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Insights into specificity and catalytic mechanism of amphotericin B/nystatin thioesterase
Polyene polyketides amphotericin B (AMB) and nystatin (NYS) are important antifungal drugs. Thioesterases (TEs), located at the last module of PKS, control the release of polyketides by cyclization or hydrolysis. Intrigued by the tiny structural difference between AMB and NYS, as well as the high se...
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Published in: | Proteins, structure, function, and bioinformatics structure, function, and bioinformatics, 2021-05, Vol.89 (5), p.558-568 |
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description | Polyene polyketides amphotericin B (AMB) and nystatin (NYS) are important antifungal drugs. Thioesterases (TEs), located at the last module of PKS, control the release of polyketides by cyclization or hydrolysis. Intrigued by the tiny structural difference between AMB and NYS, as well as the high sequence identity between AMB TE and NYS TE, we constructed four systems to study the structural characteristics, catalytic mechanism, and product release of AMB TE and NYS TE with combined MD simulations and quantum mechanics/molecular mechanics calculations. The results indicated that compared with AMB TE, NYS TE shows higher specificity on its natural substrate and R26 as well as D186 were proposed to a key role in substrate recognition. The energy barrier of macrocyclization in AMB‐TE‐Amb and AMB‐TE‐Nys systems were calculated to be 14.0 and 22.7 kcal/mol, while in NYS‐TE‐Nys and NYS‐TE‐Amb systems, their energy barriers were 17.5 and 25.7 kcal/mol, suggesting the cyclization with their natural substrates were more favorable than that with exchanged substrates. At last, the binding free energy obtained with the MM‐PBSA.py program suggested that it was easier for natural products to leave TE enzymes after cyclization. And key residues to the departure of polyketide product from the active site were highlighted. We provided a catalytic overview of AMB TE and NYS TE including substrate recognition, catalytic mechanism and product release. These will improve the comprehension of polyene polyketide TEs and benefit for broadening the substrate flexibility of polyketide TEs. |
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Thioesterases (TEs), located at the last module of PKS, control the release of polyketides by cyclization or hydrolysis. Intrigued by the tiny structural difference between AMB and NYS, as well as the high sequence identity between AMB TE and NYS TE, we constructed four systems to study the structural characteristics, catalytic mechanism, and product release of AMB TE and NYS TE with combined MD simulations and quantum mechanics/molecular mechanics calculations. The results indicated that compared with AMB TE, NYS TE shows higher specificity on its natural substrate and R26 as well as D186 were proposed to a key role in substrate recognition. The energy barrier of macrocyclization in AMB‐TE‐Amb and AMB‐TE‐Nys systems were calculated to be 14.0 and 22.7 kcal/mol, while in NYS‐TE‐Nys and NYS‐TE‐Amb systems, their energy barriers were 17.5 and 25.7 kcal/mol, suggesting the cyclization with their natural substrates were more favorable than that with exchanged substrates. At last, the binding free energy obtained with the MM‐PBSA.py program suggested that it was easier for natural products to leave TE enzymes after cyclization. And key residues to the departure of polyketide product from the active site were highlighted. We provided a catalytic overview of AMB TE and NYS TE including substrate recognition, catalytic mechanism and product release. These will improve the comprehension of polyene polyketide TEs and benefit for broadening the substrate flexibility of polyketide TEs.</description><identifier>ISSN: 0887-3585</identifier><identifier>EISSN: 1097-0134</identifier><identifier>DOI: 10.1002/prot.26041</identifier><identifier>PMID: 33389775</identifier><language>eng</language><publisher>Hoboken, USA: John Wiley & Sons, Inc</publisher><subject>Amphotericin B ; Antifungal agents ; Free energy ; Fungicides ; macrocyclization ; Mathematical analysis ; MD simulations ; Natural products ; Nystatin ; Polyketides ; QM/MM calculations ; Quantum mechanics ; Recognition ; Substrates ; Thioesterase</subject><ispartof>Proteins, structure, function, and bioinformatics, 2021-05, Vol.89 (5), p.558-568</ispartof><rights>2021 Wiley Periodicals LLC</rights><rights>2021 Wiley Periodicals LLC.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3931-1931fa88fbd487dfa242e2876ce51f91ba892c64da6e27585a87c97d5d259ef83</citedby><cites>FETCH-LOGICAL-c3931-1931fa88fbd487dfa242e2876ce51f91ba892c64da6e27585a87c97d5d259ef83</cites><orcidid>0000-0003-3921-4412</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33389775$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Rufan</creatorcontrib><creatorcontrib>Tao, Wentao</creatorcontrib><creatorcontrib>Liu, Lei</creatorcontrib><creatorcontrib>Li, Chen</creatorcontrib><creatorcontrib>Bai, Linquan</creatorcontrib><creatorcontrib>Zhao, Yi‐Lei</creatorcontrib><creatorcontrib>Shi, Ting</creatorcontrib><title>Insights into specificity and catalytic mechanism of amphotericin B/nystatin thioesterase</title><title>Proteins, structure, function, and bioinformatics</title><addtitle>Proteins</addtitle><description>Polyene polyketides amphotericin B (AMB) and nystatin (NYS) are important antifungal drugs. Thioesterases (TEs), located at the last module of PKS, control the release of polyketides by cyclization or hydrolysis. Intrigued by the tiny structural difference between AMB and NYS, as well as the high sequence identity between AMB TE and NYS TE, we constructed four systems to study the structural characteristics, catalytic mechanism, and product release of AMB TE and NYS TE with combined MD simulations and quantum mechanics/molecular mechanics calculations. The results indicated that compared with AMB TE, NYS TE shows higher specificity on its natural substrate and R26 as well as D186 were proposed to a key role in substrate recognition. The energy barrier of macrocyclization in AMB‐TE‐Amb and AMB‐TE‐Nys systems were calculated to be 14.0 and 22.7 kcal/mol, while in NYS‐TE‐Nys and NYS‐TE‐Amb systems, their energy barriers were 17.5 and 25.7 kcal/mol, suggesting the cyclization with their natural substrates were more favorable than that with exchanged substrates. At last, the binding free energy obtained with the MM‐PBSA.py program suggested that it was easier for natural products to leave TE enzymes after cyclization. And key residues to the departure of polyketide product from the active site were highlighted. We provided a catalytic overview of AMB TE and NYS TE including substrate recognition, catalytic mechanism and product release. These will improve the comprehension of polyene polyketide TEs and benefit for broadening the substrate flexibility of polyketide TEs.</description><subject>Amphotericin B</subject><subject>Antifungal agents</subject><subject>Free energy</subject><subject>Fungicides</subject><subject>macrocyclization</subject><subject>Mathematical analysis</subject><subject>MD simulations</subject><subject>Natural products</subject><subject>Nystatin</subject><subject>Polyketides</subject><subject>QM/MM calculations</subject><subject>Quantum mechanics</subject><subject>Recognition</subject><subject>Substrates</subject><subject>Thioesterase</subject><issn>0887-3585</issn><issn>1097-0134</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNp9kMtKAzEUhoMotlY3PoAMuBFh2lwmk2SpxUtBqEhduAppJrEpc6mTDDJvb2qrCxducgLn4z_nfACcIzhGEOLJpm3CGOcwQwdgiKBgKUQkOwRDyDlLCeV0AE68X0MIc0HyYzAghHDBGB2Ct1nt3fsq-MTVoUn8xmhnnXahT1RdJFoFVfbB6aQyeqVq56uksYmqNqsmmDaCdXI7qXsfVIjfsHKN8bGhvDkFR1aV3pzt6wi83t8tpo_p0_xhNr15SjURBKUoPlZxbpdFxllhFc6wwZzl2lBkBVoqLrDOs0LlBrN4i-JMC1bQAlNhLCcjcLXLjRo-ujhdVs5rU5aqNk3nJc4YjSJwhiJ6-QddN11bx-0kplBgTBDNInW9o3TbeN8aKzetq1TbSwTlVrjcCpffwiN8sY_slpUpftEfwxFAO-DTlab_J0o-v8wXu9AvVD2L-w</recordid><startdate>202105</startdate><enddate>202105</enddate><creator>Wang, Rufan</creator><creator>Tao, Wentao</creator><creator>Liu, Lei</creator><creator>Li, Chen</creator><creator>Bai, Linquan</creator><creator>Zhao, Yi‐Lei</creator><creator>Shi, Ting</creator><general>John Wiley & Sons, Inc</general><general>Wiley Subscription Services, Inc</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>7QO</scope><scope>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-3921-4412</orcidid></search><sort><creationdate>202105</creationdate><title>Insights into specificity and catalytic mechanism of amphotericin B/nystatin thioesterase</title><author>Wang, Rufan ; Tao, Wentao ; Liu, Lei ; Li, Chen ; Bai, Linquan ; Zhao, Yi‐Lei ; Shi, Ting</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3931-1931fa88fbd487dfa242e2876ce51f91ba892c64da6e27585a87c97d5d259ef83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Amphotericin B</topic><topic>Antifungal agents</topic><topic>Free energy</topic><topic>Fungicides</topic><topic>macrocyclization</topic><topic>Mathematical analysis</topic><topic>MD simulations</topic><topic>Natural products</topic><topic>Nystatin</topic><topic>Polyketides</topic><topic>QM/MM calculations</topic><topic>Quantum mechanics</topic><topic>Recognition</topic><topic>Substrates</topic><topic>Thioesterase</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Rufan</creatorcontrib><creatorcontrib>Tao, Wentao</creatorcontrib><creatorcontrib>Liu, Lei</creatorcontrib><creatorcontrib>Li, Chen</creatorcontrib><creatorcontrib>Bai, Linquan</creatorcontrib><creatorcontrib>Zhao, Yi‐Lei</creatorcontrib><creatorcontrib>Shi, Ting</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Proteins, structure, function, and bioinformatics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Rufan</au><au>Tao, Wentao</au><au>Liu, Lei</au><au>Li, Chen</au><au>Bai, Linquan</au><au>Zhao, Yi‐Lei</au><au>Shi, Ting</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Insights into specificity and catalytic mechanism of amphotericin B/nystatin thioesterase</atitle><jtitle>Proteins, structure, function, and bioinformatics</jtitle><addtitle>Proteins</addtitle><date>2021-05</date><risdate>2021</risdate><volume>89</volume><issue>5</issue><spage>558</spage><epage>568</epage><pages>558-568</pages><issn>0887-3585</issn><eissn>1097-0134</eissn><abstract>Polyene polyketides amphotericin B (AMB) and nystatin (NYS) are important antifungal drugs. Thioesterases (TEs), located at the last module of PKS, control the release of polyketides by cyclization or hydrolysis. Intrigued by the tiny structural difference between AMB and NYS, as well as the high sequence identity between AMB TE and NYS TE, we constructed four systems to study the structural characteristics, catalytic mechanism, and product release of AMB TE and NYS TE with combined MD simulations and quantum mechanics/molecular mechanics calculations. The results indicated that compared with AMB TE, NYS TE shows higher specificity on its natural substrate and R26 as well as D186 were proposed to a key role in substrate recognition. The energy barrier of macrocyclization in AMB‐TE‐Amb and AMB‐TE‐Nys systems were calculated to be 14.0 and 22.7 kcal/mol, while in NYS‐TE‐Nys and NYS‐TE‐Amb systems, their energy barriers were 17.5 and 25.7 kcal/mol, suggesting the cyclization with their natural substrates were more favorable than that with exchanged substrates. At last, the binding free energy obtained with the MM‐PBSA.py program suggested that it was easier for natural products to leave TE enzymes after cyclization. And key residues to the departure of polyketide product from the active site were highlighted. We provided a catalytic overview of AMB TE and NYS TE including substrate recognition, catalytic mechanism and product release. These will improve the comprehension of polyene polyketide TEs and benefit for broadening the substrate flexibility of polyketide TEs.</abstract><cop>Hoboken, USA</cop><pub>John Wiley & Sons, Inc</pub><pmid>33389775</pmid><doi>10.1002/prot.26041</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0003-3921-4412</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Amphotericin B Antifungal agents Free energy Fungicides macrocyclization Mathematical analysis MD simulations Natural products Nystatin Polyketides QM/MM calculations Quantum mechanics Recognition Substrates Thioesterase |
title | Insights into specificity and catalytic mechanism of amphotericin B/nystatin thioesterase |
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