Biosynthesis of the Bis-Prenylated Alkaloids Muscoride A and B
Prenylation is a common step in the biosynthesis of many natural products and plays an important role in increasing their structural diversity and enhancing biological activity. Muscoride A is a linear peptide alkaloid that contain two contiguous oxazoles and unusual prenyl groups that protect the a...
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| Veröffentlicht in: | ACS chemical biology 2019-12, Vol.14 (12), p.2683-2690 |
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| creator | Mattila, Antti Andsten, Rose-Marie Jumppanen, Mikael Assante, Michele Jokela, Jouni Wahlsten, Matti Mikula, Kornelia M Sigindere, Cihad Kwak, Daniel H Gugger, Muriel Koskela, Harri Sivonen, Kaarina Liu, Xinyu Yli-Kauhaluoma, Jari Iwaï, Hideo Fewer, David P |
| description | Prenylation is a common step in the biosynthesis of many natural products and plays an important role in increasing their structural diversity and enhancing biological activity. Muscoride A is a linear peptide alkaloid that contain two contiguous oxazoles and unusual prenyl groups that protect the amino- and carboxy-termini. Here we identified the 12.7 kb muscoride (mus) biosynthetic gene clusters from Nostoc spp. PCC 7906 and UHCC 0398. The mus biosynthetic gene clusters encode enzymes for the heterocyclization, oxidation, and prenylation of the MusE precursor protein. The mus biosynthetic gene clusters encode two copies of the cyanobactin prenyltransferase, MusF1 and MusF2. The predicted tetrapeptide substrate of MusF1 and MusF2 was synthesized through a novel tandem cyclization route in only eight steps. Biochemical assays demonstrated that MusF1 acts on the carboxy-terminus while MusF2 acts on the amino-terminus of the tetrapeptide substrate. We show that the MusF2 enzyme catalyzes the reverse or forward prenylation of amino-termini from Nostoc spp. PCC 7906 and UHCC 0398, respectively. This finding expands the regiospecific chemical functionality of cyanobactin prenyltransferases and the chemical diversity of the cyanobactin family of natural products to include bis-prenylated polyoxazole linear peptides. |
| doi_str_mv | 10.1021/acschembio.9b00620 |
| format | Article |
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Muscoride A is a linear peptide alkaloid that contain two contiguous oxazoles and unusual prenyl groups that protect the amino- and carboxy-termini. Here we identified the 12.7 kb muscoride (mus) biosynthetic gene clusters from Nostoc spp. PCC 7906 and UHCC 0398. The mus biosynthetic gene clusters encode enzymes for the heterocyclization, oxidation, and prenylation of the MusE precursor protein. The mus biosynthetic gene clusters encode two copies of the cyanobactin prenyltransferase, MusF1 and MusF2. The predicted tetrapeptide substrate of MusF1 and MusF2 was synthesized through a novel tandem cyclization route in only eight steps. Biochemical assays demonstrated that MusF1 acts on the carboxy-terminus while MusF2 acts on the amino-terminus of the tetrapeptide substrate. We show that the MusF2 enzyme catalyzes the reverse or forward prenylation of amino-termini from Nostoc spp. PCC 7906 and UHCC 0398, respectively. This finding expands the regiospecific chemical functionality of cyanobactin prenyltransferases and the chemical diversity of the cyanobactin family of natural products to include bis-prenylated polyoxazole linear peptides.</description><identifier>ISSN: 1554-8929</identifier><identifier>EISSN: 1554-8937</identifier><identifier>DOI: 10.1021/acschembio.9b00620</identifier><identifier>PMID: 31674754</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Biosynthetic Pathways ; Biosynthetic Pathways - genetics ; Dimethylallyltranstransferase ; Dimethylallyltranstransferase - genetics ; Dimethylallyltranstransferase - metabolism ; Life Sciences ; Multigene Family ; Oxazoles ; Oxazoles - metabolism ; Peptides, Cyclic ; Peptides, Cyclic - metabolism ; Prenylation ; Pyrrolidines ; Pyrrolidines - metabolism</subject><ispartof>ACS chemical biology, 2019-12, Vol.14 (12), p.2683-2690</ispartof><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a490t-9f9200c28c02c1b44c595657bb78afcdceab6e72ab34bdb6dc551ce7a80b34053</citedby><cites>FETCH-LOGICAL-a490t-9f9200c28c02c1b44c595657bb78afcdceab6e72ab34bdb6dc551ce7a80b34053</cites><orcidid>0000-0002-2904-0458 ; 0000-0001-5096-3575 ; 0000-0002-7078-9671 ; 0000-0001-7376-5264 ; 0000-0003-0370-7653 ; 0000-0002-4107-1695 ; 0000-0003-3978-4845</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acschembio.9b00620$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acschembio.9b00620$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,314,776,780,881,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31674754$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://pasteur.hal.science/pasteur-03026836$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Mattila, Antti</creatorcontrib><creatorcontrib>Andsten, Rose-Marie</creatorcontrib><creatorcontrib>Jumppanen, Mikael</creatorcontrib><creatorcontrib>Assante, Michele</creatorcontrib><creatorcontrib>Jokela, Jouni</creatorcontrib><creatorcontrib>Wahlsten, Matti</creatorcontrib><creatorcontrib>Mikula, Kornelia M</creatorcontrib><creatorcontrib>Sigindere, Cihad</creatorcontrib><creatorcontrib>Kwak, Daniel H</creatorcontrib><creatorcontrib>Gugger, Muriel</creatorcontrib><creatorcontrib>Koskela, Harri</creatorcontrib><creatorcontrib>Sivonen, Kaarina</creatorcontrib><creatorcontrib>Liu, Xinyu</creatorcontrib><creatorcontrib>Yli-Kauhaluoma, Jari</creatorcontrib><creatorcontrib>Iwaï, Hideo</creatorcontrib><creatorcontrib>Fewer, David P</creatorcontrib><title>Biosynthesis of the Bis-Prenylated Alkaloids Muscoride A and B</title><title>ACS chemical biology</title><addtitle>ACS Chem. Biol</addtitle><description>Prenylation is a common step in the biosynthesis of many natural products and plays an important role in increasing their structural diversity and enhancing biological activity. Muscoride A is a linear peptide alkaloid that contain two contiguous oxazoles and unusual prenyl groups that protect the amino- and carboxy-termini. Here we identified the 12.7 kb muscoride (mus) biosynthetic gene clusters from Nostoc spp. PCC 7906 and UHCC 0398. The mus biosynthetic gene clusters encode enzymes for the heterocyclization, oxidation, and prenylation of the MusE precursor protein. The mus biosynthetic gene clusters encode two copies of the cyanobactin prenyltransferase, MusF1 and MusF2. The predicted tetrapeptide substrate of MusF1 and MusF2 was synthesized through a novel tandem cyclization route in only eight steps. Biochemical assays demonstrated that MusF1 acts on the carboxy-terminus while MusF2 acts on the amino-terminus of the tetrapeptide substrate. We show that the MusF2 enzyme catalyzes the reverse or forward prenylation of amino-termini from Nostoc spp. PCC 7906 and UHCC 0398, respectively. This finding expands the regiospecific chemical functionality of cyanobactin prenyltransferases and the chemical diversity of the cyanobactin family of natural products to include bis-prenylated polyoxazole linear peptides.</description><subject>Biosynthetic Pathways</subject><subject>Biosynthetic Pathways - genetics</subject><subject>Dimethylallyltranstransferase</subject><subject>Dimethylallyltranstransferase - genetics</subject><subject>Dimethylallyltranstransferase - metabolism</subject><subject>Life Sciences</subject><subject>Multigene Family</subject><subject>Oxazoles</subject><subject>Oxazoles - metabolism</subject><subject>Peptides, Cyclic</subject><subject>Peptides, Cyclic - metabolism</subject><subject>Prenylation</subject><subject>Pyrrolidines</subject><subject>Pyrrolidines - metabolism</subject><issn>1554-8929</issn><issn>1554-8937</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kEFLwzAYhoMoTqd_wIPk6KUzSZu0uQjdUCdM9KDnkKQpy2ybmbTC_r2Rznnz9H18PO_7wQPAFUYzjAi-lTrotWmVdTOuEGIEHYEzTGmWFDzNjw874RNwHsIGoSxlBT8FkxSzPMtpdgbu5taFXdevTbABuhrGDc5tSF696XaN7E0Fy-ZDNs5WAT4PQTtvKwNLKLsKzi_ASS2bYC73cwreH-7fFstk9fL4tChXicw46hNec4KQJoVGRGOVZZpyymiuVF7IWlfaSMVMTqRKM1UpVmlKsTa5LFC8IJpOQTL2rmUjtt620u-Ek1Ysy5XYytCbwQuUIsKKlH3hyN-M_Na7z8GEXrQ2aNM0sjNuCIKkGMf_BWURJSOqvQvBm_rQj5H48Sz-PIu95xi63vcPqjXVIfIrNgKzEYhhsXGD76Ke_xq_AZL8iig</recordid><startdate>20191220</startdate><enddate>20191220</enddate><creator>Mattila, Antti</creator><creator>Andsten, Rose-Marie</creator><creator>Jumppanen, Mikael</creator><creator>Assante, Michele</creator><creator>Jokela, Jouni</creator><creator>Wahlsten, Matti</creator><creator>Mikula, Kornelia M</creator><creator>Sigindere, Cihad</creator><creator>Kwak, Daniel H</creator><creator>Gugger, Muriel</creator><creator>Koskela, Harri</creator><creator>Sivonen, Kaarina</creator><creator>Liu, Xinyu</creator><creator>Yli-Kauhaluoma, Jari</creator><creator>Iwaï, Hideo</creator><creator>Fewer, David P</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>1XC</scope><orcidid>https://orcid.org/0000-0002-2904-0458</orcidid><orcidid>https://orcid.org/0000-0001-5096-3575</orcidid><orcidid>https://orcid.org/0000-0002-7078-9671</orcidid><orcidid>https://orcid.org/0000-0001-7376-5264</orcidid><orcidid>https://orcid.org/0000-0003-0370-7653</orcidid><orcidid>https://orcid.org/0000-0002-4107-1695</orcidid><orcidid>https://orcid.org/0000-0003-3978-4845</orcidid></search><sort><creationdate>20191220</creationdate><title>Biosynthesis of the Bis-Prenylated Alkaloids Muscoride A and B</title><author>Mattila, Antti ; Andsten, Rose-Marie ; Jumppanen, Mikael ; Assante, Michele ; Jokela, Jouni ; Wahlsten, Matti ; Mikula, Kornelia M ; Sigindere, Cihad ; Kwak, Daniel H ; Gugger, Muriel ; Koskela, Harri ; Sivonen, Kaarina ; Liu, Xinyu ; Yli-Kauhaluoma, Jari ; Iwaï, Hideo ; Fewer, David P</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a490t-9f9200c28c02c1b44c595657bb78afcdceab6e72ab34bdb6dc551ce7a80b34053</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Biosynthetic Pathways</topic><topic>Biosynthetic Pathways - genetics</topic><topic>Dimethylallyltranstransferase</topic><topic>Dimethylallyltranstransferase - genetics</topic><topic>Dimethylallyltranstransferase - metabolism</topic><topic>Life Sciences</topic><topic>Multigene Family</topic><topic>Oxazoles</topic><topic>Oxazoles - metabolism</topic><topic>Peptides, Cyclic</topic><topic>Peptides, Cyclic - metabolism</topic><topic>Prenylation</topic><topic>Pyrrolidines</topic><topic>Pyrrolidines - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mattila, Antti</creatorcontrib><creatorcontrib>Andsten, Rose-Marie</creatorcontrib><creatorcontrib>Jumppanen, Mikael</creatorcontrib><creatorcontrib>Assante, Michele</creatorcontrib><creatorcontrib>Jokela, Jouni</creatorcontrib><creatorcontrib>Wahlsten, Matti</creatorcontrib><creatorcontrib>Mikula, Kornelia M</creatorcontrib><creatorcontrib>Sigindere, Cihad</creatorcontrib><creatorcontrib>Kwak, Daniel H</creatorcontrib><creatorcontrib>Gugger, Muriel</creatorcontrib><creatorcontrib>Koskela, Harri</creatorcontrib><creatorcontrib>Sivonen, Kaarina</creatorcontrib><creatorcontrib>Liu, Xinyu</creatorcontrib><creatorcontrib>Yli-Kauhaluoma, Jari</creatorcontrib><creatorcontrib>Iwaï, Hideo</creatorcontrib><creatorcontrib>Fewer, David P</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><jtitle>ACS chemical biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mattila, Antti</au><au>Andsten, Rose-Marie</au><au>Jumppanen, Mikael</au><au>Assante, Michele</au><au>Jokela, Jouni</au><au>Wahlsten, Matti</au><au>Mikula, Kornelia M</au><au>Sigindere, Cihad</au><au>Kwak, Daniel H</au><au>Gugger, Muriel</au><au>Koskela, Harri</au><au>Sivonen, Kaarina</au><au>Liu, Xinyu</au><au>Yli-Kauhaluoma, Jari</au><au>Iwaï, Hideo</au><au>Fewer, David P</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Biosynthesis of the Bis-Prenylated Alkaloids Muscoride A and B</atitle><jtitle>ACS chemical biology</jtitle><addtitle>ACS Chem. Biol</addtitle><date>2019-12-20</date><risdate>2019</risdate><volume>14</volume><issue>12</issue><spage>2683</spage><epage>2690</epage><pages>2683-2690</pages><issn>1554-8929</issn><eissn>1554-8937</eissn><abstract>Prenylation is a common step in the biosynthesis of many natural products and plays an important role in increasing their structural diversity and enhancing biological activity. Muscoride A is a linear peptide alkaloid that contain two contiguous oxazoles and unusual prenyl groups that protect the amino- and carboxy-termini. Here we identified the 12.7 kb muscoride (mus) biosynthetic gene clusters from Nostoc spp. PCC 7906 and UHCC 0398. The mus biosynthetic gene clusters encode enzymes for the heterocyclization, oxidation, and prenylation of the MusE precursor protein. The mus biosynthetic gene clusters encode two copies of the cyanobactin prenyltransferase, MusF1 and MusF2. The predicted tetrapeptide substrate of MusF1 and MusF2 was synthesized through a novel tandem cyclization route in only eight steps. Biochemical assays demonstrated that MusF1 acts on the carboxy-terminus while MusF2 acts on the amino-terminus of the tetrapeptide substrate. We show that the MusF2 enzyme catalyzes the reverse or forward prenylation of amino-termini from Nostoc spp. PCC 7906 and UHCC 0398, respectively. This finding expands the regiospecific chemical functionality of cyanobactin prenyltransferases and the chemical diversity of the cyanobactin family of natural products to include bis-prenylated polyoxazole linear peptides.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>31674754</pmid><doi>10.1021/acschembio.9b00620</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0002-2904-0458</orcidid><orcidid>https://orcid.org/0000-0001-5096-3575</orcidid><orcidid>https://orcid.org/0000-0002-7078-9671</orcidid><orcidid>https://orcid.org/0000-0001-7376-5264</orcidid><orcidid>https://orcid.org/0000-0003-0370-7653</orcidid><orcidid>https://orcid.org/0000-0002-4107-1695</orcidid><orcidid>https://orcid.org/0000-0003-3978-4845</orcidid><oa>free_for_read</oa></addata></record> |
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| source | ACS Publications; MEDLINE |
| subjects | Biosynthetic Pathways Biosynthetic Pathways - genetics Dimethylallyltranstransferase Dimethylallyltranstransferase - genetics Dimethylallyltranstransferase - metabolism Life Sciences Multigene Family Oxazoles Oxazoles - metabolism Peptides, Cyclic Peptides, Cyclic - metabolism Prenylation Pyrrolidines Pyrrolidines - metabolism |
| title | Biosynthesis of the Bis-Prenylated Alkaloids Muscoride A and B |
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