A novel micellular fluorogenic substrate for quantitating the activity of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma
The activities of the phospholipase C gamma (PLC[gamma]) 1 and 2 enzymes are essential for numerous cellular processes. Unsurprisingly, dysregulation of PLC[gamma]1 or PLC[gamma]2 activity is associated with multiple maladies including immune disorders, cancers, and neurodegenerative diseases. There...
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| Veröffentlicht in: | PloS one 2024-03, Vol.19 (3), p.e0299541 |
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| container_title | PloS one |
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| creator | Clayton, W. Brent Lendy, Emma Zhang, Zhong-Yin Hering, Kirk W Beck, Daniel E Visvanathan, Ramya Liu, Yinghui Sun, Kuai-lin Mesecar, Andrew Utsuki, Tadanobu Putt, Karson S |
| description | The activities of the phospholipase C gamma (PLC[gamma]) 1 and 2 enzymes are essential for numerous cellular processes. Unsurprisingly, dysregulation of PLC[gamma]1 or PLC[gamma]2 activity is associated with multiple maladies including immune disorders, cancers, and neurodegenerative diseases. Therefore, the modulation of either of these two enzymes has been suggested as a therapeutic strategy to combat these diseases. To aid in the discovery of PLC[gamma] family enzyme modulators that could be developed into therapeutic agents, we have synthesized a high-throughput screening-amenable micellular fluorogenic substrate called C16CF3-coumarin. Herein, the ability of PLC[gamma]1 and PLC[gamma]2 to enzymatically process C16CF3-coumarin was confirmed, the micellular assay conditions were optimized, and the kinetics of the reaction were determined. A proof-of-principle pilot screen of the Library of Pharmacologically Active Compounds 1280 (LOPAC.sub.1280) was performed. This new substrate allows for an additional screening methodology to identify modulators of the PLC[gamma] family of enzymes. |
| doi_str_mv | 10.1371/journal.pone.0299541 |
| format | Article |
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Brent ; Lendy, Emma ; Zhang, Zhong-Yin ; Hering, Kirk W ; Beck, Daniel E ; Visvanathan, Ramya ; Liu, Yinghui ; Sun, Kuai-lin ; Mesecar, Andrew ; Utsuki, Tadanobu ; Putt, Karson S</creator><creatorcontrib>Clayton, W. Brent ; Lendy, Emma ; Zhang, Zhong-Yin ; Hering, Kirk W ; Beck, Daniel E ; Visvanathan, Ramya ; Liu, Yinghui ; Sun, Kuai-lin ; Mesecar, Andrew ; Utsuki, Tadanobu ; Putt, Karson S</creatorcontrib><description>The activities of the phospholipase C gamma (PLC[gamma]) 1 and 2 enzymes are essential for numerous cellular processes. Unsurprisingly, dysregulation of PLC[gamma]1 or PLC[gamma]2 activity is associated with multiple maladies including immune disorders, cancers, and neurodegenerative diseases. Therefore, the modulation of either of these two enzymes has been suggested as a therapeutic strategy to combat these diseases. To aid in the discovery of PLC[gamma] family enzyme modulators that could be developed into therapeutic agents, we have synthesized a high-throughput screening-amenable micellular fluorogenic substrate called C16CF3-coumarin. Herein, the ability of PLC[gamma]1 and PLC[gamma]2 to enzymatically process C16CF3-coumarin was confirmed, the micellular assay conditions were optimized, and the kinetics of the reaction were determined. A proof-of-principle pilot screen of the Library of Pharmacologically Active Compounds 1280 (LOPAC.sub.1280) was performed. 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Brent</creatorcontrib><creatorcontrib>Lendy, Emma</creatorcontrib><creatorcontrib>Zhang, Zhong-Yin</creatorcontrib><creatorcontrib>Hering, Kirk W</creatorcontrib><creatorcontrib>Beck, Daniel E</creatorcontrib><creatorcontrib>Visvanathan, Ramya</creatorcontrib><creatorcontrib>Liu, Yinghui</creatorcontrib><creatorcontrib>Sun, Kuai-lin</creatorcontrib><creatorcontrib>Mesecar, Andrew</creatorcontrib><creatorcontrib>Utsuki, Tadanobu</creatorcontrib><creatorcontrib>Putt, Karson S</creatorcontrib><collection>Gale In Context: Science</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Clayton, W. Brent</au><au>Lendy, Emma</au><au>Zhang, Zhong-Yin</au><au>Hering, Kirk W</au><au>Beck, Daniel E</au><au>Visvanathan, Ramya</au><au>Liu, Yinghui</au><au>Sun, Kuai-lin</au><au>Mesecar, Andrew</au><au>Utsuki, Tadanobu</au><au>Putt, Karson S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A novel micellular fluorogenic substrate for quantitating the activity of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma</atitle><jtitle>PloS one</jtitle><date>2024-03-29</date><risdate>2024</risdate><volume>19</volume><issue>3</issue><spage>e0299541</spage><pages>e0299541-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>The activities of the phospholipase C gamma (PLC[gamma]) 1 and 2 enzymes are essential for numerous cellular processes. Unsurprisingly, dysregulation of PLC[gamma]1 or PLC[gamma]2 activity is associated with multiple maladies including immune disorders, cancers, and neurodegenerative diseases. Therefore, the modulation of either of these two enzymes has been suggested as a therapeutic strategy to combat these diseases. To aid in the discovery of PLC[gamma] family enzyme modulators that could be developed into therapeutic agents, we have synthesized a high-throughput screening-amenable micellular fluorogenic substrate called C16CF3-coumarin. Herein, the ability of PLC[gamma]1 and PLC[gamma]2 to enzymatically process C16CF3-coumarin was confirmed, the micellular assay conditions were optimized, and the kinetics of the reaction were determined. A proof-of-principle pilot screen of the Library of Pharmacologically Active Compounds 1280 (LOPAC.sub.1280) was performed. This new substrate allows for an additional screening methodology to identify modulators of the PLC[gamma] family of enzymes.</abstract><pub>Public Library of Science</pub><doi>10.1371/journal.pone.0299541</doi><tpages>e0299541</tpages></addata></record> |
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| subjects | Analysis Care and treatment Diagnosis Dosage and administration Dose-response relationship (Biochemistry) Enzymes Health aspects Nervous system diseases Phospholipids Triflupromazine |
| title | A novel micellular fluorogenic substrate for quantitating the activity of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma |
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