Roseoglobuloside A, a Novel Nonanolide, and Identification of Specialized Metabolites as hPTP1B1 – 400 Inhibitors from Mangrove-Dwelling Aspergillus spp

Carlos A. Fajardo-Hernández; Ángeles G. Zavala-Sierra; Verenice I. Merlin-Lucas; Jesús I. Morales-Jiménez; José Rivera-Chávez

doi:10.1055/a-2515-9491

Planta Medica, Inhaltsverzeichnis

Planta Med 2025; 91(04): 197-207
DOI: 10.1055/a-2515-9491

Original Papers

Roseoglobuloside A, a Novel Nonanolide, and Identification of Specialized Metabolites as hPTP1B_{1 – 400} Inhibitors from Mangrove-Dwelling Aspergillus spp

Carlos A. Fajardo-Hernández

¹Instituto de Química, Departamento de Productos Naturales, Universidad Nacional Autónoma de México, Mexico City, Mexico

,

Ángeles G. Zavala-Sierra

¹Instituto de Química, Departamento de Productos Naturales, Universidad Nacional Autónoma de México, Mexico City, Mexico

,

Verenice I. Merlin-Lucas

¹Instituto de Química, Departamento de Productos Naturales, Universidad Nacional Autónoma de México, Mexico City, Mexico

,

Jesús I. Morales-Jiménez

²Departamento El Hombre y su Ambiente, Universidad Autónoma Metropolitana, Mexico City, Mexico

,

José Rivera-Chávez

¹Instituto de Química, Departamento de Productos Naturales, Universidad Nacional Autónoma de México, Mexico City, Mexico

› Institutsangaben

Abstract

An approach combining enzymatic inhibition and untargeted metabolomics through molecular networking was employed to search for human recombinant full-length protein tyrosine phosphatase 1B (hPTP1 B_{1 – 400}) inhibitors from a collection of 66 mangrove-associated fungal taxa. This strategy prioritized two Aspergillus strains (IQ-1612, section Circumdati, and IQ-1620, section Nigri) for further studies. Chemical investigation of strain IQ-1612 resulted in the isolation of a new nonanolide derivative, roseoglobuloside A (1), along with two known metabolites (2 and 3), whereas strain IQ-1620 led to the isolation of four known naphtho-γ-pyrones and one known diketopiperazine (4–8). Of all isolates, compounds 2, 3, and 7 showed a marked inhibitory effect on hPTP1B_{1 – 400} with an IC₅₀ value < 20 µM, while 6 showed moderate inhibition with IC₅₀ of 65 µM. Compounds 1 and 8 were inactive at a concentration of 100 µM, whereas 4 and 5 demonstrated significant inhibition at 20 µM. The structure of 1 was established by comprehensive spectroscopic analysis, and its relative and absolute configuration was assigned based on NOE correlations and by comparison of calculated and experimental ECD curves. Molecular docking indicated that these molecules primarily bind to two different allosteric sites, thereby inducing conformational changes that impact enzymatic activity.

Keywords

Aspergillus - Aspergillaceae - nonanolide - hPTP1B_{1 – 400} - molecular networking - insulin regulation pathway

Volltext

Referenzen

References
1 Palit K, Rath S, Chatterjee S, Das S. Microbial diversity and ecological interactions of microorganisms in the mangrove ecosystem: Threats, vulnerability, and adaptations. Environ Sci Pollut Res Int 2022; 29: 32467-32512
2 Li K, Chen S, Pang X, Cai J, Zhang X, Liu Y, Zhu Y, Zhou X. Natural products from mangrove sediments-derived microbes: Structural diversity, bioactivities, biosynthesis, and total synthesis. Eur J Med Chem 2022; 230: 114117
3 Sridhar K, Anand K. Diversity, Biogeography, and Ecological Functions of Filamentous Fungi in Mangrove Ecosystem. In: Sati SC. Recent mycological researches. New Delhi: IK International Publishing House; 2006: 158-193
4 Senanayake IC, Pem D, Rathnayaka AR, Wijesinghe SN, Tibpromma S, Wanasinghe DN, Phookamsak R, Kularathnage ND, Gomdola D, Harishchandra D. Predicting global numbers of teleomorphic ascomycetes. Fungal Divers 2022; 114: 237-278
5 Carroll AR, Copp BR, Davis RA, Keyzers RA, Prinsep MR. Marine natural products. Nat Prod Rep 2022; 39: 1122-1171
6 Devadatha B, Jones E, Pang K, Abdel-Wahab M, Hyde K, Sakayaroj J, Bahkali A, Calabon M, Sarma V, Sutreong S. Occurrence and geographical distribution of mangrove fungi. Fungal Divers 2021; 106: 137-227
7 Roy PD, Natarajan L, Chokkalingam L. Changes in Lu/Lc and vegetation around the Acapulco Bay at southwest Mexico from the hurricane Otis (October 25, 2023). J South Am Earth Sci 2024; 136: 104819
8 Ancheeva E, Daletos G, Proksch P. Lead compounds from mangrove-associated microorganisms. Mar Drugs 2018; 16: 319
9 Chen S, Cai R, Liu Z, Cui H, She Z. Secondary metabolites from mangrove-associated fungi: Source, chemistry and bioactivities. Nat Prod Rep 2022; 39: 560-595
10 Carrillo-Jaimes K, Fajardo-Hernández CA, Hernández-Sedano F, Cano-Sánchez P, Morales-Jiménez J, Quiroz-García B, Rivera-Chávez J. Antibacterial activity and Ab FtsZ binding properties of fungal metabolites isolated from Mexican mangroves. Rev Bras Farmacogn 2024; 34: 564-576
11 Martínez-Aldino IY, Rivera-Chávez J, Morales-Jiménez J. Integrating taxonomic and chemical diversity of mangrove-associated ascomycetes to discover or repurpose bioactive natural products. J Nat Prod 2023; 86: 2423-2434
12 Lagunes I, Lumbreras-Martínez H, Espinoza C, Padrón JM, López-Portillo J, Trigos Á. Diversity and bioactivity of sediment-associated fungi from a mangrove forest in Mexico with different conservation conditions. Lat Am J Aquat Res 2023; 51: 379-387
13 Egawa K, Maegawa H, Shimizu S, Morino K, Nishio Y, Bryer-Ash M, Cheung AT, Kolls JK, Kikkawa R, Kashiwagi A. Protein-tyrosine phosphatase-1B negatively regulates insulin signaling in l6 myocytes and Fao hepatoma cells. J Biol Chem 2001; 276: 10207-10211
14 Teimouri M, Hosseini H, ArabSadeghabadi Z, Babaei-Khorzoughi R, Gorgani-Firuzjaee S, Meshkani R. The role of protein tyrosine phosphatase 1B (PTP1B) in the pathogenesis of type 2 diabetes mellitus and its complications. J Physiol Biochem 2022; 78: 307-322
15 Olivon F, Allard PM, Koval A, Righi D, Genta-Jouve G, Neyts J, Apel C, Pannecouque C, Nothias LF, Cachet X. Bioactive natural products prioritization using massive multi-informational molecular networks. ACS Chem. Biol 2017; 12: 2644-2651
16 Olivon F, Remy S, Grelier G, Apel C, Eydoux C, Guillemot JC, Neyts J, Delang L, Touboul D, Roussi F. Antiviral compounds from Codiaeum peltatum targeted by a multi-informative molecular networks approach. J Nat Prod 2019; 82: 330-340
17 Olivon F, Apel C, Retailleau P, Allard P, Wolfender J, Touboul D, Roussi F, Litaudon M, Desrat S. Searching for original natural products by molecular networking: Detection, isolation and total synthesis of chloroaustralasines. Org Chem Front 2018; 5: 2171-2178
18 Ernst M, Kang KB, Caraballo-Rodríguez AM, Nothias LF, Wandy J, Chen C, Wang M, Rogers S, Medema MH, Dorrestein PC. MolNetEnhancer: Enhanced molecular networks by integrating metabolome mining and annotation tools. Metabolites 2019; 9: 144
19 Xu XY, Zhang XY, He F, Peng J, Nong XH, Qi SH. Two new compounds from gorgonian-associated fungus Aspergillus sp. Nat Prod Commun 2013; 8: 1069-1070
20 Kim DC, Minh Ha T, Sohn JH, Yim JH, Oh H. Protein tyrosine phosphatase 1B inhibitors from a marine-derived fungal strain Aspergillus sp. SF-5929. Nat Prod Res 2020; 34: 675-682
21 Wang M, Carver JJ, Phelan VV, Sanchez LM, Garg N, Peng Y, Nguyen DD, Watrous J, Kapono CA, Luzzatto-Knaan T, Porto C, Bouslimani A, Melnik AV, Meehan MJ, Liu WT, Crüsemann M, Boudreau PD, Esquenazi E, Sandoval-Calderón M, Kersten RD, Pace LA, Quinn RA, Duncan KR, Hsu CC, Floros DJ, Gavilan RG, Kleigrewe K, Northen T, Dutton RJ, Parrot D, Carlson EE, Aigle B, Michelsen CF, Jelsbak L, Sohlenkamp C, Pevzner P, Edlund A, McLean J, Piel J, Murphy BT, Gerwick L, Liaw CC, Yang YL, Humpf HU, Maansson M, Keyzers RA, Sims AC, Johnson AR, Sidebottom AM, Sedio BE, Klitgaard A, Larson CB, Boya P CA, Torres-Mendoza D, Gonzalez DJ, Silva DB, Marques LM, Demarque DP, Pociute E, OʼNeill EC, Briand E, Helfrich EJN, Granatosky EA, Glukhov E, Ryffel F, Houson H, Mohimani H, Kharbush JJ, Zeng Y, Vorholt JA, Kurita KL, Charusanti P, McPhail KL, Nielsen KF, Vuong L, Elfeki M, Traxler MF, Engene N, Koyama N, Vining OB, Baric R, Silva RR, Mascuch SJ, Tomasi S, Jenkins S, Macherla V, Hoffman T, Agarwal V, Williams PG, Dai J, Neupane R, Gurr J, Rodríguez AMC, Lamsa A, Zhang C, Dorrestein K, Duggan BM, Almaliti J, Allard PM, Phapale P, Nothias LF, Alexandrov T, Litaudon M, Wolfender JL, Kyle JE, Metz TO, Peryea T, Nguyen DT, VanLeer D, Shinn P, Jadhav A, Müller R, Waters KM, Shi W, Liu X, Zhang L, Knight R, Jensen PR, Palsson BØ, Pogliano K, Linington RG, Gutiérrez M, Lopes NP, Gerwick WH, Moore BS, Dorrestein PC, Bandeira N. Sharing and community curation of mass spectrometry data with Global Natural Products Social Molecular Networking. Nat Biotechnol 2016; 34: 828-837
22 Mohimani H, Gurevich A, Shlemov A, Mikheenko A, Korobeynikov A, Cao L, Shcherbin E, Nothias LF, Dorrestein PC, Pevzner PA. Dereplication of microbial metabolites through database search of mass spectra. Nat Commun 2018; 9: 4035
23 Djoumbou Feunang Y, Eisner R, Knox C, Chepelev L, Hastings J, Owen G, Fahy E, Steinbeck C, Subramanian S, Bolton E. ClassyFire: Automated chemical classification with a comprehensive, computable taxonomy. J Cheminform 2016; 8: 1-20
24 Gardes M, Bruns TD. ITS primers with enhanced specificity for basidiomycetes‐application to the identification of mycorrhizae and rusts. Mol Ecol 1993; 2: 113-118
25 White TJ, Bruns T, Lee S, Taylor J. Amplification and direct sequencing of fungal ribosomal RNA genes for phylogenetics. In: Innis MA, Gelfand DH, Sninsky JJ, White TJ PCR protocols: a guide to methods and applications. San Diego, CA: Academic Press, Inc.; 1990. 18. 315-322
26 Wang X, Jarmusch SA, Frisvad JC, Larsen TO. Current status of secondary metabolite pathways linked to their related biosynthetic gene clusters in Aspergillus section Nigri. Nat Prod Rep 2023; 40: 237-274
27 Larsen TO, Smedsgaard J, Nielsen KF, Hansen ME, Frisvad JC. Phenotypic taxonomy and metabolite profiling in microbial drug discovery. Nat Prod Rep 2005; 22: 672-695
28 Visagie C, Varga J, Houbraken J, Meijer M, Kocsubé S, Yilmaz N, Fotedar R, Seifert K, Frisvad JC, Samson R. Ochratoxin production and taxonomy of the yellow Aspergilli (Aspergillus section Circumdati). Stud Mycol 2014; 78: 1-61
29 Yang W, Chen T, Tan Q, Zang Z, Chen Y, Ou Y, Li G, Hu D, Wang B, Yao H. Plasmodium-resistant indole diterpenoid biosynthesis gene cluster derived from Aspergillus oryzae was activated by exogenous P450 gene Ast B. J Nat Prod 2023; 86: 1392-1401
30 Takahashi H, Hosoe T, Nozawa K, Kawai KI. Two new sesterterpenes from the ascomycetous fungus Emericella purpurea . J Nat Prod 1999; 62: 1712-1713
31 Schmidt B, Kunz O, Petersen MH. Total syntheses of naturally occurring seimatopolide A and its enantiomer from chiral pool starting materials using a bidirectional strategy. J Org Chem 2012; 77: 10897-10906
32 Dubovik V, Dalinova A, Berestetskiy A. Natural ten-membered lactones: sources, structural diversity, biological activity, and intriguing future. Nat Prod Rep 2024; 41: 85-112
33 Hiep NT, Choi YH, Kim N, Hong SS, Hong SB, Hwang BY, Lee HJ, Lee SJ, Jang DS, Lee D. Polyhydroxylated macrolides from Seimatosporium discosioides and their effects on the activation of peroxisome proliferator-activated receptor gamma. J Nat Prod 2012; 75: 784-788
34 Lu S, Kurtán T, Yang G, Sun P, Mándi A, Krohn K, Draeger S, Schulz B, Yi Y, Li L. Cytospolides A–E, new nonanolides from an endophytic fungus, Cytospora sp. Eur J Org Chem 2011; 28: 5452-5459
35 Reddy CR, Dilipkumar U, Reddy MD, Rao NN. Total synthesis and revision of the absolute configuration of seimatopolide B. Org Biomol Chem 2013; 11: 3355-3364
36 Sakurai M, Kohno J, Yamamoto K, Okuda T, Nishio M, Kawano K, Ohnuki T. TMC-256A1 and C1, new inhibitors of IL-4 signal transduction produced by Aspergillus niger var niger TC 1629. J Antibiot 2002; 55: 685-692
37 Priestap HA. ¹³C NMR spectroscopy of naphtho‐γ‐pyrones. Magn Reson Chem 1986; 24: 875-878
38 Akiyama K, Teraguchi S, Hamasaki Y, Mori M, Tatsumi K, Ohnishi K, Hayashi H. New dimeric naphthopyrones from Aspergillus niger . J Nat Prod 2003; 66: 136-139
39 Pilevneli AD, Ebada SS, Kaşkatepe B, Konuklugil B. Penicacids H–J, three new mycophenolic acid derivatives from the marine-derived fungus Rhizopus oryzae . RSC Adv 2021; 11: 34938-34944
40 Loach RP, Fenton OS, Movassaghi M. Concise total synthesis of (+)-asperazine,(+)-pestalazine A, and (+)-iso-pestalazine A. Structure revision of (+)-pestalazine A. J Am Chem Soc 2016; 138: 1057-1064
41 Jiménez-Arreola BS, Aguilar-Ramírez E, Cano-Sánchez P, Morales-Jiménez J, González-Andrade M, Medina-Franco JL, Rivera-Chávez J. Dimeric phenalenones from Talaromyces sp.(IQ-313) inhibit hPTP1B1–400: insights into mechanistic kinetics from in vitro and in silico studies. Bioorg Chem 2020; 101: 103893
42 Martínez-Aldino IY, Villaseca-Murillo M, Morales-Jiménez J, Rivera-Chávez J. Absolute configuration and protein tyrosine phosphatase 1B inhibitory activity of xanthoepocin, a dimeric naphtopyrone from Penicillium sp. IQ-429. Bioorg Chem 2021; 115: 105166
43 Elhassan RM, Hou X, Fang H. Recent advances in the development of allosteric protein tyrosine phosphatase inhibitors for drug discovery. Med Res Rev 2022; 42: 1064-1110
44 Krishnan N, Koveal D, Miller DH, Xue B, Akshinthala SD, Kragelj J, Jensen MR, Gauss CM, Page R, Blackledge M. Targeting the disordered C terminus of PTP1B with an allosteric inhibitor. Nat Chem Biol 2014; 10: 558-566
45 Zhang ZY, Wang Y, Dixon JE. Dissecting the catalytic mechanism of protein-tyrosine phosphatases. Proc Natl Acad Sci U S A 1994; 91: 1624-1627
46 Choy MS, Li Y, Machado LE, Kunze MB, Connors CR, Wei X, Lindorff-Larsen K, Page R, Peti W. Conformational rigidity and protein dynamics at distinct timescales regulate PTP1B activity and allostery. Mol Cell 2017; 65: 644-658
47 Whittier SK, Hengge AC, Loria JP. Conformational motions regulate phosphoryl transfer in related protein tyrosine phosphatases. Science 2013; 341: 899-903
48 Tamura K, Stecher G, Kumar S. MEGA11: molecular evolutionary genetics analysis version 11. Mol Biol Evol 2021; 38: 3022-3027
49 Aron AT, Gentry EC, McPhail KL, Nothias LF, Nothias-Esposito M, Bouslimani A, Petras D, Gauglitz JM, Sikora N, Vargas F. Reproducible molecular networking of untargeted mass spectrometry data using GNPS. Nat Protoc 2020; 15: 1954-1991
50 Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T. Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res 2003; 13: 2498-2504
51 Aguilar-Ramírez E, Reyes-Pérez V, Fajardo-Hernández CA, Quezada-Suaste CD, Carreón-Escalante M, Merlin-Lucas V, Quiroz-García B, Granados-Soto V, Rivera-Chávez J. Harnessing the reactivity of duclauxin toward obtaining hPTP1 B_1–400 inhibitors. J Med Chem 2023; 66: 16222-16234

Zusatzmaterial

Ergänzendes Material