{"title":"Lichens are a treasure chest of bioactive compounds: fact or fake?","authors":"Anna Pasinato, Garima Singh","doi":"10.1111/nph.70034","DOIUrl":null,"url":null,"abstract":"<p>Lichenized fungi are regarded as a treasure chest of natural products. This idea stems from the variety of metabolites detected in the extracts of a single lichen (Türk <i>et al</i>., <span>2006</span>; Le Pogam <i>et al</i>., <span>2016a</span>,<span>b</span>; Singh <i>et al</i>., <span>2022</span>). However, the notion that lichens are a treasure chest of secondary metabolites as compared to the non-lichenized fungi (nLFF) has never been systematically tested.</p><p>Lichens are symbiotic associations consisting of a fungal partner in an obligate symbiotic association with one or more photosynthetic partners, such as algae, cyanobacteria, or both (Honegger, <span>1998</span>, <span>2023</span>; DePriest, <span>2004</span>; Grube, <span>2024</span>). Over time, their definition has expanded to include the associated microbiota, such as yeasts, bacteria, and other life forms, collectively forming the lichen holobiont (Hawksworth & Grube, <span>2020</span>; Allen & Lendemer, <span>2022</span>; Cometto <i>et al</i>., <span>2022</span>; Lücking & Spribille, <span>2024</span>).</p><p>Overall, <i>c</i>. 1000 metabolites have been characterized from lichens, many of which are bioactive (Huneck & Schreiber, <span>1972</span>; Huneck & Yoshimura, <span>1996a</span>,<span>b</span>; Boustie & Grube, <span>2005</span>; Ranković, <span>2015</span>; Emsen <i>et al</i>., <span>2017</span>; Calcott <i>et al</i>., <span>2018</span>). While initially whole lichen extracts were tested for bioactivity, recent studies have focused on isolating individual lichen metabolites and evaluating their bioactivity (Ebrahim <i>et al</i>., <span>2016</span>; Ranković & Kosanić, <span>2019</span>; Ingelfinger <i>et al</i>., <span>2020</span>; Poulsen-Silva <i>et al</i>., <span>2025</span>). Furthermore, a recent review article highlighted that fine-scale analyses, such as mass spectrometry, reveal a plethora of unidentified metabolites (Singh <i>et al</i>., <span>2025</span>).</p><p>Comparing the metabolic potential of fungi can be challenging as the secreted metabolome of organisms depends on the combination of biotic and abiotic factors, as well as life-stage-dependent cues. Secondary metabolites are secreted by a set of dedicated genes called biosynthetic genes, organized in a collinear fashion, resulting in metabolic or biosynthetic gene clusters (BGCs) (Firn & Jones, <span>2000</span>; Keller <i>et al</i>., <span>2005</span>; Devashree <i>et al</i>., <span>2021</span>). Depending on the structure of the metabolite coded, BGCs can be classified as polyketide synthase (PKS), nonribosomal peptide synthetase (NRPS), terpene, or ribosomally synthesized and post-translationally modified peptides (RiPP) cluster (Arnison <i>et al</i>., <span>2013</span>; Helaly <i>et al</i>., <span>2018</span>; Gill <i>et al</i>., <span>2023</span>). These clusters constitute the majority of the BGC landscape of organisms, and a minor portion is also contributed by indoles, isocyanide synthase, and PKS–NRPS hybrid clusters (Nickles <i>et al</i>., <span>2023</span>). The same fungi, under different life stages and in reaction to different cues, activate different sets of metabolic genes (Keller, <span>2019</span>). Consequently, organisms possess a broader chemical potential than evident in the secreted metabolome at a particular time (Machado <i>et al</i>., <span>2017</span>; Calcott <i>et al</i>., <span>2018</span>; Gavriilidou <i>et al</i>., <span>2022</span>). Furthermore, studies show that silent BGCs can be activated, leading to the production of metabolites. These facts imply that BGC content is a better indicator of the metabolic potential of fungi. (Fujii <i>et al</i>., <span>1996</span>; Bok <i>et al</i>., <span>2006</span>; Guo & Wang, <span>2014</span>; Chen <i>et al</i>., <span>2017</span>; Miethke <i>et al</i>., <span>2021</span>; Navarro-Muñoz & Collemare, <span>2022</span>).</p><p>Here, we assess whether lichens are a treasure trove of natural products using the total number of BGCs as a proxy for their biochemical potential and comparing this metric between LFF and nLFF. Additionally, we investigate whether certain BGC classes are specifically enriched in either group.</p><p>In this study, we test whether LFF are a treasure chest of natural products, by mining the genomes of LFF and nLFF in Pezizomycotina (Ascomycota). We used BGC count as a proxy for biosynthetic potential.</p><p>We found that LFF possess a significantly higher number of BGCs than nLFF, providing statistical evidence to support this long-standing concept. Interestingly, while the total number of BGCs is generally higher in LFF than in nLFF, this effect is primarily driven by the PKS clusters. This is consistent with the remarkable diversity of PKS metabolites produced by LFF (Boustie & Grube, <span>2005</span>; Goga <i>et al</i>., <span>2018</span>). Conversely, nLFF genomes contain a higher number of NRPS and PKS–NRPS hybrid BGCs. Since the primary distinction between these two groups is that LFF exist in an obligate symbiotic association with algae, it is compelling to suggest that the long-term evolutionary relationship with algae may have driven the expansion of metabolism-related gene families in LFF.</p><p>A recent study investigating major evolutionary changes between fungi and animals revealed expansions in carbohydrate and secondary metabolism-related gene families in fungi (Ocaña-Pallarès <i>et al</i>., <span>2022</span>), underscoring the fundamental role of secondary metabolism in fungal evolution. This expansion of genes families related to secondary metabolism is especially pronounced in symbiotic fungi, such as in LFF, where complex associations seem to have driven further diversification of metabolic pathways. Notably, the lichenized lifestyle involves several steps that require an interplay of metabolic interactions between symbionts – for instance, lichenization (reformation of the symbiotic association between the LFF and the photobiont) itself comprises various steps including partner recognition and contact establishment (Pichler <i>et al</i>., <span>2023</span>). It is thus reasonable to infer that organisms involved in complex relationships evolve a sophisticated array of mechanisms to enable metabolic cross talk between symbionts.</p><p>Experimental evidence reinforces this effect as coculturing fungi with other microorganisms activates numerous BGCs, including even the silent ones (Wang <i>et al</i>., <span>2023</span>; Xu <i>et al</i>., <span>2023</span>). For example, in experiments involving <i>Heterobasidion annosum</i>, <i>Gloeophyllum sepiarium</i>, and <i>Armillaria ostoyae</i> (Xu <i>et al</i>., <span>2023</span>), the presence of other fungi triggered an increase of up to 400-fold in secondary metabolite production, underscoring how biotic interactions can enhance metabolic output in fungi. Similarly, cocultivating <i>Aspergillus nidulans</i> with a collection of soil bacteria activated secondary metabolism genes in the fungus (Schroeckh <i>et al</i>., <span>2009</span>). This study showed that intimate physical interaction between the bacterial and fungal mycelia was essential for eliciting the response. Interestingly, one of the BGCs activated by the cocultivation codes for the polyketide orsellinic acid, which is similar to, or an intermediate of, the metabolite lecanoric acid, secreted by several LFF. This further suggests that the long evolutionary relationship between bacteria, algae, and fungi may have contributed to the high metabolic potential observed in LFF. Furthermore, the metabolic profile of mycobiont grown in isolation is different from that of the lichen (Cordeiro <i>et al</i>., <span>2004</span>; Alors <i>et al</i>., <span>2023</span>), highlighting the influence of biotic associations on the secondary metabolite profile of lichens.</p><p>Furthermore, several recent studies suggest that lichens are complex ecosystems hosting a plethora of other organisms, including yeast and bacteria (Grube & Spribille, <span>2012</span>; Spribille <i>et al</i>., <span>2016</span>; Allen & Lendemer, <span>2022</span>; Cometto <i>et al</i>., <span>2022</span>). Although we do not currently know the levels of interdependence and specificity of some of the organisms in lichen thalli, these associations may have served as an evolutionary engine for metabolite diversification, enriching the metabolic ‘treasure’ of lichens. In fact, variations in lichen metabolite profiles appear to be influenced by the algal partner, with distinct BGCs activated when associating with different alga (Farkas <i>et al</i>., <span>2024</span>). This suggests that the algal partner plays a role in shaping the metabolic profile of LFF.</p><p>Beyond the role of symbiosis, lichens exhibit an extraordinary adaptability to diverse ecological niches, from arctic tundras to desert landscapes. This ecological success, in some cases, could be due to their ability to switch between different algal partners (e.g. Dal Grande <i>et al</i>., <span>2017</span>), but recent evidence suggests that chemical diversity also plays a critical role (Schweiger <i>et al</i>., <span>2022</span>). Studies on <i>Umbilicaria</i> have shown climate-driven BGC variation, indicating that environmental conditions can act as triggers for unique biosynthetic outputs (Singh <i>et al</i>., <span>2021</span>).</p><p>Despite the high biosynthetic potential of LFF, the pharmaceutical utilization of their metabolites is negligible due to the complex lifestyle, which presents significant challenges for metabolite production under controlled conditions. For instance, the slow growth rates of LFF in culture may place them at a disadvantage compared to nLFF when it comes to producing useful metabolites <i>in vitro</i>. However, these obstacles may soon be overcome, as several protocols for the successful culturing of LFF and the heterologous expression of their metabolites are already available (Kealey <i>et al</i>., <span>2021</span>; Kim <i>et al</i>., <span>2021</span>; Singh, <span>2023</span>; Rosabal & Pino-Bodas, <span>2024</span>).</p><p>In conclusion, we demonstrate the higher biosynthetic potential of LFF as compared to nLFF and propose that the remarkable biosynthetic diversity observed in lichens arises from a combination of intricate biotic interactions and exceptional ecological adaptability. Specifically, the symbiotic relationship between the fungus and its algal partner, along with interactions with other microbial inhabitants within the lichen thallus, creates a dynamic metabolic environment. This environment may have driven the evolution of metabolic versatility in these organisms, making them a treasure chest of bioactive metabolites. Given these factors, we advocate for the utility of coculturing studies to activate silent BGCs in lichens. Since the enrichment of BGCs in LFF is primarily driven by PKS clusters, future studies should focus on comparing the evolutionary history of PKS clusters between LFF and nLFF.</p><p>None declared.</p><p>GS planned and designed the research. GS and AP gathered and analyzed data. GS and AP wrote the manuscript. Both authors have read and approved the final version of the manuscript.</p><p>The New Phytologist Foundation remains neutral with regard to jurisdictional claims in maps and in any institutional affiliations.</p>","PeriodicalId":214,"journal":{"name":"New Phytologist","volume":"246 2","pages":"389-395"},"PeriodicalIF":8.1000,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11923404/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"New Phytologist","FirstCategoryId":"99","ListUrlMain":"https://nph.onlinelibrary.wiley.com/doi/10.1111/nph.70034","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PLANT SCIENCES","Score":null,"Total":0}
引用次数: 0
Abstract
Lichenized fungi are regarded as a treasure chest of natural products. This idea stems from the variety of metabolites detected in the extracts of a single lichen (Türk et al., 2006; Le Pogam et al., 2016a,b; Singh et al., 2022). However, the notion that lichens are a treasure chest of secondary metabolites as compared to the non-lichenized fungi (nLFF) has never been systematically tested.
Lichens are symbiotic associations consisting of a fungal partner in an obligate symbiotic association with one or more photosynthetic partners, such as algae, cyanobacteria, or both (Honegger, 1998, 2023; DePriest, 2004; Grube, 2024). Over time, their definition has expanded to include the associated microbiota, such as yeasts, bacteria, and other life forms, collectively forming the lichen holobiont (Hawksworth & Grube, 2020; Allen & Lendemer, 2022; Cometto et al., 2022; Lücking & Spribille, 2024).
Overall, c. 1000 metabolites have been characterized from lichens, many of which are bioactive (Huneck & Schreiber, 1972; Huneck & Yoshimura, 1996a,b; Boustie & Grube, 2005; Ranković, 2015; Emsen et al., 2017; Calcott et al., 2018). While initially whole lichen extracts were tested for bioactivity, recent studies have focused on isolating individual lichen metabolites and evaluating their bioactivity (Ebrahim et al., 2016; Ranković & Kosanić, 2019; Ingelfinger et al., 2020; Poulsen-Silva et al., 2025). Furthermore, a recent review article highlighted that fine-scale analyses, such as mass spectrometry, reveal a plethora of unidentified metabolites (Singh et al., 2025).
Comparing the metabolic potential of fungi can be challenging as the secreted metabolome of organisms depends on the combination of biotic and abiotic factors, as well as life-stage-dependent cues. Secondary metabolites are secreted by a set of dedicated genes called biosynthetic genes, organized in a collinear fashion, resulting in metabolic or biosynthetic gene clusters (BGCs) (Firn & Jones, 2000; Keller et al., 2005; Devashree et al., 2021). Depending on the structure of the metabolite coded, BGCs can be classified as polyketide synthase (PKS), nonribosomal peptide synthetase (NRPS), terpene, or ribosomally synthesized and post-translationally modified peptides (RiPP) cluster (Arnison et al., 2013; Helaly et al., 2018; Gill et al., 2023). These clusters constitute the majority of the BGC landscape of organisms, and a minor portion is also contributed by indoles, isocyanide synthase, and PKS–NRPS hybrid clusters (Nickles et al., 2023). The same fungi, under different life stages and in reaction to different cues, activate different sets of metabolic genes (Keller, 2019). Consequently, organisms possess a broader chemical potential than evident in the secreted metabolome at a particular time (Machado et al., 2017; Calcott et al., 2018; Gavriilidou et al., 2022). Furthermore, studies show that silent BGCs can be activated, leading to the production of metabolites. These facts imply that BGC content is a better indicator of the metabolic potential of fungi. (Fujii et al., 1996; Bok et al., 2006; Guo & Wang, 2014; Chen et al., 2017; Miethke et al., 2021; Navarro-Muñoz & Collemare, 2022).
Here, we assess whether lichens are a treasure trove of natural products using the total number of BGCs as a proxy for their biochemical potential and comparing this metric between LFF and nLFF. Additionally, we investigate whether certain BGC classes are specifically enriched in either group.
In this study, we test whether LFF are a treasure chest of natural products, by mining the genomes of LFF and nLFF in Pezizomycotina (Ascomycota). We used BGC count as a proxy for biosynthetic potential.
We found that LFF possess a significantly higher number of BGCs than nLFF, providing statistical evidence to support this long-standing concept. Interestingly, while the total number of BGCs is generally higher in LFF than in nLFF, this effect is primarily driven by the PKS clusters. This is consistent with the remarkable diversity of PKS metabolites produced by LFF (Boustie & Grube, 2005; Goga et al., 2018). Conversely, nLFF genomes contain a higher number of NRPS and PKS–NRPS hybrid BGCs. Since the primary distinction between these two groups is that LFF exist in an obligate symbiotic association with algae, it is compelling to suggest that the long-term evolutionary relationship with algae may have driven the expansion of metabolism-related gene families in LFF.
A recent study investigating major evolutionary changes between fungi and animals revealed expansions in carbohydrate and secondary metabolism-related gene families in fungi (Ocaña-Pallarès et al., 2022), underscoring the fundamental role of secondary metabolism in fungal evolution. This expansion of genes families related to secondary metabolism is especially pronounced in symbiotic fungi, such as in LFF, where complex associations seem to have driven further diversification of metabolic pathways. Notably, the lichenized lifestyle involves several steps that require an interplay of metabolic interactions between symbionts – for instance, lichenization (reformation of the symbiotic association between the LFF and the photobiont) itself comprises various steps including partner recognition and contact establishment (Pichler et al., 2023). It is thus reasonable to infer that organisms involved in complex relationships evolve a sophisticated array of mechanisms to enable metabolic cross talk between symbionts.
Experimental evidence reinforces this effect as coculturing fungi with other microorganisms activates numerous BGCs, including even the silent ones (Wang et al., 2023; Xu et al., 2023). For example, in experiments involving Heterobasidion annosum, Gloeophyllum sepiarium, and Armillaria ostoyae (Xu et al., 2023), the presence of other fungi triggered an increase of up to 400-fold in secondary metabolite production, underscoring how biotic interactions can enhance metabolic output in fungi. Similarly, cocultivating Aspergillus nidulans with a collection of soil bacteria activated secondary metabolism genes in the fungus (Schroeckh et al., 2009). This study showed that intimate physical interaction between the bacterial and fungal mycelia was essential for eliciting the response. Interestingly, one of the BGCs activated by the cocultivation codes for the polyketide orsellinic acid, which is similar to, or an intermediate of, the metabolite lecanoric acid, secreted by several LFF. This further suggests that the long evolutionary relationship between bacteria, algae, and fungi may have contributed to the high metabolic potential observed in LFF. Furthermore, the metabolic profile of mycobiont grown in isolation is different from that of the lichen (Cordeiro et al., 2004; Alors et al., 2023), highlighting the influence of biotic associations on the secondary metabolite profile of lichens.
Furthermore, several recent studies suggest that lichens are complex ecosystems hosting a plethora of other organisms, including yeast and bacteria (Grube & Spribille, 2012; Spribille et al., 2016; Allen & Lendemer, 2022; Cometto et al., 2022). Although we do not currently know the levels of interdependence and specificity of some of the organisms in lichen thalli, these associations may have served as an evolutionary engine for metabolite diversification, enriching the metabolic ‘treasure’ of lichens. In fact, variations in lichen metabolite profiles appear to be influenced by the algal partner, with distinct BGCs activated when associating with different alga (Farkas et al., 2024). This suggests that the algal partner plays a role in shaping the metabolic profile of LFF.
Beyond the role of symbiosis, lichens exhibit an extraordinary adaptability to diverse ecological niches, from arctic tundras to desert landscapes. This ecological success, in some cases, could be due to their ability to switch between different algal partners (e.g. Dal Grande et al., 2017), but recent evidence suggests that chemical diversity also plays a critical role (Schweiger et al., 2022). Studies on Umbilicaria have shown climate-driven BGC variation, indicating that environmental conditions can act as triggers for unique biosynthetic outputs (Singh et al., 2021).
Despite the high biosynthetic potential of LFF, the pharmaceutical utilization of their metabolites is negligible due to the complex lifestyle, which presents significant challenges for metabolite production under controlled conditions. For instance, the slow growth rates of LFF in culture may place them at a disadvantage compared to nLFF when it comes to producing useful metabolites in vitro. However, these obstacles may soon be overcome, as several protocols for the successful culturing of LFF and the heterologous expression of their metabolites are already available (Kealey et al., 2021; Kim et al., 2021; Singh, 2023; Rosabal & Pino-Bodas, 2024).
In conclusion, we demonstrate the higher biosynthetic potential of LFF as compared to nLFF and propose that the remarkable biosynthetic diversity observed in lichens arises from a combination of intricate biotic interactions and exceptional ecological adaptability. Specifically, the symbiotic relationship between the fungus and its algal partner, along with interactions with other microbial inhabitants within the lichen thallus, creates a dynamic metabolic environment. This environment may have driven the evolution of metabolic versatility in these organisms, making them a treasure chest of bioactive metabolites. Given these factors, we advocate for the utility of coculturing studies to activate silent BGCs in lichens. Since the enrichment of BGCs in LFF is primarily driven by PKS clusters, future studies should focus on comparing the evolutionary history of PKS clusters between LFF and nLFF.
None declared.
GS planned and designed the research. GS and AP gathered and analyzed data. GS and AP wrote the manuscript. Both authors have read and approved the final version of the manuscript.
The New Phytologist Foundation remains neutral with regard to jurisdictional claims in maps and in any institutional affiliations.
地衣真菌被认为是天然产物的宝库。这一想法源于在单一地衣提取物中检测到的各种代谢物(t<e:1> rk等人,2006;Le Pogam等,2016a,b;Singh et al., 2022)。然而,与非地衣化真菌(nLFF)相比,地衣是次生代谢物的宝库这一概念从未得到系统的验证。地衣是一种共生关系,由一个真菌伙伴与一个或多个光合伙伴(如藻类、蓝藻,或两者兼而有之)的特定共生关系组成(Honegger, 1998,2023;DePriest, 2004;他还,2024)。随着时间的推移,它们的定义已经扩展到包括相关的微生物群,如酵母、细菌和其他生命形式,共同形成地衣全息生物(Hawksworth &;他还,2020;艾伦,Lendemer, 2022;Cometto等人,2022;高年级队,Spribille, 2024)。总的来说,大约1000种代谢物已经从地衣中被鉴定出来,其中许多是生物活性的(Huneck &;以下,1972;Huneck,Yoshimura, 1996 a, b;Boustie,他还,2005;Ranković,2015;Emsen等人,2017;Calcott et al., 2018)。虽然最初对整个地衣提取物进行了生物活性测试,但最近的研究主要集中在分离单个地衣代谢物并评估其生物活性(Ebrahim等人,2016;Ranković,Kosanić,2019;Ingelfinger et al., 2020;Poulsen-Silva et al., 2025)。此外,最近的一篇综述文章强调,精细分析,如质谱分析,揭示了大量未识别的代谢物(Singh et al., 2025)。比较真菌的代谢潜力可能具有挑战性,因为生物体分泌的代谢组取决于生物和非生物因素的组合,以及生命阶段依赖的线索。次生代谢物由一组称为生物合成基因的专用基因分泌,它们以共线方式组织,形成代谢或生物合成基因簇(bgc) (Firn &;琼斯,2000;Keller et al., 2005;Devashree et al., 2021)。根据编码代谢物的结构,bgc可分为聚酮合成酶(PKS)、非核糖体肽合成酶(NRPS)、萜烯或核糖体合成和翻译后修饰肽(RiPP)簇(Arnison et al., 2013;Helaly等人,2018;Gill et al., 2023)。这些团簇构成了生物BGC景观的大部分,还有一小部分是由吲哚、异氰酸合成酶和PKS-NRPS杂交团簇贡献的(Nickles等,2023)。同样的真菌,在不同的生命阶段,对不同的线索做出反应,激活不同的代谢基因(Keller, 2019)。因此,生物体在特定时间内具有比分泌代谢组所显示的更广泛的化学势(Machado等人,2017;Calcott et al., 2018;Gavriilidou et al., 2022)。此外,研究表明沉默的bgc可以被激活,导致代谢物的产生。这些事实表明,BGC含量是真菌代谢潜力的较好指标。(Fujii等,1996;Bok et al., 2006;郭先生,王,2014;Chen et al., 2017;Miethke et al., 2021;Navarro-Munoz,Collemare, 2022)。在这里,我们使用bgc总数作为其生化潜力的代理来评估地衣是否是天然产物的宝库,并比较了LFF和nLFF之间的这一指标。此外,我们研究了某些BGC类是否在两组中特异性富集。在本研究中,我们通过挖掘Pezizomycotina (Ascomycota)中LFF和nLFF的基因组,来检验LFF是否是天然产物的宝库。我们使用BGC计数作为生物合成潜力的代理。我们发现,LFF的bgc数量明显高于nLFF,为这一长期存在的概念提供了统计证据。有趣的是,虽然LFF中的bgc总数通常高于nLFF,但这种效应主要是由PKS集群驱动的。这与LFF产生的PKS代谢物的显著多样性一致(Boustie &;他还,2005;Goga et al., 2018)。相反,nLFF基因组含有更多的NRPS和PKS-NRPS杂交bgc。由于这两组之间的主要区别是LFF与藻类存在一种强制性的共生关系,因此有理由认为,与藻类的长期进化关系可能推动了LFF中代谢相关基因家族的扩展。最近一项研究调查了真菌和动物之间的主要进化变化,揭示了真菌中碳水化合物和次级代谢相关基因家族的扩展(Ocaña-Pallarès等人,2022),强调了次级代谢在真菌进化中的基本作用。 这种与次级代谢相关的基因家族的扩展在共生真菌中尤其明显,如LFF,其中复杂的关联似乎推动了代谢途径的进一步多样化。值得注意的是,地衣化的生活方式包括几个步骤,这些步骤需要共生体之间的代谢相互作用的相互作用——例如,地衣化(LFF与光生物之间共生关系的改造)本身包括各种步骤,包括伴侣识别和联系建立(Pichler et al., 2023)。因此,有理由推断,参与复杂关系的生物体进化出一系列复杂的机制,使共生体之间的代谢串扰成为可能。实验证据强化了这种效应,因为真菌与其他微生物共培养可以激活许多bgc,甚至包括沉默的bgc (Wang et al., 2023;Xu et al., 2023)。例如,在涉及Heterobasidion annosum、Gloeophyllum sepiarium和蜜环菌(Armillaria ostoyae, Xu et al., 2023)的实验中,其他真菌的存在导致次生代谢物产量增加了400倍,强调了生物相互作用如何增强真菌的代谢输出。同样地,与一组土壤细菌共培养,可激活真菌的次级代谢基因(Schroeckh et al., 2009)。该研究表明,细菌和真菌菌丝体之间的密切物理相互作用对于引起反应是必不可少的。有趣的是,其中一个被共培养激活的BGCs编码聚酮orsellinic酸,它类似于几个LFF分泌的代谢物lecanoric酸,或者是其中间产物。这进一步表明,细菌、藻类和真菌之间的长期进化关系可能促成了LFF中观察到的高代谢潜力。此外,分离生长的真菌菌体的代谢谱与地衣不同(Cordeiro等,2004;Alors等人,2023),强调了生物关联对地衣次生代谢物谱的影响。此外,最近的几项研究表明,地衣是一个复杂的生态系统,承载着大量其他生物,包括酵母和细菌(Grube &;Spribille, 2012;Spribille et al., 2016;艾伦,Lendemer, 2022;Cometto等人,2022)。虽然我们目前还不知道地衣菌体中某些生物的相互依赖程度和特异性,但这些关联可能是代谢物多样化的进化引擎,丰富了地衣的代谢“宝藏”。事实上,地衣代谢物谱的变化似乎受到藻类伴侣的影响,当与不同的藻类结合时,不同的bgc被激活(Farkas et al., 2024)。这表明藻类伴侣在塑造LFF的代谢特征中起作用。除了共生作用之外,地衣对从北极苔原到沙漠景观的各种生态位表现出非凡的适应性。在某些情况下,这种生态成功可能是由于它们在不同藻类伙伴之间切换的能力(例如Dal Grande等人,2017),但最近的证据表明,化学多样性也起着关键作用(Schweiger等人,2022)。对脐带的研究表明气候驱动的BGC变化,表明环境条件可以作为独特生物合成输出的触发因素(Singh等人,2021)。尽管LFF具有很高的生物合成潜力,但由于其复杂的生活方式,其代谢物的药物利用可以忽略不计,这对在受控条件下生产代谢物提出了重大挑战。例如,与nLFF相比,LFF在培养物中的缓慢生长速度可能使它们在体外产生有用的代谢物时处于不利地位。然而,这些障碍可能很快就会被克服,因为已经有几种成功培养LFF及其代谢物异源表达的方案(Kealey等人,2021;Kim et al., 2021;辛格,2023;Rosabal,Pino-Bodas, 2024)。总之,我们证明了与nLFF相比,LFF具有更高的生物合成潜力,并提出地衣中观察到的显著生物合成多样性源于复杂的生物相互作用和卓越的生态适应性的结合。具体来说,真菌与其藻类伙伴之间的共生关系,以及与地衣菌体内其他微生物居民的相互作用,创造了一个动态的代谢环境。这种环境可能推动了这些生物代谢多样性的进化,使它们成为生物活性代谢物的宝库。考虑到这些因素,我们提倡利用共培养研究来激活地衣中沉默的bgc。 由于LFF中bgc的富集主要是由PKS集群驱动的,因此未来的研究应侧重于比较LFF和nLFF中PKS集群的进化史。没有宣布。GS公司对本次研究进行了规划设计。GS和AP收集并分析了数据。美国新闻社和美联社撰写了手稿。两位作者都阅读并批准了手稿的最终版本。新植物学家基金会对地图和任何机构的管辖权要求保持中立。
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