Mycobacterial Phenolic Glycolipid Virulence Factor Biosynthesis: Mechanism and Small-Molecule Inhibition of Polyketide Chain Initiation
Phenolic glycolipids (PGLs) are polyketide-derived virulence factors produced by Mycobacterium tuberculosis, M. leprae, and other mycobacterial pathogens. We have combined bioinformatic, genetic, biochemical, and chemical biology approaches to illuminate the mechanism of chain initiation required fo...
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| Veröffentlicht in: | Chemistry & biology 2008-01, Vol.15 (1), p.51-61 |
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| creator | Ferreras, Julian A. Stirrett, Karen L. Lu, Xuequan Ryu, Jae-Sang Soll, Clifford E. Tan, Derek S. Quadri, Luis E.N. |
| description | Phenolic glycolipids (PGLs) are polyketide-derived virulence factors produced by
Mycobacterium tuberculosis,
M. leprae, and other mycobacterial pathogens. We have combined bioinformatic, genetic, biochemical, and chemical biology approaches to illuminate the mechanism of chain initiation required for assembly of the
p-hydroxyphenyl-polyketide moiety of PGLs. Our studies have led to the identification of a stand-alone, didomain initiation module, FadD22, comprised of a
p-hydroxybenzoic acid adenylation domain and an aroyl carrier protein domain. FadD22 forms an acyl-
S-enzyme covalent intermediate in the
p-hydroxyphenyl-polyketide chain assembly line. We also used this information to develop a small-molecule inhibitor of PGL biosynthesis. Overall, these studies provide insights into the biosynthesis of an important group of small-molecule mycobacterial virulence factors and support the feasibility of targeting PGL biosynthesis to develop new drugs to treat mycobacterial infections. |
| doi_str_mv | 10.1016/j.chembiol.2007.11.010 |
| format | Article |
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Mycobacterium tuberculosis,
M. leprae, and other mycobacterial pathogens. We have combined bioinformatic, genetic, biochemical, and chemical biology approaches to illuminate the mechanism of chain initiation required for assembly of the
p-hydroxyphenyl-polyketide moiety of PGLs. Our studies have led to the identification of a stand-alone, didomain initiation module, FadD22, comprised of a
p-hydroxybenzoic acid adenylation domain and an aroyl carrier protein domain. FadD22 forms an acyl-
S-enzyme covalent intermediate in the
p-hydroxyphenyl-polyketide chain assembly line. We also used this information to develop a small-molecule inhibitor of PGL biosynthesis. Overall, these studies provide insights into the biosynthesis of an important group of small-molecule mycobacterial virulence factors and support the feasibility of targeting PGL biosynthesis to develop new drugs to treat mycobacterial infections.</description><identifier>ISSN: 1074-5521</identifier><identifier>EISSN: 1879-1301</identifier><identifier>DOI: 10.1016/j.chembiol.2007.11.010</identifier><identifier>PMID: 18158259</identifier><language>eng</language><publisher>United States: Elsevier Ltd</publisher><subject>Adenosine - chemistry ; Adenosine - metabolism ; CHEMBIO ; Coenzyme A Ligases - antagonists & inhibitors ; Coenzyme A Ligases - metabolism ; Enzyme Inhibitors - pharmacology ; Glycolipids - antagonists & inhibitors ; Glycolipids - biosynthesis ; Glycolipids - chemistry ; Humans ; Macrolides - chemistry ; Macrolides - pharmacology ; MICROBIO ; Models, Chemical ; Mycobacterium leprae ; Mycobacterium tuberculosis ; Mycobacterium tuberculosis - enzymology ; Mycobacterium tuberculosis - genetics ; Parabens - chemistry ; Parabens - metabolism ; Phenols - antagonists & inhibitors ; Phenols - chemistry ; Phenols - metabolism ; Virulence Factors - antagonists & inhibitors ; Virulence Factors - biosynthesis ; Virulence Factors - chemistry</subject><ispartof>Chemistry & biology, 2008-01, Vol.15 (1), p.51-61</ispartof><rights>2008 Elsevier Ltd</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c511t-d25fd223fa94f6a8924f4f4a0102707383cab2eda5152d89fd7244c1570752e73</citedby><cites>FETCH-LOGICAL-c511t-d25fd223fa94f6a8924f4f4a0102707383cab2eda5152d89fd7244c1570752e73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.chembiol.2007.11.010$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18158259$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ferreras, Julian A.</creatorcontrib><creatorcontrib>Stirrett, Karen L.</creatorcontrib><creatorcontrib>Lu, Xuequan</creatorcontrib><creatorcontrib>Ryu, Jae-Sang</creatorcontrib><creatorcontrib>Soll, Clifford E.</creatorcontrib><creatorcontrib>Tan, Derek S.</creatorcontrib><creatorcontrib>Quadri, Luis E.N.</creatorcontrib><title>Mycobacterial Phenolic Glycolipid Virulence Factor Biosynthesis: Mechanism and Small-Molecule Inhibition of Polyketide Chain Initiation</title><title>Chemistry & biology</title><addtitle>Chem Biol</addtitle><description>Phenolic glycolipids (PGLs) are polyketide-derived virulence factors produced by
Mycobacterium tuberculosis,
M. leprae, and other mycobacterial pathogens. We have combined bioinformatic, genetic, biochemical, and chemical biology approaches to illuminate the mechanism of chain initiation required for assembly of the
p-hydroxyphenyl-polyketide moiety of PGLs. Our studies have led to the identification of a stand-alone, didomain initiation module, FadD22, comprised of a
p-hydroxybenzoic acid adenylation domain and an aroyl carrier protein domain. FadD22 forms an acyl-
S-enzyme covalent intermediate in the
p-hydroxyphenyl-polyketide chain assembly line. We also used this information to develop a small-molecule inhibitor of PGL biosynthesis. Overall, these studies provide insights into the biosynthesis of an important group of small-molecule mycobacterial virulence factors and support the feasibility of targeting PGL biosynthesis to develop new drugs to treat mycobacterial infections.</description><subject>Adenosine - chemistry</subject><subject>Adenosine - metabolism</subject><subject>CHEMBIO</subject><subject>Coenzyme A Ligases - antagonists & inhibitors</subject><subject>Coenzyme A Ligases - metabolism</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Glycolipids - antagonists & inhibitors</subject><subject>Glycolipids - biosynthesis</subject><subject>Glycolipids - chemistry</subject><subject>Humans</subject><subject>Macrolides - chemistry</subject><subject>Macrolides - pharmacology</subject><subject>MICROBIO</subject><subject>Models, Chemical</subject><subject>Mycobacterium leprae</subject><subject>Mycobacterium tuberculosis</subject><subject>Mycobacterium tuberculosis - enzymology</subject><subject>Mycobacterium tuberculosis - genetics</subject><subject>Parabens - chemistry</subject><subject>Parabens - metabolism</subject><subject>Phenols - antagonists & inhibitors</subject><subject>Phenols - chemistry</subject><subject>Phenols - metabolism</subject><subject>Virulence Factors - antagonists & inhibitors</subject><subject>Virulence Factors - biosynthesis</subject><subject>Virulence Factors - chemistry</subject><issn>1074-5521</issn><issn>1879-1301</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc9u1DAQxiNERUvLK1Q-cUvwOHH-cAJWtFTqqpWgXC3HniizOPFiZyvtE_DaeLWLOFY-2PL3-zwz_rLsGngBHOoPm8KMOPXkXSE4bwqAggN_lV1A23Q5lBxepzNvqlxKAefZ2xg3nHNou_pNdg4tyFbI7iL7s94b32uzYCDt2OOIs3dk2K1L9462ZNlPCjuHs0F2kzgf2BfycT8vI0aKH9kazahnihPTs2XfJ-1cvvYOTTKxu3mknhbyM_MDe_Ru_wsXsshWo6Y5yUnTB_kqOxu0i_jutF9mTzdff6y-5fcPt3erz_e5kQBLboUcrBDloLtqqHXbiWpIS6fZRcObsi2N7gVaLUEK23aDbURVGZBJlAKb8jJ7f3x3G_zvHcZFTRQNOqdn9LuoGi5EywV_EYRO1i0HkcD6CJrgYww4qG2gSYe9Aq4OWamN-peVOmSlAFTqNxmvTxV2_YT2v-0UTgI-HQFMH_JMGFQ0dAjCUkCzKOvppRp_AZ7Iqng</recordid><startdate>20080101</startdate><enddate>20080101</enddate><creator>Ferreras, Julian A.</creator><creator>Stirrett, Karen L.</creator><creator>Lu, Xuequan</creator><creator>Ryu, Jae-Sang</creator><creator>Soll, Clifford E.</creator><creator>Tan, Derek S.</creator><creator>Quadri, Luis E.N.</creator><general>Elsevier Ltd</general><scope>6I.</scope><scope>AAFTH</scope><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>7QL</scope><scope>7T7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20080101</creationdate><title>Mycobacterial Phenolic Glycolipid Virulence Factor Biosynthesis: Mechanism and Small-Molecule Inhibition of Polyketide Chain Initiation</title><author>Ferreras, Julian A. ; Stirrett, Karen L. ; Lu, Xuequan ; Ryu, Jae-Sang ; Soll, Clifford E. ; Tan, Derek S. ; Quadri, Luis E.N.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c511t-d25fd223fa94f6a8924f4f4a0102707383cab2eda5152d89fd7244c1570752e73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Adenosine - chemistry</topic><topic>Adenosine - metabolism</topic><topic>CHEMBIO</topic><topic>Coenzyme A Ligases - antagonists & inhibitors</topic><topic>Coenzyme A Ligases - metabolism</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Glycolipids - antagonists & inhibitors</topic><topic>Glycolipids - biosynthesis</topic><topic>Glycolipids - chemistry</topic><topic>Humans</topic><topic>Macrolides - chemistry</topic><topic>Macrolides - pharmacology</topic><topic>MICROBIO</topic><topic>Models, Chemical</topic><topic>Mycobacterium leprae</topic><topic>Mycobacterium tuberculosis</topic><topic>Mycobacterium tuberculosis - enzymology</topic><topic>Mycobacterium tuberculosis - genetics</topic><topic>Parabens - chemistry</topic><topic>Parabens - metabolism</topic><topic>Phenols - antagonists & inhibitors</topic><topic>Phenols - chemistry</topic><topic>Phenols - metabolism</topic><topic>Virulence Factors - antagonists & inhibitors</topic><topic>Virulence Factors - biosynthesis</topic><topic>Virulence Factors - chemistry</topic><toplevel>online_resources</toplevel><creatorcontrib>Ferreras, Julian A.</creatorcontrib><creatorcontrib>Stirrett, Karen L.</creatorcontrib><creatorcontrib>Lu, Xuequan</creatorcontrib><creatorcontrib>Ryu, Jae-Sang</creatorcontrib><creatorcontrib>Soll, Clifford E.</creatorcontrib><creatorcontrib>Tan, Derek S.</creatorcontrib><creatorcontrib>Quadri, Luis E.N.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Chemistry & biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ferreras, Julian A.</au><au>Stirrett, Karen L.</au><au>Lu, Xuequan</au><au>Ryu, Jae-Sang</au><au>Soll, Clifford E.</au><au>Tan, Derek S.</au><au>Quadri, Luis E.N.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mycobacterial Phenolic Glycolipid Virulence Factor Biosynthesis: Mechanism and Small-Molecule Inhibition of Polyketide Chain Initiation</atitle><jtitle>Chemistry & biology</jtitle><addtitle>Chem Biol</addtitle><date>2008-01-01</date><risdate>2008</risdate><volume>15</volume><issue>1</issue><spage>51</spage><epage>61</epage><pages>51-61</pages><issn>1074-5521</issn><eissn>1879-1301</eissn><abstract>Phenolic glycolipids (PGLs) are polyketide-derived virulence factors produced by
Mycobacterium tuberculosis,
M. leprae, and other mycobacterial pathogens. We have combined bioinformatic, genetic, biochemical, and chemical biology approaches to illuminate the mechanism of chain initiation required for assembly of the
p-hydroxyphenyl-polyketide moiety of PGLs. Our studies have led to the identification of a stand-alone, didomain initiation module, FadD22, comprised of a
p-hydroxybenzoic acid adenylation domain and an aroyl carrier protein domain. FadD22 forms an acyl-
S-enzyme covalent intermediate in the
p-hydroxyphenyl-polyketide chain assembly line. We also used this information to develop a small-molecule inhibitor of PGL biosynthesis. Overall, these studies provide insights into the biosynthesis of an important group of small-molecule mycobacterial virulence factors and support the feasibility of targeting PGL biosynthesis to develop new drugs to treat mycobacterial infections.</abstract><cop>United States</cop><pub>Elsevier Ltd</pub><pmid>18158259</pmid><doi>10.1016/j.chembiol.2007.11.010</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Full-Text Journals in Chemistry (Open access); Elsevier ScienceDirect Journals Complete; Cell Press Free Archives; EZB Electronic Journals Library |
| subjects | Adenosine - chemistry Adenosine - metabolism CHEMBIO Coenzyme A Ligases - antagonists & inhibitors Coenzyme A Ligases - metabolism Enzyme Inhibitors - pharmacology Glycolipids - antagonists & inhibitors Glycolipids - biosynthesis Glycolipids - chemistry Humans Macrolides - chemistry Macrolides - pharmacology MICROBIO Models, Chemical Mycobacterium leprae Mycobacterium tuberculosis Mycobacterium tuberculosis - enzymology Mycobacterium tuberculosis - genetics Parabens - chemistry Parabens - metabolism Phenols - antagonists & inhibitors Phenols - chemistry Phenols - metabolism Virulence Factors - antagonists & inhibitors Virulence Factors - biosynthesis Virulence Factors - chemistry |
| title | Mycobacterial Phenolic Glycolipid Virulence Factor Biosynthesis: Mechanism and Small-Molecule Inhibition of Polyketide Chain Initiation |
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