Anion inhibition profiles of the complete domain of the η-carbonic anhydrase from Plasmodium falciparum
[Display omitted] We have cloned, purified and investigated the catalytic activity and anion inhibition profiles of a full catalytic domain (358 amino acid residues) carbonic anhydrase (CA, EC 4.2.1.1) from Plasmodium falciparum, PfCAdom, an enzyme belonging to the η-CA class and identified in the g...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2016-09, Vol.24 (18), p.4410-4414 |
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| container_title | Bioorganic & medicinal chemistry |
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| creator | Del Prete, Sonia Vullo, Daniela De Luca, Viviana Carginale, Vincenzo di Fonzo, Pietro Osman, Sameh M. AlOthman, Zeid Supuran, Claudiu T. Capasso, Clemente |
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We have cloned, purified and investigated the catalytic activity and anion inhibition profiles of a full catalytic domain (358 amino acid residues) carbonic anhydrase (CA, EC 4.2.1.1) from Plasmodium falciparum, PfCAdom, an enzyme belonging to the η-CA class and identified in the genome of the malaria-producing protozoa. A truncated such enzyme, PfCA1, containing 235 residues was investigated earlier for its catalytic and inhibition profiles. The two enzymes were efficient catalysts for CO2 hydration: PfCAdom showed a kcat of 3.8×105s−1 and kcat/Km of 7.2×107M−1×s−1, whereas PfCA showed a lower activity compared to PfCAdom, with a kcat of 1.4×105s−1 and kcat/Km of 5.4×106M−1×s−1. PfCAdom was generally less inhibited by most anions and small molecules compared to PfCA1. The best PfCAdom inhibitors were sulfamide, sulfamic acid, phenylboronic acid and phenylarsonic acid, which showed KIs in the range of 9–68μM, followed by bicarbonate, hydrogensulfide, stannate and N,N-diethyldithiocarbamate, which were submillimolar inhibitors, with KIs in the range of 0.53–0.97mM. Malaria parasites CA inhibition was proposed as a new strategy to develop antimalarial drugs, with a novel mechanism of action. |
| doi_str_mv | 10.1016/j.bmc.2016.07.034 |
| format | Article |
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We have cloned, purified and investigated the catalytic activity and anion inhibition profiles of a full catalytic domain (358 amino acid residues) carbonic anhydrase (CA, EC 4.2.1.1) from Plasmodium falciparum, PfCAdom, an enzyme belonging to the η-CA class and identified in the genome of the malaria-producing protozoa. A truncated such enzyme, PfCA1, containing 235 residues was investigated earlier for its catalytic and inhibition profiles. The two enzymes were efficient catalysts for CO2 hydration: PfCAdom showed a kcat of 3.8×105s−1 and kcat/Km of 7.2×107M−1×s−1, whereas PfCA showed a lower activity compared to PfCAdom, with a kcat of 1.4×105s−1 and kcat/Km of 5.4×106M−1×s−1. PfCAdom was generally less inhibited by most anions and small molecules compared to PfCA1. The best PfCAdom inhibitors were sulfamide, sulfamic acid, phenylboronic acid and phenylarsonic acid, which showed KIs in the range of 9–68μM, followed by bicarbonate, hydrogensulfide, stannate and N,N-diethyldithiocarbamate, which were submillimolar inhibitors, with KIs in the range of 0.53–0.97mM. Malaria parasites CA inhibition was proposed as a new strategy to develop antimalarial drugs, with a novel mechanism of action.</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2016.07.034</identifier><identifier>PMID: 27480028</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Animals ; Anions ; Antimalarials - chemistry ; Antimalarials - pharmacology ; Carbonic anhydrase ; Carbonic Anhydrase Inhibitors - pharmacology ; Carbonic Anhydrases - chemistry ; Carbonic Anhydrases - drug effects ; Carbonic Anhydrases - metabolism ; Hydratase activity ; Inhibitors ; Kinetics ; Malaria ; Metalloenzymes ; Plasmodium falciparum - enzymology ; Protozoa</subject><ispartof>Bioorganic & medicinal chemistry, 2016-09, Vol.24 (18), p.4410-4414</ispartof><rights>2016 Elsevier Ltd</rights><rights>Copyright © 2016 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c353t-1a2dff5a4f5a20e5e69a58707c8229f4b5b4428282bf26350d18e7a914d8f0623</citedby><cites>FETCH-LOGICAL-c353t-1a2dff5a4f5a20e5e69a58707c8229f4b5b4428282bf26350d18e7a914d8f0623</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0968089616305417$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27480028$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Del Prete, Sonia</creatorcontrib><creatorcontrib>Vullo, Daniela</creatorcontrib><creatorcontrib>De Luca, Viviana</creatorcontrib><creatorcontrib>Carginale, Vincenzo</creatorcontrib><creatorcontrib>di Fonzo, Pietro</creatorcontrib><creatorcontrib>Osman, Sameh M.</creatorcontrib><creatorcontrib>AlOthman, Zeid</creatorcontrib><creatorcontrib>Supuran, Claudiu T.</creatorcontrib><creatorcontrib>Capasso, Clemente</creatorcontrib><title>Anion inhibition profiles of the complete domain of the η-carbonic anhydrase from Plasmodium falciparum</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>[Display omitted]
We have cloned, purified and investigated the catalytic activity and anion inhibition profiles of a full catalytic domain (358 amino acid residues) carbonic anhydrase (CA, EC 4.2.1.1) from Plasmodium falciparum, PfCAdom, an enzyme belonging to the η-CA class and identified in the genome of the malaria-producing protozoa. A truncated such enzyme, PfCA1, containing 235 residues was investigated earlier for its catalytic and inhibition profiles. The two enzymes were efficient catalysts for CO2 hydration: PfCAdom showed a kcat of 3.8×105s−1 and kcat/Km of 7.2×107M−1×s−1, whereas PfCA showed a lower activity compared to PfCAdom, with a kcat of 1.4×105s−1 and kcat/Km of 5.4×106M−1×s−1. PfCAdom was generally less inhibited by most anions and small molecules compared to PfCA1. The best PfCAdom inhibitors were sulfamide, sulfamic acid, phenylboronic acid and phenylarsonic acid, which showed KIs in the range of 9–68μM, followed by bicarbonate, hydrogensulfide, stannate and N,N-diethyldithiocarbamate, which were submillimolar inhibitors, with KIs in the range of 0.53–0.97mM. Malaria parasites CA inhibition was proposed as a new strategy to develop antimalarial drugs, with a novel mechanism of action.</description><subject>Animals</subject><subject>Anions</subject><subject>Antimalarials - chemistry</subject><subject>Antimalarials - pharmacology</subject><subject>Carbonic anhydrase</subject><subject>Carbonic Anhydrase Inhibitors - pharmacology</subject><subject>Carbonic Anhydrases - chemistry</subject><subject>Carbonic Anhydrases - drug effects</subject><subject>Carbonic Anhydrases - metabolism</subject><subject>Hydratase activity</subject><subject>Inhibitors</subject><subject>Kinetics</subject><subject>Malaria</subject><subject>Metalloenzymes</subject><subject>Plasmodium falciparum - enzymology</subject><subject>Protozoa</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kM9q3DAQxkVJ6W43fYBego652JVkWZbpKSxJWgi0h-YsZGnEarGsjWQX9sn6Fn2maNkkxzAM84dvPpgfQl8pqSmh4tu-HoKpWWlr0tWk4R_QmnLBq6bp6QVak17IisherNDnnPeEEMZ7-gmtWMdlGeQa7W4mHyfsp50f_HxqDyk6P0LG0eF5B9jEcBhhBmxj0H56Xf__Vxmdhjh5g_W0O9qkM2CXYsC_R51DtH4J2OnR-INOS7hEH8uQ4ctL3aDHu9s_2x_Vw6_7n9ubh8o0bTNXVDPrXKt5SUagBdHrVnakM5Kx3vGhHThnssTgmGhaYqmETveUW-mIYM0GXZ99yx9PC-RZBZ8NjKOeIC5ZUUkbwaTgtEjpWWpSzDmBU4fkg05HRYk6AVZ7VQCrE2BFOlUAl5urF_tlCGDfLl6JFsH3swDKk389JJWNh8mA9QnMrGz079g_A1YUjKk</recordid><startdate>20160915</startdate><enddate>20160915</enddate><creator>Del Prete, Sonia</creator><creator>Vullo, Daniela</creator><creator>De Luca, Viviana</creator><creator>Carginale, Vincenzo</creator><creator>di Fonzo, Pietro</creator><creator>Osman, Sameh M.</creator><creator>AlOthman, Zeid</creator><creator>Supuran, Claudiu T.</creator><creator>Capasso, Clemente</creator><general>Elsevier Ltd</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></search><sort><creationdate>20160915</creationdate><title>Anion inhibition profiles of the complete domain of the η-carbonic anhydrase from Plasmodium falciparum</title><author>Del Prete, Sonia ; Vullo, Daniela ; De Luca, Viviana ; Carginale, Vincenzo ; di Fonzo, Pietro ; Osman, Sameh M. ; AlOthman, Zeid ; Supuran, Claudiu T. ; Capasso, Clemente</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c353t-1a2dff5a4f5a20e5e69a58707c8229f4b5b4428282bf26350d18e7a914d8f0623</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Animals</topic><topic>Anions</topic><topic>Antimalarials - chemistry</topic><topic>Antimalarials - pharmacology</topic><topic>Carbonic anhydrase</topic><topic>Carbonic Anhydrase Inhibitors - pharmacology</topic><topic>Carbonic Anhydrases - chemistry</topic><topic>Carbonic Anhydrases - drug effects</topic><topic>Carbonic Anhydrases - metabolism</topic><topic>Hydratase activity</topic><topic>Inhibitors</topic><topic>Kinetics</topic><topic>Malaria</topic><topic>Metalloenzymes</topic><topic>Plasmodium falciparum - enzymology</topic><topic>Protozoa</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Del Prete, Sonia</creatorcontrib><creatorcontrib>Vullo, Daniela</creatorcontrib><creatorcontrib>De Luca, Viviana</creatorcontrib><creatorcontrib>Carginale, Vincenzo</creatorcontrib><creatorcontrib>di Fonzo, Pietro</creatorcontrib><creatorcontrib>Osman, Sameh M.</creatorcontrib><creatorcontrib>AlOthman, Zeid</creatorcontrib><creatorcontrib>Supuran, Claudiu T.</creatorcontrib><creatorcontrib>Capasso, Clemente</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><jtitle>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Del Prete, Sonia</au><au>Vullo, Daniela</au><au>De Luca, Viviana</au><au>Carginale, Vincenzo</au><au>di Fonzo, Pietro</au><au>Osman, Sameh M.</au><au>AlOthman, Zeid</au><au>Supuran, Claudiu T.</au><au>Capasso, Clemente</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Anion inhibition profiles of the complete domain of the η-carbonic anhydrase from Plasmodium falciparum</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2016-09-15</date><risdate>2016</risdate><volume>24</volume><issue>18</issue><spage>4410</spage><epage>4414</epage><pages>4410-4414</pages><issn>0968-0896</issn><eissn>1464-3391</eissn><abstract>[Display omitted]
We have cloned, purified and investigated the catalytic activity and anion inhibition profiles of a full catalytic domain (358 amino acid residues) carbonic anhydrase (CA, EC 4.2.1.1) from Plasmodium falciparum, PfCAdom, an enzyme belonging to the η-CA class and identified in the genome of the malaria-producing protozoa. A truncated such enzyme, PfCA1, containing 235 residues was investigated earlier for its catalytic and inhibition profiles. The two enzymes were efficient catalysts for CO2 hydration: PfCAdom showed a kcat of 3.8×105s−1 and kcat/Km of 7.2×107M−1×s−1, whereas PfCA showed a lower activity compared to PfCAdom, with a kcat of 1.4×105s−1 and kcat/Km of 5.4×106M−1×s−1. PfCAdom was generally less inhibited by most anions and small molecules compared to PfCA1. The best PfCAdom inhibitors were sulfamide, sulfamic acid, phenylboronic acid and phenylarsonic acid, which showed KIs in the range of 9–68μM, followed by bicarbonate, hydrogensulfide, stannate and N,N-diethyldithiocarbamate, which were submillimolar inhibitors, with KIs in the range of 0.53–0.97mM. Malaria parasites CA inhibition was proposed as a new strategy to develop antimalarial drugs, with a novel mechanism of action.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>27480028</pmid><doi>10.1016/j.bmc.2016.07.034</doi><tpages>5</tpages></addata></record> |
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| subjects | Animals Anions Antimalarials - chemistry Antimalarials - pharmacology Carbonic anhydrase Carbonic Anhydrase Inhibitors - pharmacology Carbonic Anhydrases - chemistry Carbonic Anhydrases - drug effects Carbonic Anhydrases - metabolism Hydratase activity Inhibitors Kinetics Malaria Metalloenzymes Plasmodium falciparum - enzymology Protozoa |
| title | Anion inhibition profiles of the complete domain of the η-carbonic anhydrase from Plasmodium falciparum |
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