Linked Life Data

15832508

Source:http://linkedlifedata.com/resource/pubmed/id/15832508

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2005-4-18
pubmed:abstractText
Biphenyl hydrolase-like protein (BPHL, NCBI accession number NP_004323) is a novel human serine hydrolase recently identified as a human valacyclovirase, catalyzing the hydrolytic activation of the antiviral prodrugs valacyclovir and valganciclovir. The substrate specificity of BPHL was investigated with a series of amino acid ester prodrugs of the therapeutic nucleoside analogues: acyclovir, zidovudine, floxuridine, 2-bromo-5,6-dichloro-1-(beta-D-ribofuranosyl) benzimidazole, and gemcitabine. The hydrolysis of typical esterase and aminopeptidase substrates by BPHL was also investigated. The results indicate that the substrate specificity of BPHL is largely determined by the amino acid acyl promoiety, and is less sensitive to the nucleoside parent drugs. For all nucleoside parent drugs, BPHL preferred the hydrophobic amino acids valine, phenylalanine, and proline over the charged amino acids lysine and aspartic acid. The position and monoester or diester form of the prodrug were also important, with BPHL exhibiting higher affinity for the 5'-esters than for the 3'-esters and the 3',5'-diesters irrespective of amino acid type. Further, the presence of the 3'-amino acid ester considerably reduced the hydrolysis rate of the 5'-amino acid ester functionality. BPHL exhibited stereoselectivity with an L/D specificity ratio of 32 for 5'-valyl floxuridine and 1.5 for 5'-phenylalanyl floxuridine. The substrate specificity suggests that the substrate-binding pocket of BPHL has a hydrophobic acyl binding site which can accommodate the positively charged alpha-amino group, while having an alcohol leaving group binding site that can accommodate nucleoside analogues with a relatively generous spatial allowance. In conclusion, BPHL catalyzes the hydrolytic activation of amino acid esters of a broad range of therapeutic nucleoside analogues in addition to valacyclovir and valganciclovir and has considerable potential for utilization as an activation target for design of antiviral and anticancer nucleoside analogue prodrugs.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:issn
1543-8384
pubmed:author
pubmed:issnType
Print
pubmed:volume
1
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
117-27
pubmed:dateRevised
2008-11-21
pubmed:meshHeading
pubmed-meshheading:15832508-Acyclovir, pubmed-meshheading:15832508-Amino Acid Sequence, pubmed-meshheading:15832508-Antiviral Agents, pubmed-meshheading:15832508-Carboxylic Ester Hydrolases, pubmed-meshheading:15832508-Cloning, Molecular, pubmed-meshheading:15832508-Drug Design, pubmed-meshheading:15832508-Enzyme Activation, pubmed-meshheading:15832508-Escherichia coli, pubmed-meshheading:15832508-Ganciclovir, pubmed-meshheading:15832508-Genetic Variation, pubmed-meshheading:15832508-Humans, pubmed-meshheading:15832508-Kinetics, pubmed-meshheading:15832508-Molecular Sequence Data, pubmed-meshheading:15832508-Prodrugs, pubmed-meshheading:15832508-Recombinant Fusion Proteins, pubmed-meshheading:15832508-Sequence Alignment, pubmed-meshheading:15832508-Sequence Homology, Amino Acid, pubmed-meshheading:15832508-Substrate Specificity, pubmed-meshheading:15832508-Valine
pubmed:articleTitle
A novel nucleoside prodrug-activating enzyme: substrate specificity of biphenyl hydrolase-like protein.
pubmed:affiliation
Department of Pharmaceutical Sciences, College of Pharmacy, The University of Michigan, 428 Church Street, Ann Arbor, Michigan 48109-1065, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural