ArticleThe Journal of biological chemistry2008
Molecular basis of prodrug activation by human valacyclovirase, an alpha-amino acid ester hydrolase.
Article in The Journal of biological chemistry, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
31 citing papers in PubMed, 68 citations in OpenAlex.
- Chiral methionine oxidation reagents reveal stereospecific proteome modifications.bioRxiv : the preprint server for biology · 2026Article
- Polymorphic pseudogenes in the human genome - a comprehensive assessment.Human genetics · 2024Article
- Homocysteine Thiolactone Detoxifying Enzymes and Alzheimer's Disease.International journal of molecular sciences · 2024Review
- Inhibition ofTranslational lung cancer research · 2023Article
- Human carboxylesterases and fluorescent probes to image their activity in live cells.RSC medicinal chemistry · 2021Review
- Review
- Tissue-Specific Proteomics Analysis of Anti-COVID-19 Nucleoside and Nucleotide Prodrug-Activating Enzymes Provides Insights into the Optimization of Prodrug Design and Pharmacotherapy Strategy.ACS pharmacology & translational science · 2021Article
- Computational Simulations to Guide Enzyme-Mediated Prodrug Activation.International journal of molecular sciences · 2020Review
- Strategy for the Biosynthesis of Short Oligopeptides: Green and Sustainable Chemistry.Biomolecules · 2019Review
- Distinctive structural motifs co-ordinate the catalytic nucleophile and the residues of the oxyanion hole in the alpha/beta-hydrolase fold enzymes.Protein science : a publication of the Protein Society · 2019Article
- Effect of biphenyl hydrolase-like (BPHL) gene disruption on the intestinal stability, permeability and absorption of valacyclovir in wildtype and Bphl knockout mice.Biochemical pharmacology · 2018Article
- Amino Acids in the Development of Prodrugs.Molecules (Basel, Switzerland) · 2018Review
- Antiviral Therapies for Herpesviruses: Current Agents and New Directions.Clinical therapeutics · 2018Review
- Rerouting the Pathway for the Biosynthesis of the Side Ring System of Nosiheptide: The Roles of NosI, NosJ, and NosK.Journal of the American Chemical Society · 2017Article
- Enzymatic activation of double-targeted 5'-O-L-valyl-decitabine prodrug by biphenyl hydrolase-like protein and its molecular design basis.Drug delivery and translational research · 2017Article
- Carrier-Mediated Prodrug Uptake to Improve the Oral Bioavailability of Polar Drugs: An Application to an Oseltamivir Analogue.Journal of pharmaceutical sciences · 2016Article
- Synthesis and characterization of valyloxy methoxy luciferin for the detection of valacyclovirase and peptide transporter.Bioorganic & medicinal chemistry letters · 2014Article
- Modern prodrug design for targeted oral drug delivery.Molecules (Basel, Switzerland) · 2014Article
- The Biopharmaceutics Classification System: subclasses for in vivo predictive dissolution (IPD) methodology and IVIVC.European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences · 2014Article
- Human valacyclovir hydrolase/biphenyl hydrolase-like protein is a highly efficient homocysteine thiolactonase.PloS one · 2014Article
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.