Crystal structures of T. b. rhodesiense adenosine kinase complexed with inhibitor and activator: implications for catalysis and hyperactivation.
BACKGROUND: The essential purine salvage pathway of Trypanosoma brucei bears interesting catalytic enzymes for chemotherapeutic intervention of Human African Trypanosomiasis. Unlike mammalian cells, trypanosomes lack de novo purine synthesis and completely rely on salvage from their hosts. One of th...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2011-05-01
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| Series: | PLoS Neglected Tropical Diseases |
| Online Access: | http://europepmc.org/articles/PMC3101181?pdf=render |
| _version_ | 1818838524002041856 |
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| author | Sabine Kuettel Jason Greenwald Dirk Kostrewa Shaheen Ahmed Leonardo Scapozza Remo Perozzo |
| author_facet | Sabine Kuettel Jason Greenwald Dirk Kostrewa Shaheen Ahmed Leonardo Scapozza Remo Perozzo |
| author_sort | Sabine Kuettel |
| collection | DOAJ |
| description | BACKGROUND: The essential purine salvage pathway of Trypanosoma brucei bears interesting catalytic enzymes for chemotherapeutic intervention of Human African Trypanosomiasis. Unlike mammalian cells, trypanosomes lack de novo purine synthesis and completely rely on salvage from their hosts. One of the key enzymes is adenosine kinase which catalyzes the phosphorylation of ingested adenosine to form adenosine monophosphate (AMP) utilizing adenosine triphosphate (ATP) as the preferred phosphoryl donor. METHODS AND FINDINGS: Here, we present the first structures of Trypanosoma brucei rhodesiense adenosine kinase (TbrAK): the structure of TbrAK in complex with the bisubstrate inhibitor P(1),P(5)-di(adenosine-5')-pentaphosphate (AP5A) at 1.55 Å, and TbrAK complexed with the recently discovered activator 4-[5-(4-phenoxyphenyl)-2H-pyrazol-3-yl]morpholine (compound 1) at 2.8 Å resolution. CONCLUSIONS: The structural details and their comparison give new insights into substrate and activator binding to TbrAK at the molecular level. Further structure-activity relationship analyses of a series of derivatives of compound 1 support the observed binding mode of the activator and provide a possible mechanism of action with respect to their activating effect towards TbrAK. |
| first_indexed | 2024-12-19T03:39:46Z |
| format | Article |
| id | doaj.art-9f9bc0bfb8b94db08b605f7775812a2d |
| institution | Directory Open Access Journal |
| issn | 1935-2735 |
| language | English |
| last_indexed | 2024-12-19T03:39:46Z |
| publishDate | 2011-05-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Neglected Tropical Diseases |
| spelling | doaj.art-9f9bc0bfb8b94db08b605f7775812a2d2022-12-21T20:37:17ZengPublic Library of Science (PLoS)PLoS Neglected Tropical Diseases1935-27352011-05-0155e116410.1371/journal.pntd.0001164Crystal structures of T. b. rhodesiense adenosine kinase complexed with inhibitor and activator: implications for catalysis and hyperactivation.Sabine KuettelJason GreenwaldDirk KostrewaShaheen AhmedLeonardo ScapozzaRemo PerozzoBACKGROUND: The essential purine salvage pathway of Trypanosoma brucei bears interesting catalytic enzymes for chemotherapeutic intervention of Human African Trypanosomiasis. Unlike mammalian cells, trypanosomes lack de novo purine synthesis and completely rely on salvage from their hosts. One of the key enzymes is adenosine kinase which catalyzes the phosphorylation of ingested adenosine to form adenosine monophosphate (AMP) utilizing adenosine triphosphate (ATP) as the preferred phosphoryl donor. METHODS AND FINDINGS: Here, we present the first structures of Trypanosoma brucei rhodesiense adenosine kinase (TbrAK): the structure of TbrAK in complex with the bisubstrate inhibitor P(1),P(5)-di(adenosine-5')-pentaphosphate (AP5A) at 1.55 Å, and TbrAK complexed with the recently discovered activator 4-[5-(4-phenoxyphenyl)-2H-pyrazol-3-yl]morpholine (compound 1) at 2.8 Å resolution. CONCLUSIONS: The structural details and their comparison give new insights into substrate and activator binding to TbrAK at the molecular level. Further structure-activity relationship analyses of a series of derivatives of compound 1 support the observed binding mode of the activator and provide a possible mechanism of action with respect to their activating effect towards TbrAK.http://europepmc.org/articles/PMC3101181?pdf=render |
| spellingShingle | Sabine Kuettel Jason Greenwald Dirk Kostrewa Shaheen Ahmed Leonardo Scapozza Remo Perozzo Crystal structures of T. b. rhodesiense adenosine kinase complexed with inhibitor and activator: implications for catalysis and hyperactivation. PLoS Neglected Tropical Diseases |
| title | Crystal structures of T. b. rhodesiense adenosine kinase complexed with inhibitor and activator: implications for catalysis and hyperactivation. |
| title_full | Crystal structures of T. b. rhodesiense adenosine kinase complexed with inhibitor and activator: implications for catalysis and hyperactivation. |
| title_fullStr | Crystal structures of T. b. rhodesiense adenosine kinase complexed with inhibitor and activator: implications for catalysis and hyperactivation. |
| title_full_unstemmed | Crystal structures of T. b. rhodesiense adenosine kinase complexed with inhibitor and activator: implications for catalysis and hyperactivation. |
| title_short | Crystal structures of T. b. rhodesiense adenosine kinase complexed with inhibitor and activator: implications for catalysis and hyperactivation. |
| title_sort | crystal structures of t b rhodesiense adenosine kinase complexed with inhibitor and activator implications for catalysis and hyperactivation |
| url | http://europepmc.org/articles/PMC3101181?pdf=render |
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