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| | ==Crystal structure of human valacyclovir hydrolase== | | ==Crystal structure of human valacyclovir hydrolase== |
| - | <StructureSection load='2ocg' size='340' side='right' caption='[[2ocg]], [[Resolution|resolution]] 1.75Å' scene=''> | + | <StructureSection load='2ocg' size='340' side='right'caption='[[2ocg]], [[Resolution|resolution]] 1.75Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2ocg]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2OCG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2OCG FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2ocg]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2OCG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2OCG FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.75Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2oci|2oci]], [[2ock|2ock]], [[2ocl|2ocl]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BPHL ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2ocg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ocg OCA], [https://pdbe.org/2ocg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ocg RCSB], [https://www.ebi.ac.uk/pdbsum/2ocg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ocg ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2ocg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ocg OCA], [http://pdbe.org/2ocg PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2ocg RCSB], [http://www.ebi.ac.uk/pdbsum/2ocg PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2ocg ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/BPHL_HUMAN BPHL_HUMAN]] Serine hydrolase that catalyzes the hydrolytic activation of amino acid ester prodrugs of nucleoside analogs such as valacyclovir and valganciclovir. Activates valacyclovir to acyclovir. May play a role in detoxification processes. It is a specific alpha-amino acid ester hydrolase that prefers small, hydrophobic, and aromatic side chains and does not have a stringent requirement for the leaving group other than preferring a primary alcohol.<ref>PMID:18256025</ref> | + | [https://www.uniprot.org/uniprot/BPHL_HUMAN BPHL_HUMAN] Serine hydrolase that catalyzes the hydrolytic activation of amino acid ester prodrugs of nucleoside analogs such as valacyclovir and valganciclovir. Activates valacyclovir to acyclovir. May play a role in detoxification processes. It is a specific alpha-amino acid ester hydrolase that prefers small, hydrophobic, and aromatic side chains and does not have a stringent requirement for the leaving group other than preferring a primary alcohol.<ref>PMID:18256025</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Amidon, G L]] | + | [[Category: Large Structures]] |
| - | [[Category: Lai, L]] | + | [[Category: Amidon GL]] |
| - | [[Category: Xu, Z]] | + | [[Category: Lai L]] |
| - | [[Category: Alpha beta hydrolase fold]] | + | [[Category: Xu Z]] |
| - | [[Category: Hydrolase]]
| + | |
| Structural highlights
Function
BPHL_HUMAN Serine hydrolase that catalyzes the hydrolytic activation of amino acid ester prodrugs of nucleoside analogs such as valacyclovir and valganciclovir. Activates valacyclovir to acyclovir. May play a role in detoxification processes. It is a specific alpha-amino acid ester hydrolase that prefers small, hydrophobic, and aromatic side chains and does not have a stringent requirement for the leaving group other than preferring a primary alcohol.[1]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Chemical modification to improve biopharmaceutical properties, especially oral absorption and bioavailability, is a common strategy employed by pharmaceutical chemists. The approach often employs a simple structural modification and utilizes ubiquitous endogenous esterases as activation enzymes, although such enzymes are often unidentified. This report describes the crystal structure and specificity of a novel activating enzyme for valacyclovir and valganciclovir. Our structural insights show that human valacyclovirase has a unique binding mode and specificity for amino acid esters. Biochemical data demonstrate that the enzyme hydrolyzes esters of alpha-amino acids exclusively and displays a broad specificity spectrum for the aminoacyl moiety similar to tricorn-interacting aminopeptidase F1. Crystal structures of the enzyme, two mechanistic mutants, and a complex with a product analogue, when combined with biochemical analysis, reveal the key determinants for substrate recognition; that is, a flexible and mostly hydrophobic acyl pocket, a localized negative electrostatic potential, a large open leaving group-accommodating groove, and a pivotal acidic residue, Asp-123, after the nucleophile Ser-122. This is the first time that a residue immediately after the nucleophile has been found to have its side chain directed into the substrate binding pocket and play an essential role in substrate discrimination in serine hydrolases. These results as well as a phylogenetic analysis establish that the enzyme functions as a specific alpha-amino acid ester hydrolase. Valacyclovirase is a valuable target for amino acid ester prodrug-based oral drug delivery enhancement strategies.
Molecular basis of prodrug activation by human valacyclovirase, an alpha-amino acid ester hydrolase.,Lai L, Xu Z, Zhou J, Lee KD, Amidon GL J Biol Chem. 2008 Apr 4;283(14):9318-27. Epub 2008 Feb 5. PMID:18256025[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Lai L, Xu Z, Zhou J, Lee KD, Amidon GL. Molecular basis of prodrug activation by human valacyclovirase, an alpha-amino acid ester hydrolase. J Biol Chem. 2008 Apr 4;283(14):9318-27. Epub 2008 Feb 5. PMID:18256025 doi:10.1074/jbc.M709530200
- ↑ Lai L, Xu Z, Zhou J, Lee KD, Amidon GL. Molecular basis of prodrug activation by human valacyclovirase, an alpha-amino acid ester hydrolase. J Biol Chem. 2008 Apr 4;283(14):9318-27. Epub 2008 Feb 5. PMID:18256025 doi:10.1074/jbc.M709530200
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