{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:05:50Z","timestamp":1760144750709,"version":"build-2065373602"},"reference-count":23,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2024,5,7]],"date-time":"2024-05-07T00:00:00Z","timestamp":1715040000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The Hainan Provincial Joint Project of Sanya Yazhou Bay Science and Technology City","award":["2021CXLH0008","22077113"],"award-info":[{"award-number":["2021CXLH0008","22077113"]}]},{"name":"The National Natural Science Foundation of China","award":["2021CXLH0008","22077113"],"award-info":[{"award-number":["2021CXLH0008","22077113"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Marine Drugs"],"abstract":"<jats:p>Naturally occurring echinocandin B and FR901379 are potent antifungal lipopeptides featuring a cyclic hexapeptide nucleus and a fatty acid side chain. They are the parent compounds of echinocandin drugs for the treatment of severe fungal infections caused by the Candida and Aspergilla species. To minimize hemolytic toxicity, the native fatty acid side chains in these drug molecules are replaced with designer acyl side chains. The deacylation of the N-acyl side chain is, therefore, a crucial step for the development and manufacturing of echinocandin-type antibiotics. Echinocandin E (ECE) is a novel echinocandin congener with enhanced stability generated via the engineering of the biosynthetic machinery of echinocandin B (ECB). In the present study, we report the discovery of the first echinocandin E acylase (ECEA) using the enzyme similarity tool (EST) for enzymatic function mining across protein families. ECEA is derived from Streptomyces sp. SY1965 isolated from a sediment collected from the Mariana Trench. It was cloned and heterologously expressed in S. lividans TK24. The resultant TKecea66 strain showed efficient cleavage activity of the acyl side chain of ECE, showing promising applications in the development of novel echinocandin-type therapeutics. Our results also provide a showcase for harnessing the essentially untapped biodiversity from the hadal ecosystems for the discovery of functional molecules.<\/jats:p>","DOI":"10.3390\/md22050212","type":"journal-article","created":{"date-parts":[[2024,5,7]],"date-time":"2024-05-07T06:53:27Z","timestamp":1715064807000},"page":"212","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Hadal Streptomyces-Derived Echinocandin Acylase Discovered through the Prioritization of Protein Families"],"prefix":"10.3390","volume":"22","author":[{"given":"Xuejian","family":"Jiang","sequence":"first","affiliation":[{"name":"Ocean College, Zhejiang University, Zhoushan 316021, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongjun","family":"Shu","sequence":"additional","affiliation":[{"name":"Ocean College, Zhejiang University, Zhoushan 316021, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuting","family":"Feng","sequence":"additional","affiliation":[{"name":"Ocean College, Zhejiang University, Zhoushan 316021, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2960-8573","authenticated-orcid":false,"given":"Pinmei","family":"Wang","sequence":"additional","affiliation":[{"name":"Ocean College, Zhejiang University, Zhoushan 316021, China"},{"name":"Hainan Institute of Zhejiang University, Sanya 572025, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8290-3507","authenticated-orcid":false,"given":"Zhizhen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Ocean College, Zhejiang University, Zhoushan 316021, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nan","family":"Wang","sequence":"additional","affiliation":[{"name":"Ocean College, Zhejiang University, Zhoushan 316021, China"},{"name":"Hainan Institute of Zhejiang University, Sanya 572025, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1016\/S0140-6736(03)14472-8","article-title":"Echinocandin antifungal drugs","volume":"362","author":"Denning","year":"2003","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/nyas.12831","article-title":"Mechanisms of echinocandin antifungal drug resistance","volume":"1354","author":"Perlin","year":"2015","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.ejim.2016.06.029","article-title":"Candidemia and invasive candidiasis in adults: A narrative review","volume":"34","author":"Antinori","year":"2016","journal-title":"Eur. J. Intern. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1080\/14756366.2022.2050224","article-title":"Echinocandins\u2014Structure, mechanism of action and use in antifungal therapy","volume":"37","author":"Chmielewska","year":"2022","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1007\/s40265-023-01891-8","article-title":"Rezafungin: First Approval","volume":"83","author":"Syed","year":"2023","journal-title":"Drugs"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1128\/AEM.02792-12","article-title":"Efficient Bioconversion of Echinocandin B to Its Nucleus by Overexpression of Deacylase Genes in Different Host Strains","volume":"79","author":"Shao","year":"2013","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1016\/j.ijbiomac.2021.07.146","article-title":"Functional expression of an echinocandin B deacylase from Actinoplanes utahensis in Escherichia coli","volume":"187","author":"Zou","year":"2021","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1038\/sj.jim.2900796","article-title":"Membrane-associated echinocandin B deacylase of Actinoplanes utahensis: Purification, characterization, heterologous cloning and enzymatic deacylation reaction","volume":"24","author":"Kreuzman","year":"2000","journal-title":"J. Ind. Microbiol. Biotechnol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1038\/ja.2010.151","article-title":"Cloning and expression of the FR901379 acylase gene from Streptomyces sp. no. 6907","volume":"64","author":"Ueda","year":"2011","journal-title":"J. Antibiot."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3552","DOI":"10.1039\/D3OB00075C","article-title":"Unnatural tetradeoxy echinocandins produced by gene cluster design and heterologous expression","volume":"21","author":"Yu","year":"2023","journal-title":"Org. Biomol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1128\/AEM.68.1.211-218.2002","article-title":"Cloning, sequence analysis, and expression in Escherichia coli of the gene encoding an alpha-amino acid ester hydrolase from Acetobacter turbidans","volume":"68","author":"Jekel","year":"2002","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4169","DOI":"10.1021\/acs.biochem.9b00735","article-title":"The EFI Web Resource for Genomic Enzymology Tools: Leveraging Protein, Genome, and Metagenome Databases to Discover Novel Enzymes and Metabolic Pathways","volume":"58","author":"Zallot","year":"2019","journal-title":"Biochemistry"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Oberg, N., Zallot, R., and Gerlt, J.A. (2023). EFI-EST, EFI-GNT, and EFI-CGFP: Enzyme Function Initiative (EFI) Web Resource for Genomic Enzymology Tools. J. Mol. Biol., 435.","DOI":"10.1016\/j.jmb.2023.168018"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1016\/j.bbapap.2015.04.015","article-title":"Enzyme Function Initiative-Enzyme Similarity Tool (EFI-EST): A web tool for generating protein sequence similarity networks","volume":"1854","author":"Gerlt","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1038\/nmeth.2212","article-title":"A travel guide to Cytoscape plugins","volume":"9","author":"Saito","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Yi, W., Qin, L., Lian, X.-Y., and Zhang, Z. (2020). New Antifungal Metabolites from the Mariana Trench Sediment-Associated Actinomycete Streptomyces sp. SY1965. Mar. Drugs, 18.","DOI":"10.3390\/md18080385"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1038\/s41467-022-28865-w","article-title":"Improved prediction of protein-protein interactions using AlphaFold2","volume":"13","author":"Bryant","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2329","DOI":"10.1110\/ps.9.12.2329","article-title":"Structural comparison of Ntn-hydrolases","volume":"9","author":"Oinonen","year":"2001","journal-title":"Protein Sci."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Linhorst, A., and L\u00fcbke, T. (2022). The Human Ntn-Hydrolase Superfamily: Structure, Functions and Perspectives. Cells, 11.","DOI":"10.3390\/cells11101592"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1016\/S0969-2126(00)00505-0","article-title":"The 2.0 \u00c5 Crystal Structure of Cephalosporin Acylase","volume":"8","author":"Kim","year":"2000","journal-title":"Structure"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.7164\/antibiotics.39.1304","article-title":"Transformation of Streptomyces erythraeus","volume":"39","author":"Yamamoto","year":"1986","journal-title":"J. Antibiot."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Elbing, K.L., and Brent, R. (2019). Recipes and Tools for Culture of Escherichia coli. Curr. Protoc. Mol. Biol., 125.","DOI":"10.1002\/cpmb.83"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3583","DOI":"10.1128\/jb.171.6.3583-3585.1989","article-title":"Intergeneric conjugation between Escherichia coli and Streptomyces species","volume":"171","author":"Mazodier","year":"1989","journal-title":"J. Bacteriol."}],"container-title":["Marine Drugs"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-3397\/22\/5\/212\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:40:43Z","timestamp":1760107243000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-3397\/22\/5\/212"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,7]]},"references-count":23,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2024,5]]}},"alternative-id":["md22050212"],"URL":"https:\/\/doi.org\/10.3390\/md22050212","relation":{},"ISSN":["1660-3397"],"issn-type":[{"type":"electronic","value":"1660-3397"}],"subject":[],"published":{"date-parts":[[2024,5,7]]}}}