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Fungi, though mesophilic, include thermophilic and thermostable species, as well. The thermostability of proteins observed in these fungi is most likely to be attributed to several molecular factors, such as the presence of salt bridges and hydrogen bond interactions between side chains. These factors cannot be generalized for all fungi. Factors impacting thermostability can guide how fungal thermophilic proteins gain thermostability. We curated a dataset of proteins for 14 thermophilic fungi and their evolutionarily closer mesophiles. Additionally, the proteome of Chaetomium thermophilum and its evolutionarily related mesophile Chaetomium globosum was analyzed. Using eggNOG, we categorized the proteomes into clusters of orthologous groups (COGs). While the individual count of proteins is over-represented in mesophiles (for COGs S, G, L, and Q), there are certain features that are significantly enriched in thermophiles (such as charged residues, exposed residues, polar residues, etc.). Since fungi are known to be cellulolytic and chitinolytic by nature, we selected 37 existing carbohydrate-active enzymes (CAZyme) families in Eurotiales, Mucorales, and Sordariales. We looked at closely similar sequences and their modeled structures for further comparison. Comparing solvent accessibilities of thermophilic and mesophilic proteins, exposed and intermediate residues are observed higher in thermophiles whereas buried residues are observed higher in mesophiles. For specific five CAZYme families (GH7, GH11, GH18, GH45, and CBM1) we looked at position-specific substitutions between thermophiles and mesophiles. We also found that there are relatively more intramolecular interactions in thermophiles compared to mesophiles. Thus, we found factors such as surface exposed residues and charged residues that are highly likely to impart thermostability in fungi, and this study sets the stage for further studies in the area of fungal thermostability., (© 2023 Wiley Periodicals LLC.)

Proper chromosome segregation during cell division relies on the timely dissolution of chromosome cohesion. Separase (EC3.4.22.49), a cysteine protease, plays a critical role in mitosis by cleaving the kleisin subunit of cohesin, thereby presenting a promising target for cancer therapy. However, challenges in isolating active human separase suitable for high-throughput screening have limited the identification of effective inhibitors. Here, we conducted a high-throughput screening of small-molecule inhibitors using the protease domain of Chaetomium thermophilum separase (ctSPD), which not only shares significant sequence similarity with human separase but is also readily available. After conducting a primary screening of a library containing 9,172 compounds and subsequent validation using human separase, we identified walrycin B and its analogs, toxoflavin, 3-methyltoxoflavin, and 3-phenyltoxoflavin, as potent inhibitors of human separase. Subsequent microscale thermophoresis assays and molecular dynamics simulations revealed that walrycin B binds to the active site of separase and competes with substrates for binding. Additionally, cell-based studies showed that walrycin B and its analogs effectively induce cell cycle arrest at the M phase, activate apoptosis, and ultimately lead to cell death in mitosis. Finally, in a mouse xenograft model, walrycin B exhibited significant antitumor efficacy with minimal side effects. Together, these findings highlight the therapeutic potential of walrycin B for cancer treatment and its utility as a chemical tool in future studies involving separase., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Two new cytochalasans, marcytoglobosins A (1) and B (2) were isolated from the marine sponge associated fungus Chaetomium globosum 162105, along with six known compounds (3-8). The complete structures of two new compounds were determined based on 1D/2D NMR and HR-MS spectroscopic analyses coupled with ECD calculations. All eight isolates were evaluated for their antibacterial activity. Among them, compounds 3-8 displayed antibacterial effects against Staphylococcus epidermidis, Bacillus thuringiensis, Pseudomonas syringae pv. Actinidiae, Vibrio alginolyticus, and Edwardsiella piscicida with minimum inhibitory concentration (MIC) values ranging from 10 to 25 μg/mL., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Chetocochliodin M ( 5 ) containing a rare cage-ring and chetocochliodin N ( 6 ) featuring an unusual piperazine-2,3-dione ring system together with known analogues chetomin ( 1 ), chetoseminudin C ( 2 ), chetocochliodin I ( 3 ), and oidioperazine E ( 4 ) were targeted for purification from the fungus Chaetomium cochliodes using a UPLC-Q-TOF-MS/MS approach. The structures of the new compounds were elucidated using HR-ESI-MS, NMR, and ECD spectra. Compounds 1 , 3 , and 6 exhibited strong cytotoxic activities against A549 and HeLa cancer cell lines.

By co-culturing two endophytic fungi (Chaetomium virescens and Xylaria grammica) collected from the medicinal and edible plant Smilax glabra Roxb. and analyzing them with MolNetEnhancer module on GNPS platform, seven undescribed chromone-derived polyketides (chaetoxylariones A-G), including three pairs of enantiomer ones (2a/2b, 4a/4b and 6a/6b) and four optical pure ones (1, 3, 5 and 7), as well as five known structural analogues (8-12), were obtained. The structures of these new compounds were characterized by NMR spectroscopy, single-crystal X-ray diffraction, 13 C NMR calculation and DP4+ probability analyses, as well as the comparison of the experimental electronic circular dichroism (ECD) data. Structurally, compound 1 featured an unprecedented chromone-derived sulfonamide tailored by two isoleucine-derived δ-hydroxy-3-methylpentenoic acids via the acylamide and NO bonds, respectively; compound 2 represented the first example of enantiomeric chromone derivative bearing a unique spiro-[3.3]alkane ring system; compound 3 featured a decane alkyl side chain that formed an undescribed five-membered lactone ring between C-7' and C-10'; compound 4 contained an unexpected highly oxidized five-membered carbocyclic system featuring rare adjacent keto groups; compound 7 featured a rare methylsulfonyl moiety. In addition, compound 10 showed a significant inhibition towards SW620/AD300 cells with an IC 50 value of PTX significantly decreased from 4.09 μM to 120 nM, and a further study uncovered that compound 10 could obviously reverse the MDR of SW620/AD300 cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The endophytic fungus Chaetomium nigricolor culture filtrate's hexane extract was used to identify a cytotoxic very long-chain fatty acid. Based on multiple spectroscopic investigations, the structure of the compound was predicted to be an unsaturated fatty acid, Nonacosenoic acid (NA). Using the MTT assay, the compound's cytotoxic potential was evaluated against MCF-7, A-431, U-251, and HEK-293 T cells. The compound was moderately cytotoxic to breast carcinoma cell line, MCF-7 cells and negligibly cytotoxic to non-cancerous cell line HEK-293 T cells. The compound exhibited mild cytotoxic activity against A-431 and U-251 cells. The compound also induced ROS generation and mitochondrial depolarization in MCF-7 cells when assessed via the NBT and JC-1 assays, respectively. This is the first report on the production of nonacosenoic acid from the endophytic fungus Chaetomium nigricolor and the assessment of its bioactivity., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 British Mycological Society. Published by Elsevier Ltd. All rights reserved.)

Using CRISPR-Cas9 technology and a microhomology-mediated end-joining repair system, we substituted genes of the gliotoxin pathway in Aspergillus fumigatus with genes responsible for chetomin biosynthesis from Chaetomium cochliodes , leading to the production of three new epipolythiodioxopiperazines (ETPs). This work represents the first successful endeavor to produce ETPs in a non-native host. Additionally, the simultaneous disruption of five genes in a single transformation marks the most extensive gene knockout event in filamentous fungi to date.

Two new sesterterpenoids, sesterchaetins A and B (1 and 2), and two new diepoxide polyketides, chaetoketoics A and B (3 and 4), were characterized from the culture extract of Chaetomium globosum SD-347, a fungal strain derived from deep sea-sediment. Their structures and absolute configurations were unambiguously determined by detailed NMR, mass spectra, and X-ray crystallographic analysis. Compounds 1 and 2 contained a distinctive 5/8/6/5 tetracyclic carbon-ring-system, which represented a rarely occurring natural product framework. The new isolates 1-4 exhibited selective antimicrobial activities against human and aquatic pathogenic bacteria and plant-pathogenic fungi.

Armochaetoglasins L ( 1 ) and M ( 2 ), two new cytochalasans, were isolated from the EtOAc extract of an arthropod-derived fungus Chaetomium globosum . Armochaetoglasin L ( 1 ) is a rare 19,20- seco -chaetoglobosin. Their structures were elucidated by NMR spectroscopy and comparison of their electronic circular dichroism (ECD) data. Compounds 1 and 2 were evaluated for anti-inflammatory activity against the NO production by using LPS-stimulated murine macrophage RAW264.7 cells and antibacterial activity against three drug-resistant microbial pathogens.

Seven new polyketides including three chromone derivatives (1-3) and four linear ones incorporating a tetrahydrofuran ring (4-7), along with three known compounds (8-10), were obtained from the fermentation of an endophytic fungus (Chaetomium sp. UJN-EF006) isolated from the leaves of Vaccinium bracteatum. The structures of these fungal metabolites have been elucidated by spectroscopic means including MS, NMR and electronic circular dichroism. A preliminary anti-inflammatory screening with the lipopolysaccharide (LPS) induced RAW264.7 cell model revealed moderate NO production inhibitory activity for compounds 1 and 4. In addition, the expression of three LPS-induced inflammatory factors IL-6, iNOS and COX-2 was also blocked by 1 and 4., (© 2024 Wiley‐VHCA AG, Zurich, Switzerland.)

The antimicrobial resistance of pathogenic microorganisms against commercial drugs has become a major problem worldwide. This study is the first of its kind to be carried out in Egypt to produce antimicrobial pharmaceuticals from isolated native taxa of the fungal Chaetomium , followed by a chemical investigation of the existing bioactive metabolites. Here, of the 155 clinical specimens in total, 100 pathogenic microbial isolates were found to be multi-drug resistant (MDR) bacteria. The Chaetomium isolates were recovered from different soil samples, and wild host plants collected from Egypt showed strong inhibitory activity against MDR isolates. Chaetomium isolates displayed broad-spectrum antimicrobial activity against C. albicans, Gram-positive, and Gram-negative bacteria, with inhibition zones of 11.3 to 25.6 mm, 10.4 to 26.0 mm, and 10.5 to 26.5 mm, respectively. As a consecutive result, the minimum inhibitory concentration (MIC) values of Chaetomium isolates ranged from 3.9 to 62.5 µg/mL. Liquid chromatography combined with tandem mass spectrometry (LC-MS/MS) analysis was performed for selected Chaetomium isolates with the most promising antimicrobial potential against MDR bacteria. The LC-MS/MS analysis of Chaetomium species isolated from cultivated soil at Assuit Governate, Upper Egypt ( 3 ), and the host plant Zygophyllum album grown in Wadi El-Arbaein, Saint Katherine, South Sinai ( 5 ), revealed the presence of alkaloids as the predominant bioactive metabolites. Most detected bioactive metabolites previously displayed antimicrobial activity, confirming the antibacterial potential of selected isolates. Therefore, the Chaetomium isolates recovered from harsh habitats in Egypt are rich sources of antimicrobial metabolites, which will be a possible solution to the multi-drug resistant bacteria tragedy.

DEAH-box helicases play a crucial role in pre-mRNA splicing as they are responsible for major rearrangements of the spliceosome and are involved in various quality-ensuring steps. Prp16 is the driving force during spliceosomal catalysis, remodeling the C state into the C* state. Here, the first crystal structure of Prp16 from Chaetomium thermophilum in complex with ADP is reported at 1.9 Å resolution. Comparison with the other spliceosomal DEAH-box helicases Prp2, Prp22 and Prp43 reveals an overall identical domain architecture. The β-hairpin, which is a structural element of the RecA2 domain, exhibits a unique position, punctuating its flexibility. Analysis of cryo-EM models of spliceosomal complexes containing Prp16 reveals that these models show Prp16 in its nucleotide-free state, rendering the model presented here the first structure of Prp16 in complex with a nucleotide., (open access.)

Loss of H2A-H2B histone dimers is a hallmark of actively transcribed genes, but how the cellular machinery functions in the context of noncanonical nucleosomal particles remains largely elusive. In this work, we report the structural mechanism for adenosine 5'-triphosphate-dependent chromatin remodeling of hexasomes by the INO80 complex. We show how INO80 recognizes noncanonical DNA and histone features of hexasomes that emerge from the loss of H2A-H2B. A large structural rearrangement switches the catalytic core of INO80 into a distinct, spin-rotated mode of remodeling while its nuclear actin module remains tethered to long stretches of unwrapped linker DNA. Direct sensing of an exposed H3-H4 histone interface activates INO80, independently of the H2A-H2B acidic patch. Our findings reveal how the loss of H2A-H2B grants remodelers access to a different, yet unexplored layer of energy-driven chromatin regulation.

The DEAH-box helicase Prp43 has essential functions in pre-mRNA splicing and ribosome biogenesis, remodeling structured RNAs. To initiate unwinding, Prp43 must first accommodate a single-stranded RNA segment into its RNA binding channel. This allows translocation of the helicase on the RNA. G-patch (gp) factors activate Prp43 in its cellular context enhancing the intrinsically low ATPase and RNA unwinding activity. It is unclear how the RNA loading process is accomplished by Prp43 and how it is regulated by its substrates, ATP and RNA, and the G-patch partners. We developed single-molecule (sm) FRET reporters on Prp43 from Chaetomium thermophilum to monitor the conformational dynamics of the RNA binding channel in Prp43 in real-time. We show that the channel can alternate between open and closed conformations. Binding of Pfa1(gp) and ATP shifts the distribution of states towards channel opening, facilitating the accommodation of RNA. After completion of the loading process, the channel remains firmly closed during successive cycles of ATP hydrolysis, ensuring stable interaction with the RNA and processive translocation. Without Pfa1(gp), it remains predominantly closed preventing efficient RNA loading. Our data reveal how the ligands of Prp43 regulate the structural dynamics of the RNA binding channel controlling the initial binding of RNA., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Punctaporonins T ( 1 ) and U ( 2 ), new caryophyllene sesquiterpenes, were isolated with three known punctaporonins, A ( 3 ), B ( 4 ), and C ( 5 ), from the endophytic fungus Chaetomium globosum (TC2-041). The structures and relative configurations of punctaporonins T and U were elucidated based on a combination of HRESIMS, 1D/2D NMR spectroscopic analysis, and X-ray diffraction analysis, while their absolute configuration is presumed to be consistent with the co-isolated 3 - 5 on biogenetic arguments. Compound 1 showed weak inhibitory activity against both Mycobacterium tuberculosis and Staphylococcus aureus .

Chaetomium (Chaetomiaceae), a large fungal genus consisting of at least 400 species, has been acknowledged as a promising resource for the exploration of novel compounds with potential bioactivities. Over the past decades, emerging chemical and biological investigations have suggested the structural diversity and extensive potent bioactivity of the specialized metabolites in the Chaetomium species. To date, over 500 compounds with diverse chemical types have been isolated and identified from this genus, including azaphilones, cytochalasans, pyrones, alkaloids, diketopiperazines, anthraquinones, polyketides, and steroids. Biological research has indicated that these compounds possess a broad range of bioactivities, including antitumor, anti-inflammatory, antimicrobial, antioxidant, enzyme inhibitory, phytotoxic, and plant growth inhibitory activities. This paper summarizes current knowledge referring to the chemical structure, biological activity, and pharmacologic potency of the specialized metabolites in the Chaetomium species from 2013 to 2022, which might provide insights for the exploration and utilization of bioactive compounds in this genus both in the scientific field and pharmaceutical industry., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Thirteen new alkaloids (1-13) as well as ten known compounds were isolated from the solid-state fermented rice medium of the fungus Chaetomium nigricolor YT-2. Their structures were elucidated on the basis of spectroscopic data, quantum calculations, and single crystal X-ray crystallographic analysis. Chaetonigrisin A (1) represents an unprecedented carbon skeleton featuring a polycyclic 1H-pyrano[3,2:3,4-]​furo[2,​3-​b]​indole. Chaetonigrisin B (2) displays a unique carbon skeleton with a 1,3‑dioxolane bridged-ring. Chaetonigrisin C (3) is a spirocyclic indole alkaloid. Chaetonigrisins D-H (4-8) are a group of asymmetric dimers, formed with two 3-indol-3yl-1,2-propanediol (4-6) or with a 3-indol-3yl-1,2-propanediol and a 3-indol-2yl-1,2-propanediol (7-8) by a pyran ring. Chaetonigrisins I-L (9-12) each contains a 3-indol-3yl-1,2-propanediol or 3-indol-2yl-1,2-propanediol substructure. Chaetonigrisin M (13) is a new quinoline alkaloid. The neuroprotective activity assay showed that at the concentration of 40 μM, compounds (4-7, 11, and 12) improved the cell viability of PC12 cells were 49.26 %, 74.69 %, 74.76 %, 86.63 %, 66.89 %, and 69.92 %, respectively induced by 6-OHDA, compound 7 showed significant neuroprotective activity via upregulation of SOD1 mRNA and Bcl-2 mRNA., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Five hydroxamate siderophores, chaetomadramines A-E (1-5), along with seven known compounds were isolated from the fermented rice culture of the fungus Chaetomium madrasense cib-1. Compounds 1-5 were structurally elucidated on the basis of spectroscopic data, which were a group of unusual hydroxamate siderophores, bearing a long fatty acyl on the α-NH 2 of the N δ -hydroxylated ornithine. Compounds 2-5 were new. The structural elucidation and spectroscopic data of 1 were reported for the first time. Compounds 2-4 significantly improved the survival rates of PC12 cells in the neuroprotective activity assay at the concentration of 40 μM., Competing Interests: Declaration of Competing Interest We declare that we have no financial personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and or company that could be construed as influencing the position presented in, or the manuscript entitled., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Two new cytochalasans with a rare 6/6/5/5/7 pentacyclic ring system, named chaetoconvosins C-D (1: -2: ), together with two known congeners (3: -4: ), were isolated from the fermentation of an endophytic fungus, Chaetomium sp. SG-01, harbored in the fibrous roots of Schisandra glaucescens Diels. Their structures including the absolute configuration were elucidated by extensive spectroscopic (HRESIMS, NMR, and ECD) and X-ray crystallographic analyses. The TRAIL-resistance-overcoming activity of 1: -4: in a TRAIL-resistant HT29 colorectal cancer cell line was evaluated, which revealed that co-treatment of 1: -4: at 50  µ M with TRAIL (150 ng/mL) reduced the HT29 cell viability by 19.0%, 24.1%, 17.9%, and 15.5%, respectively, compared to treatment with 1: -4: alone., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Four new depsidones, mollicellins V-Y ( 1 - 4 ), together with eight known depsidones ( 5 - 12 ) were isolated from the endophytic fungus, Chaetomium brasiliense, detached from stems of Thai rice. Their structures were determined by extensive spectroscopic methods. Mollicellins X, H, and F ( 3 , 8 and 10 ) showed potent cytotoxicity against the human oral epidermoid carcinoma (KB) cell line, and mollicellin F ( 10 ) also showed a potent cytotoxicity against the human hepatocellular carcinoma (HepG2) cell line. Besides, mollicellin B ( 11 ) exhibited cytotoxicity against the colorectal adenocarcinoma (HT-29) cell line. Moreover, most of the isolated depsidones displayed potent antibacterial activity against Gram-positive bacteria, Bacillus cereus and Bacillus subtilis , and several of them showed moderate activity against Methicillin-resistant Staphylococcus aureus (MRSA) and clinical isolates of S. aureus. In addition, a few of them also showed moderate activity against a Gram-negative bacteria Pseudomonas aeruginosa.

Rubichaetoglobin A ( 1 ), a new cytochalasan alkaloid, together with nine closely related known ones ( 2 - 10 ), were isolated from the ethyl acetate extracts of the endophytic fungus Chaetomium tectifimeti S104 harbored in the root of Rubia podantha Diels. Their structures were elucidated based on comprehensive spectroscopic analysis. All isolated compounds were tested for cytotoxic, antibacterial, and nitric oxide inhibitory activities. The results showed that 2 , 4 , and 5 possessed moderate cytotoxicity against MDA-MB-231 cells with the IC 50 values of 19.14, 11.43, and 10.27 μM, respectively.

Two novel cytochalasans, armochaetoglasin J ( 1 ) and armochaetoglasin K ( 2 ), along with 14 known analogues ( 3 - 16 ) were isolated from Chaetomium globosum. Their structures were elucidated by HRESIMS, NMR spectroscopy, single-crystal X-ray crystallography, and ECD spectra. Armochaetoglasins J and K were found to be inactive against the HepG2, HT-29, K562, HL-60, and A549 cancer cell lines.

Filamentous marine fungi have proven to be a plentiful source of new natural products. Chaetomium , a widely distributed fungal genus in the marine environment, has gained much interest within the scientific community. In the last 20 years, many potential secondary metabolites have been detected from marine-derived Chaetomium . In this review, we attempt to provide a comprehensive summary of the natural products produced by marine-derived Chaetomium species. A total of 122 secondary metabolites that were described from 2001 to 2021 are covered. The structural diversity of the compounds, along with details of the sources and relevant biological properties are also provided, while the relationships between structures and their bioactivities are discussed. It is our expectation that this review will be of benefit to drug development and innovation.

Ribosomes are complex and highly conserved ribonucleoprotein assemblies catalyzing protein biosynthesis in every organism. Here we present high-resolution cryo-EM structures of the 80S ribosome from a thermophilic fungus in two rotational states, which due to increased 80S stability provide a number of mechanistic details of eukaryotic translation. We identify a universally conserved 'nested base-triple knot' in the 26S rRNA at the polypeptide tunnel exit with a bulged-out nucleotide that likely serves as an adaptable element for nascent chain containment and handover. We visualize the structure and dynamics of the ribosome protective factor Stm1 upon ribosomal 40S head swiveling. We describe the structural impact of a unique and essential m 1 acp 3 Ψ 18S rRNA hyper-modification embracing the anticodon wobble-position for eukaryotic tRNA and mRNA translocation. We complete the eEF2-GTPase switch cycle describing the GDP-bound post-hydrolysis state. Taken together, our data and their integration into the structural landscape of 80S ribosomes furthers our understanding of protein biogenesis., (© 2022. The Author(s).)

Chemical investigation on the deep-sea-derived fungus Chaetomium globosum led to the isolation of nine compounds. By extensive analyses of the 1D and 2D NMR as well as HR-ESI-MS spectra, their structures were elucidated as xylariol A (1), 1,3-dihydro-4,5,6-trihydroxy-7-methylisobenzofuran (2), epicoccone B (3), epicoccolide B (4), chaetoglobosin G (5), chaetoglobosin F ex (6), cochliodone A (7), cochliodone B (8), and chaetoviridin A (9), assorting as four phenolics (1-4), two cytochalosans (5-6), and three azaplilones (7-9). Compounds 1-3 were firstly reported from C. globosum. Under the concentrations of 20 μg/mL, 1, 2, and 3 exhibited potent in vitro anti-HIV activity with the inhibition rates of 70 %, 75 %, and 88 %, respectively., (© 2021 Wiley-VHCA AG, Zurich, Switzerland.)

Overexpression of various pro-inflammatory factors in microglial cells tends to induce neurodegenerative diseases, for which there is no effective therapy available. Aureonitol ( 1 ) and seven analogues, including six previously undescribed [elatumenol A-F ( 2 - 4 , 6 - 8 , respectively)], along with two new orsellinic acid esters [elatumone A and B ( 9 and 10 )], were isolated from Chaetomium elatum . The structures of the compounds were established through comprehensive analysis of spectroscopic data, including high-resolution mass spectra and one- and two-dimensional NMR, and absolute configurations determined by the Mosher method, dimolybdenum tetraacetate-induced circular dichroism, and theoretical calculations including electronic circular dichroism and NMR. Metabolites 3 , 4 , 7 , and 8 exhibited antineuroinflammatory activity by attenuating the production of inflammatory mediators, such as nitric oxide, interleukin-6, interleukin-1β, tumor necrosis factor-α, and reactive oxygen species. Western blot results indicated 8 decreases the level of inducible nitric oxide synthase and cyclooxygenase-2 and suppresses the expression of Toll-like receptor 4 and nuclear factor kappa-B (NF-κB) as well as the phosphorylation of the inhibitor of NF-κB and p38 mitogen-activated protein kinases in lipopolysaccharide-activated BV-2 microglial cells.

Chaetocin is a natural metabolite product with various biological activities and pharmacological functions isolated from Chaetomium species fungi belonging to the thiodiketopyrazines. Numerous studies have demonstrated a wide range of antitumor activities of chaetocin in vitro and in vivo. Several studies have demonstrated that chaetocin suppresses the growth and proliferation of various tumour cells by regulating multiple signalling pathways related to tumour initiation and progression, inducing cancer cell apoptosis (intrinsic and extrinsic), enhancing autophagy, inducing cell cycle arrest, and inhibiting tumour angiogenesis, invasion, and migration. The antitumor effects and molecular mechanisms of chaetocin are reviewed and analysed in this paper, and the prospective applications of chaetocin in cancer prevention and therapy are also discussed. This review aimed to summarize the recent advances in the antitumor activity of chaetocin and to provide a rationale for further exploring the potential application of chaetocin in overcoming cancer in the future., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

The current study was conducted to evaluate the antiproliferative and oxidative damage protection potential of endophytic fungi Aspergillus fumigatus and Chaetomium globosum isolated from Moringa oleifera. The chloroformic extract (CE) of both the fungi showed dose dependent antiproliferative activity against human prostate adenocarcinoma (PC-3) cell line with (IC 50 ) value of 0.055 mg/ml and 0.008 mg/ml, respectively. Further, CE of both the fungi was studied for their ability to induce apoptosis in PC-3 cell line. Various deformities in the cancerous cells treated with CE of both the fungi have been observed by confocal microscopy which indicates the cell death by apoptosis. Further apoptosis inducing ability of CE of both the fungi was observed using various flow cytometric studies. The chloroformic extract of both the fungi showed slight increase in the level of reactive oxygen species to induce apoptosis. It also showed arrest of cancerous cells at G0/G1 phase of cell cycle to induce apoptosis. The externalization of phosphatidylserine (PS) to induce apoptosis was also observed when analysed using Annexin V-FITC/PI double staining assay where the CE of A. fumigatus and C. globosum showed the total apoptosis of 94.2% and 90.3%, respectively, at the highest tested concentration of GI 70 . The CE of both the fungi further showed the protective behaviour for plasmid DNA pBR322, when tested for their effect against the oxidative stress caused by the Fenton's reagent. Thus, the studies demonstrated a good antiproliferative and oxidative damage protection potential of the endophytic fungi., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This study investigated the effect of molecular weight on antibacterial activity of polysaccharides. Results showed that low molecular weight (3.105 × 10 4  Da) polysaccharide (GCP-2) had higher inhibitory effects against Escherichia coli and Staphylococcus aureus than high molecular weight (5.340 × 10 4  Da) polysaccharide (GCP-1). Meanwhile, antibacterial activities of GCP-2 and GCP-1 against S. aureus were higher than those of E. coli. Minimum inhibitory concentrations (MICs) of GCP-1 against E. coli and S. aureus were 2.0 mg/mL and 1.2 mg/mL, and MICs of GCP-2 against E. coli and S. aureus were 1.75 mg/mL and 0.85 mg/mL, respectively. Antibacterial mechanisms investigation revealed that GCP-2 and GCP-1 influenced cell membrane integrity, Ca 2+ -Mg 2+ -ATPase activity on cell membrane and calcium ions in cytoplasm of E. coli and S. aureus, but not cell wall. Present work provided important implications for future studies on development of antibacterial polysaccharides based on molecular weight feature., (Copyright © 2021. Published by Elsevier B.V.)

The TSC complex is a critical negative regulator of the small GTPase Rheb and mTORC1 in cellular stress signaling. The TSC2 subunit contains a catalytic GTPase activating protein domain and interacts with multiple regulators, while the precise function of TSC1 is unknown. Here we provide a structural characterization of TSC1 and define three domains: a C-terminal coiled-coil that interacts with TSC2, a central helical domain that mediates TSC1 oligomerization, and an N-terminal HEAT repeat domain that interacts with membrane phosphatidylinositol phosphates (PIPs). TSC1 architecture, oligomerization, and membrane binding are conserved in fungi and humans. We show that lysosomal recruitment of the TSC complex and subsequent inactivation of mTORC1 upon starvation depend on the marker lipid PI3,5P 2 , demonstrating a role for lysosomal PIPs in regulating TSC complex and mTORC1 activity via TSC1. Our study thus identifies a vital role of TSC1 in TSC complex function and mTORC1 signaling., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Hsp104 and its bacterial homolog ClpB form hexameric ring structures and mediate protein disaggregation. The disaggregated polypeptide is thought to thread through the central channel of the ring. However, the dynamic behavior of Hsp104 during disaggregation remains unclear. Here, we reported the stochastic conformational dynamics and a split conformation of Hsp104 disaggregase from Chaetomium thermophilum (CtHsp104) in the presence of ADP by X-ray crystallography, cryo-electron microscopy (EM), and high-speed atomic force microscopy (AFM). ADP-bound CtHsp104 assembles into a 6 5 left-handed spiral filament in the crystal structure at a resolution of 2.7 Å. The unit of the filament is a hexamer of the split spiral structure. In the cryo-EM images, staggered and split hexameric rings were observed. Further, high-speed AFM observations showed that a substrate addition enhanced the conformational change and increased the split structure's frequency. Our data suggest that split conformation is an off-pathway state of CtHsp104 during disaggregation., Competing Interests: Declaration of interests The authors declare no competing financial interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

In human cells, P5B-ATPases execute the active export of physiologically important polyamines such as spermine from lysosomes to the cytosol, a function linked to a palette of disorders. Yet, the overall shape of P5B-ATPases and the mechanisms of polyamine recognition, uptake and transport remain elusive. Here we describe a series of cryo-electron microscopy structures of a yeast homolog of human ATP13A2-5, Ypk9, determined at resolutions reaching 3.4 Å, and depicting three separate transport cycle intermediates, including spermine-bound conformations. Surprisingly, in the absence of cargo, Ypk9 rests in a phosphorylated conformation auto-inhibited by the N-terminus. Spermine uptake is accomplished through an electronegative cleft lined by transmembrane segments 2, 4 and 6. Despite the dramatically different nature of the transported cargo, these findings pinpoint shared principles of transport and regulation among the evolutionary related P4-, P5A- and P5B-ATPases. The data also provide a framework for analysis of associated maladies, such as Parkinson's disease.

The activation of cap-dependent translation in eukaryotes requires multisite, hierarchical phosphorylation of 4E-BP by the 1 MDa kinase mammalian target of rapamycin complex 1 (mTORC1). To resolve the mechanism of this hierarchical phosphorylation at the atomic level, we monitored by NMR spectroscopy the interaction of intrinsically disordered 4E binding protein isoform 1 (4E-BP1) with the mTORC1 subunit regulatory-associated protein of mTOR (Raptor). The N-terminal RAIP motif and the C-terminal TOR signaling (TOS) motif of 4E-BP1 bind separate sites in Raptor, resulting in avidity-based tethering of 4E-BP1. This tethering orients the flexible central region of 4E-BP1 toward the mTORC1 kinase site for phosphorylation. The structural constraints imposed by the two tethering interactions, combined with phosphorylation-induced conformational switching of 4E-BP1, explain the hierarchy of 4E-BP1 phosphorylation by mTORC1. Furthermore, we demonstrate that mTORC1 recognizes both free and eIF4E-bound 4E-BP1, allowing rapid phosphorylation of the entire 4E-BP1 pool and efficient activation of translation. Finally, our findings provide a mechanistic explanation for the differential rapamycin sensitivity of the 4E-BP1 phosphorylation sites., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Chemical investigation on the solid rice culture of Chaetomium globosum D38, an endophytic fungus derived from Salvia miltiorrhiza, has afforded two new 19,20-seco-chaetoglobosins, salchaetoglobosins A (1) and B (2), along with three known analogues, chaetoglobosins E (3), Fex (4), and V b (5). Their structures and absolute configurations were elucidated by a set of spectroscopy and single-crystal X-ray crystallography. Compounds 1-5 were evaluated for their cytotoxic activities against HCT-116 (colorectal carcinoma) and PC3 (prostate cancer) cells, as well as the NO production inhibitory effects in LPS-stimulated RAW264.7 cells., (Copyright © 2021. Published by Elsevier B.V.)

Chl1 is a member of the XPD family of 5'-3' DNA helicases, which perform a variety of roles in genome maintenance and transmission. They possess a variety of unique structural features, including the presence of a highly variable, partially-ordered insertion in the helicase domain 1. Chl1 has been shown to be required for chromosome segregation in yeast due to its role in the formation of persistent chromosome cohesion during S-phase. Here we present structural and biochemical data to show that Chl1 has the same overall domain organisation as other members of the XPD family, but with some conformational alterations. We also present data suggesting the insert domain in Chl1 regulates its DNA binding., Competing Interests: The authors have declared that no competing interests exist.

Endophytic fungi are broadly dispersed residing inside plant tissues and have been demonstrated as a treasure for bioactive natural products. Unexplored harsh and heavy metal contaminant habitat of Avicennia marina may have diverse and potential fungal association. Therefore, this work aimed to isolate the culturable fungal endophytes associated with leaves of A. marina and to evaluate their medical potentialities. Seventeen isolates of endophyte fungi were isolated from healthy leaves and their antimicrobial activities were evaluated. Results showed that isolates had activity against micro-organisms in addition to their antioxidant activity produced a variety of phenolic compounds, besides exhibited a lowest cytotoxicity against ATCC-CCL-81 cell line. Consequently, selected endophytic fungal isolates were identified genetically as Chaetomium sp., Chaetomium madrasense, Chaetomium sp., Chaetomium globosum, Aspergillus hiratsukae, Aspergillus ochraceus, Alternaria tenuissima and Curvularia lunata with gene bank accession numbers MT089951, MT089952, MT089953, MT089954, MT089955, MT089956, MT089957 and MT089958 respectively. The most potent fungus extract was analysed using Gas chromatography-mass spectrometry which verified the presence of numerous bioactive compounds. These findings confirmed that new endophytic fungal strains derived from A. marina thrive in harsh ecosystem produce bioactive metabolites which can be recommended as a novel source for drug discovery., (© 2020 The Society for Applied Microbiology.)

Soil is considered an extensively explored ecological niche for microorganisms that produce useful biologically active natural products suitable for pharmaceutical applications. The current study aimed at investigating biological activities and metabolic profiles of three fungal strains identified from different desert sites in Saudi Arabia. Soil fungal isolates were collected from AlQasab, Tabuk, and Almuzahimiyah in Saudi Arabia and identified. Furthermore, their antibacterial activity was investigated against Staphylococcus aureus, Enterococcus faecalis, Klebsiella pneumonia, and Escherichia coli in blood, nutrient, and Sabouraud dextrose agars. Moreover, fungal extracts were evaluated on cell viability/proliferation against human breast carcinoma and colorectal adenocarcinoma cells. To identify the biomolecules of the fungal extracts, High-performance liquid chromatography HPLC-DAD coupled to analytical LC-QTOF-MS method was employed for fungal ethyl acetate crude extract. Identified fungal isolates, Chaetomium sp. Bipolaris sp. and Fusarium venenatum showed varied inhibitory activity against tested microbes in relation to crude extract, microbial strain tested, and growth media. F. venenatum showed higher anticancer activity compared to Chaetomium sp. and Bipolaris sp. extracts against four of the tested cancer cell lines. Screening by HPLC and LC/MS-QTOF identified nine compounds from Chaetomium sp. and three from Bipolaris sp. however, for F. venenatum extracts compounds were not fully identified. In light of the present findings, some biological activities of fungal extracts were approved in vitro, suggesting that such extracts could be a useful starting point to find compounds that possess promising agents for medical applications. Further investigations to identify exact biomolecules from F. venenatum extracts are needed.

Gold nanoparticles (AuNPs) are gaining a lot of attention in recent decades from researchers due to their unique optoelectronic properties and their significance in the field of biomedicine. Keeping this in view, our research work was designed to investigate gold nanoparticles obtained by using a fungal endophytic strain Chaetomium globosum, isolated from Vitex negundo which showed significant activity on enzyme inhibition. In the present study, the fungal isolate C. globosum was characterized using HPLC and LC-MS. A novel compound Catechin was matched with standard Catechin. Further, the endophyte C. globosum extract was utilized to synthesize gold nanoparticles (CgAuNPs) which was analysed by UV-visible spectroscopy. The CgAuNPs exhibited wine red color and the absorption peak appeared at 542 nm confirming the formation of the AuNPs. Further, Fourier Transmission Infrared Spectroscopy (FTIR) was performed to confirm the various functional groups present in mycosynthesized CgAuNPs. FTIR analysis demonstrated the presence of amines, flavonoids, as well as the presence of amide I linkage which possibly reduces Au + to Au 0 . The synthesized CgAuNPs exhibited potential cytotoxicity against HeLa cells in a dose dependent manner. Further, CgAuNPs demonstrated significant anti-inflammatory activity. Overall, the present work provides insights into the design of nano delivery and may be applied for clinical studies in future., (Copyright © 2020 Elsevier Inc. All rights reserved.)

In this study, a polysaccharide (CGP-BG) was successfully produced from waste distillers' grain by Chaetomium globosum CGMCC 6882. Chemical analysis demonstrated that CGP-BG contained 3.49 ± 0.51 % protein. The molecular weight of CGP-BG was 52.37 KDa, which was composed of rhamnose, arabinose, galactose, glucose, xylose, mannose, galacturonic acid, and glucuronic acid in the molar ratio of 4.11:7.34:13.31:20.99:1.07:0.91:4.75:0.36. In vitro assay showed that CGP-BG had scavenging activities on hydroxyl radical, DPPH radical, superoxide anion, and ABTS radical in a dose-dependent manner. Meanwhile, CGP-BG significantly inhibited nitric oxide and pro-inflammatory cytokine (TNF-α, IL-6, and IL-1β) production in the lipopolysaccharide (LPS)-induced RAW 264.7 cells. Moreover, CGP-BG notably improved the antioxidant status of LPS-treated macrophages by enhancing superoxide dismutase, glutathione peroxidase, and antioxidant capacity and mitigating malondialdehyde. This work provided the basis for the application of CGP-BG as an anti-inflammatory and antioxidant agent., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Four novel rearranged cytochalasans ( 1 - 4 ) were isolated from an endophytic fungus Chaetomium globosum P2-2-2. Pchaeglobolactone A ( 1 ) possessed an unprecedented 13-aza-21-oxa-tetracyclo-[10.6.1.2 17,19 .0 15,19 ]henicosane core. Spiropchaeglobosin A ( 2 ) was the first example of cytochalasans featuring a novel spiro[5.10]hexadecane unit. Pchaeglobosals A ( 3 ) and B ( 4 ) featured a unique 5/5/13 fused tricyclic ring system. Compounds 1 - 4 were tested for their antiproliferative, apoptosis, cell cycle arrest, and TRAIL-resistance-overcoming activities on cancer cell lines.

The superfamily 2 helicase XPB is an integral part of the general transcription factor TFIIH and assumes essential catalytic functions in transcription initiation and nucleotide excision repair. The ATPase activity of XPB is required in both processes. We investigated the interaction network that regulates XPB via the p52 and p8 subunits with functional mutagenesis based on our crystal structure of the p52/p8 complex and current cryo-EM structures. Importantly, we show that XPB's ATPase can be activated either by DNA or by the interaction with the p52/p8 proteins. Intriguingly, we observe that the ATPase activation by p52/p8 is significantly weaker than the activation by DNA and when both p52/p8 and DNA are present, p52/p8 dominates the maximum activation. We therefore define p52/p8 as the master regulator of XPB acting as an activator and speed limiter at the same time. A correlative analysis of the ATPase and translocase activities of XPB shows that XPB only acts as a translocase within the context of complete core TFIIH and that XPA increases the processivity of the translocase complex without altering XPB's ATPase activity. Our data define an intricate network that tightly controls the activity of XPB during transcription and nucleotide excision repair., (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The removal of carbon dioxide from the waste streams of industrial processes is a major challenge for creation of a sustainable circular economy. This makes the synthesis of formate from CO 2 by NAD + dependent formate dehydrogenases (FDHs) an attractive process for this purpose. The efficiency of this reaction is however low and to achieve a viable industrial process an optimised engineered enzyme needs to be developed. In order to understand the detailed enzymatic mechanism of catalysis structures of different cofactor and substrate complexes of the FDH from the thermophilic filamentous fungus, Chaetomium thermophilum have been determined to 1.2-1.3 Å resolution. The substrate formate is shown to be held by four hydrogen bonds in the FDH catalytic site within the ternary complex with substrate and NAD + and a secondary formate binding site is observed in crystals soaked with substrate. Water molecules are excluded from the FDH catalytic site when the substrate is bound. The angle between the plane of the NAD + cofactor pyridine ring and the plane of the formate molecule is around 27°. Additionally, structures of a FDH mutant enzyme, N120C, in complex with the reduced form of the cofactor have also been determined both in the presence and absence of formate bound at the secondary site. These structures provide further understanding of the catalytic mechanism of this fungal enzyme., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The recent exploration of various medicinal plants for bioactive potential has led to the growing interest to explore their endophytes for such bioactive potential which may turn out to be better option than the plants. In the present study, Chaetomium globosum, an endophytic fungus isolated from Moringa oleifera Lam has been explored for its various biological activities. The chloroformic extract of C. globosum showed good antimutagenicity against the reactive carcinogenic mutagen, 2-aminofluorene (2-AF) in Ames test. The antiproliferative activity against various cell lines such as HCT-15, HeLa and U87-MG was found to be dose dependent and the viability reduced to 9.26%, 15.7% and 16.3%, respectively. Further, the chloroformic fungal extract was investigated for free radical scavenging activity using 2, 2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethyl-benzthiazolin-6-sulfonic acid) assay which showed the IC 50 value of 45.16 µg/ml and 50.55 µg/ml, respectively. The fungal extract also showed good ferric reducing power. Total phenolic and flavonoid content was found to be in linear relationship with the antioxidant potential of the fungal extract. High performance liquid chromatography showed the presence of phenolics which may help to combat the free radicals. The presence of various bioactive compounds was analysed by GC-MS which endorsed Chaetomium globosum to be a promising candidate for drug development.

The marine ecosystem is an extraordinary reserve of pharmaceutically important, bioactive compounds even in this "synthetic age". Marine algae-associated endophytic fungi have gained prominence as an important source of bioactive compounds. This study was conducted on secondary metabolites of Chaetomium globosum-associated with marine green alga Chaetomorpha media from the Konkan coastline, India. Its ethyl acetate extract (CGEE) exhibited an IC 50 value of 7.9 ± 0.1 µg/mL on MCF-7 cells. CGEE exhibited G2M phase cell cycle arrest, ROS production and MMP loss in MCF-7 cells. The myco-components in CGEE contributing to the cytotoxicity were found by Gas Chromatography/Mass Spectrometry analyses. Chrysin, a dihydroxyflavone was one of the forty-six myco-components which is commonly found in honey, propolis and passionflower extracts. The compound was isolated and characterized as fungal chrysin using HPLC, UV-Vis spectroscopy, LC-MS, IR and NMR analyses by comparing with standard chrysin. The purified compound exhibited an IC 50 value of 49.0 ± 0.6 µM while that of standard chrysin was 48.5 ± 1.6 µM in MCF-7 cells. It induced apoptosis, G1 phase cell cycle arrest, MMP loss, and ROS production. This is the first report of chrysin from an alternative source with opportunities for yield enhancement.

Cyclin-dependent kinase 7 (CDK7), Cyclin H, and the RING-finger protein MAT1 form the heterotrimeric CDK-activating kinase (CAK) complex which is vital for transcription and cell-cycle control. When associated with the general transcription factor II H (TFIIH) it activates RNA polymerase II by hyperphosphorylation of its C-terminal domain (CTD). In the absence of TFIIH the trimeric complex phosphorylates the T-loop of CDKs that control cell-cycle progression. CAK holds a special position among the CDK branch due to this dual activity and the dependence on two proteins for activation. We solved the structure of the CAK complex from the model organism Chaetomium thermophilum at 2.6-Å resolution. Our structure reveals an intricate network of interactions between CDK7 and its two binding partners MAT1 and Cyclin H, providing a structural basis for the mechanism of CDK7 activation and CAK activity regulation. In vitro activity measurements and functional mutagenesis show that CDK7 activation can occur independent of T-loop phosphorylation and is thus exclusively MAT1-dependent by positioning the CDK7 T-loop in its active conformation., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

GCP, a polysaccharide produced by endophytic fungus Chaetomium globosum CGMCC 6882, was found to be antibacterial against Staphylococcus aureus via disrupting cell permeability. However, the antibacterial mechanism of GCP has not been studied before. In present work, results showed that GCP could retard the growth of S. aureus by inducing the depolarization of cell membrane, decreasing the activity of Ca 2+ -Mg 2+ -ATPase on cell membrane, and increasing the accumulation of calcium ions in cytoplasm. Moreover, we found that GCP could also inhibit the synthesis of whole cell proteins of S. aureus. Overall, this study proved that the antibacterial mechanism of GCP could be diversified and more studies are needed in the investigation of the antibacterial mechanisms of various polysaccharides., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The AROM complex is a multifunctional metabolic machine with ten enzymatic domains catalyzing the five central steps of the shikimate pathway in fungi and protists. We determined its crystal structure and catalytic behavior, and elucidated its conformational space using a combination of experimental and computational approaches. We derived this space in an elementary approach, exploiting an abundance of conformational information from its monofunctional homologs in the Protein Data Bank. It demonstrates how AROM is optimized for spatial compactness while allowing for unrestricted conformational transitions and a decoupled functioning of its individual enzymatic entities. With this architecture, AROM poses a tractable test case for the effects of active site proximity on the efficiency of both natural metabolic systems and biotechnological pathway optimization approaches. We show that a mere colocalization of enzymes is not sufficient to yield a detectable improvement of metabolic throughput.

Dynamin-superfamily proteins (DSPs) are large self-assembling mechanochemical GTPases that harness GTP hydrolysis to drive membrane remodeling events needed for many cellular processes. Mutation to alanine of a fully conserved lysine within the P-loop of the DSP GTPase domain results in abrogation of GTPase activity. This mutant has been widely used in the context of several DSPs as a dominant-negative to impair DSP-dependent processes. However, the precise deficit of the P-loop K to A mutation remains an open question. Here, we use biophysical, biochemical and structural approaches to characterize this mutant in the context of the endosomal DSP Vps1. We show that the Vps1 P-loop K to A mutant binds nucleotide with an affinity similar to wild type but exhibits defects in the organization of the GTPase active site that explain the lack of hydrolysis. In cells, Vps1 and Dnm1 bearing the P-loop K to A mutation are defective in disassembly. These mutants become trapped in assemblies at the typical site of action of the DSP. This work provides mechanistic insight into the widely-used DSP P-loop K to A mutation and the basis of its dominant-negative effects in the cell., (© 2020 The Protein Society.)

Chaetomium globosum is a filamentous fungus from which we have previously isolated a series of interesting natural products. Here, we isolated a previously unknown natural product from the culture of C. globosum. Through spectroscopic and crystallographic characterization, we determined the compound to be a new dimerized azaphilone-type product which we termed cochliodone J (1). Furthermore, our investigation into the biological activity of the natural product determined that 1 was cytotoxic to human cervix carcinoma HeLa cells with an IC 50 of 17.3 µM. Lastly, a plausible biosynthetic mechanism for 1 is suggested based on our previous study on the biosynthesis of a closely related compound, cochliodone A (2).

Twelve metabolites were obtained from the culture media of Chaetomium nigricolor , including a new furan derivative, methyl succinyl Sumiki's acid ( 1 ), and two new atropisomers of the previously reported bis-naphtho-γ-pyrones, (a S )-asperpyrone A and (a S )-fonsecinone A ( 2 and 3 ). The structures were elucidated by spectroscopic, chemical, and chiroptical techniques. Compounds 2 and 3 inhibited nitric oxide production in lipopolysaccharide-stimulated RAW 264.7 macrophages. Compound 2 was found to inhibit nuclear factor-kappa B and c-Jun N-terminal kinase activation, in turn suppressing pro-inflammatory mediators and cytokines including nitric oxide, prostaglandin E 2 , interleukin (IL)-1β, tumor necrosis factor-α, IL-6, and IL-12.