解决这些问题。我们总结了三种全长模块化聚酮酸酯合成酶 Lsd14、DEBS 模块 1 和 PikAIII 的三维结构和拟议机制。我们还介绍了使用 X 射线晶体学、冷冻电镜和 AlphaFold2 研究完整的 I 型多酮苷合成酶的优势和局限性。
{"title":"Architecture of full-length type I modular polyketide synthases revealed by X-ray crystallography, cryo-electron microscopy, and AlphaFold2.","authors":"Saket R Bagde, Chu-Young Kim","doi":"10.1039/d3np00060e","DOIUrl":"10.1039/d3np00060e","url":null,"abstract":"<p><p>Covering: up to the end of 2023Type I modular polyketide synthases construct polyketide natural products in an assembly line-like fashion, where the growing polyketide chain attached to an acyl carrier protein is passed from catalytic domain to catalytic domain. These enzymes have immense potential in drug development since they can be engineered to produce non-natural polyketides by strategically adding, exchanging, and deleting individual catalytic domains. In practice, however, this approach frequently results in complete failures or dramatically reduced product yields. A comprehensive understanding of modular polyketide synthase architecture is expected to resolve these issues. We summarize the three-dimensional structures and the proposed mechanisms of three full-length modular polyketide synthases, Lsd14, DEBS module 1, and PikAIII. We also describe the advantages and limitations of using X-ray crystallography, cryo-electron microscopy, and AlphaFold2 to study intact type I polyketide synthases.</p>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":null,"pages":null},"PeriodicalIF":11.9,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140157126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Covering: 1997 to July 2023The adenylation reaction has been a subject of scientific intrigue since it was first recognized as essential to many biological processes, including the homeostasis and pathogenicity of some bacteria and the activation of amino acids for protein synthesis in mammals. Several foundational studies on adenylation (A) domains have facilitated an improved understanding of their molecular structures and biochemical properties, in particular work on nonribosomal peptide synthetases (NRPSs). In NRPS pathways, A domains activate their respective acyl substrates for incorporation into a growing peptidyl chain, and many nonribosomal peptides are bioactive. From a natural product drug discovery perspective, improving existing bioinformatics platforms to predict unique NRPS products more accurately from genomic data is desirable. Here, we summarize characterization efforts of A domains primarily from NRPS pathways from July 1997 up to July 2023, covering protein structure elucidation, in vitro assay development, and in silico tools for improved predictions.
{"title":"Structural, biochemical and bioinformatic analyses of nonribosomal peptide synthetase adenylation domains.","authors":"Stephanie C Heard, Jaclyn M Winter","doi":"10.1039/d3np00064h","DOIUrl":"https://doi.org/10.1039/d3np00064h","url":null,"abstract":"<p><p>Covering: 1997 to July 2023The adenylation reaction has been a subject of scientific intrigue since it was first recognized as essential to many biological processes, including the homeostasis and pathogenicity of some bacteria and the activation of amino acids for protein synthesis in mammals. Several foundational studies on adenylation (A) domains have facilitated an improved understanding of their molecular structures and biochemical properties, in particular work on nonribosomal peptide synthetases (NRPSs). In NRPS pathways, A domains activate their respective acyl substrates for incorporation into a growing peptidyl chain, and many nonribosomal peptides are bioactive. From a natural product drug discovery perspective, improving existing bioinformatics platforms to predict unique NRPS products more accurately from genomic data is desirable. Here, we summarize characterization efforts of A domains primarily from NRPS pathways from July 1997 up to July 2023, covering protein structure elucidation, <i>in vitro</i> assay development, and <i>in silico</i> tools for improved predictions.</p>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":null,"pages":null},"PeriodicalIF":11.9,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140130216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Covering: up to the end of 2023Cephalotane diterpenoids are a unique class of natural products exclusive to the genus Cephalotaxus, featuring a rigid 7,6,5,6-fused tetracyclic architecture. The study of cephalotanes dates back to the 1970s, when harringtonolide (1), a Cephalotaxus troponoid with a peculiar norditerpenoid carbon skeleton, was first discovered. In recent years, prototype C20 diterpenoids proposed as cephalotane were disclosed, which triggered intense studies on this diterpenoid family. To date, a cumulative total of 105 cephalotane diterpenoids with great structural diversity and biological importance have been isolated. In addition, significant advances have been made in the field of total synthesis and biosynthesis of cephalotanes in recent years. This review provides a complete overview of the chemical structures, bioactivities, biosynthetic aspects, and completed total synthesis of all the isolated cephalotane diterpenoids, which will help guide future research on this class of compounds.
{"title":"Cephalotane diterpenoids: structural diversity, biological activity, biosynthetic proposal, and chemical synthesis.","authors":"Jin-Xin Zhao, Zhan-Peng Ge, Jian-Min Yue","doi":"10.1039/d3np00067b","DOIUrl":"https://doi.org/10.1039/d3np00067b","url":null,"abstract":"<p><p>Covering: up to the end of 2023Cephalotane diterpenoids are a unique class of natural products exclusive to the genus <i>Cephalotaxus</i>, featuring a rigid 7,6,5,6-fused tetracyclic architecture. The study of cephalotanes dates back to the 1970s, when harringtonolide (1), a <i>Cephalotaxus</i> troponoid with a peculiar norditerpenoid carbon skeleton, was first discovered. In recent years, prototype C<sub>20</sub> diterpenoids proposed as cephalotane were disclosed, which triggered intense studies on this diterpenoid family. To date, a cumulative total of 105 cephalotane diterpenoids with great structural diversity and biological importance have been isolated. In addition, significant advances have been made in the field of total synthesis and biosynthesis of cephalotanes in recent years. This review provides a complete overview of the chemical structures, bioactivities, biosynthetic aspects, and completed total synthesis of all the isolated cephalotane diterpenoids, which will help guide future research on this class of compounds.</p>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":null,"pages":null},"PeriodicalIF":11.9,"publicationDate":"2024-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140118133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hanne Put, Hans Gerstmans, Hanne Vande Capelle, Maarten Fauvart, Jan Michiels, Joleen Masschelein
Covering: up to October 2023Many bioactive natural products are synthesized by microorganisms that are either difficult or impossible to cultivate under laboratory conditions, or that produce only small amounts of the desired compound. By transferring biosynthetic gene clusters (BGCs) into alternative host organisms that are more easily cultured and engineered, larger quantities can be obtained and new analogues with potentially improved biological activity or other desirable properties can be generated. Moreover, expression of cryptic BGCs in a suitable host can facilitate the identification and characterization of novel natural products. Heterologous expression therefore represents a valuable tool for natural product discovery and engineering as it allows the study and manipulation of their biosynthetic pathways in a controlled setting, enabling innovative applications. Bacillus is a genus of Gram-positive bacteria that is widely used in industrial biotechnology as a host for the production of proteins from diverse origins, including enzymes and vaccines. However, despite numerous successful examples, Bacillus species remain underexploited as heterologous hosts for the expression of natural product BGCs. Here, we review important advantages that Bacillus species offer as expression hosts, such as high secretion capacity, natural competence for DNA uptake, and the increasing availability of a wide range of genetic tools for gene expression and strain engineering. We evaluate different strain optimization strategies and other critical factors that have improved the success and efficiency of heterologous natural product biosynthesis in B. subtilis. Finally, future perspectives for using B. subtilis as a heterologous host are discussed, identifying research gaps and promising areas that require further exploration.
{"title":"<i>Bacillus subtilis</i> as a host for natural product discovery and engineering of biosynthetic gene clusters.","authors":"Hanne Put, Hans Gerstmans, Hanne Vande Capelle, Maarten Fauvart, Jan Michiels, Joleen Masschelein","doi":"10.1039/d3np00065f","DOIUrl":"https://doi.org/10.1039/d3np00065f","url":null,"abstract":"<p><p>Covering: up to October 2023Many bioactive natural products are synthesized by microorganisms that are either difficult or impossible to cultivate under laboratory conditions, or that produce only small amounts of the desired compound. By transferring biosynthetic gene clusters (BGCs) into alternative host organisms that are more easily cultured and engineered, larger quantities can be obtained and new analogues with potentially improved biological activity or other desirable properties can be generated. Moreover, expression of cryptic BGCs in a suitable host can facilitate the identification and characterization of novel natural products. Heterologous expression therefore represents a valuable tool for natural product discovery and engineering as it allows the study and manipulation of their biosynthetic pathways in a controlled setting, enabling innovative applications. <i>Bacillus</i> is a genus of Gram-positive bacteria that is widely used in industrial biotechnology as a host for the production of proteins from diverse origins, including enzymes and vaccines. However, despite numerous successful examples, <i>Bacillus</i> species remain underexploited as heterologous hosts for the expression of natural product BGCs. Here, we review important advantages that <i>Bacillus</i> species offer as expression hosts, such as high secretion capacity, natural competence for DNA uptake, and the increasing availability of a wide range of genetic tools for gene expression and strain engineering. We evaluate different strain optimization strategies and other critical factors that have improved the success and efficiency of heterologous natural product biosynthesis in <i>B. subtilis</i>. Finally, future perspectives for using <i>B. subtilis</i> as a heterologous host are discussed, identifying research gaps and promising areas that require further exploration.</p>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":null,"pages":null},"PeriodicalIF":11.9,"publicationDate":"2024-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140092931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Covering: 2016 to mid 2023Transition metal catalysis, known for its remarkable capacity to expedite the assembly of molecular complexity from readily available starting materials in a single operation, occupies a central position in contemporary chemical synthesis. Within this landscape, gold-catalyzed reactions present a novel and versatile paradigm, offering robust frameworks for accessing diverse structural motifs. In this review, we highlighted a curated selection of publications in the past 8 years, focusing on the deployment of homogeneous gold catalysis in the ring-forming step for the total synthesis of natural products. These investigations are categorized based on the specific ring formations they engender, accentuating the prevailing gold-catalyzed methodologies applied to surmount intricate challenges in natural products synthesis.
{"title":"Gold-catalyzed cyclization and cycloaddition in natural product synthesis.","authors":"Boxu Lin, Tianran Liu, Tuoping Luo","doi":"10.1039/d3np00056g","DOIUrl":"https://doi.org/10.1039/d3np00056g","url":null,"abstract":"<p><p>Covering: 2016 to mid 2023Transition metal catalysis, known for its remarkable capacity to expedite the assembly of molecular complexity from readily available starting materials in a single operation, occupies a central position in contemporary chemical synthesis. Within this landscape, gold-catalyzed reactions present a novel and versatile paradigm, offering robust frameworks for accessing diverse structural motifs. In this review, we highlighted a curated selection of publications in the past 8 years, focusing on the deployment of homogeneous gold catalysis in the ring-forming step for the total synthesis of natural products. These investigations are categorized based on the specific ring formations they engender, accentuating the prevailing gold-catalyzed methodologies applied to surmount intricate challenges in natural products synthesis.</p>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":null,"pages":null},"PeriodicalIF":11.9,"publicationDate":"2024-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140058157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}