Purification and characterization of a rat liver enzyme that hydrolyzes valaciclovir, the L-valyl ester prodrug of acyclovir. 1995

T C Burnette, and J A Harrington, and J E Reardon, and B M Merrill, and P de Miranda
Division of Experimental Therapy, Burroughs Wellcome Co., Research Triangle Park, North Carolina 27709, USA.

Valaciclovir is an oral prodrug of the antiherpetic agent acyclovir. An enzyme that hydrolyzes valaciclovir to acyclovir, valaciclovir hydrolase (VACVase), was purified from rat liver and characterized. VACVase was a basic (pI 9.4) protein associated with mitochondria. It was monomeric and had a molecular mass of 29 kDa. Amino acid sequences of six VACVase peptides, including its NH2 terminus (13 amino acids) and accounting for approximately 20% of its complete sequence, were not found in the SwissProt protein data base. VACVase hydrolyzed other amino acid esters of acyclovir in addition to valaciclovir (kcat/Km = 58 mM-1 s-1), with a preference for the L-alanyl (kcat/Km = 226 mM-1 s-1) and L-methionyl (kcat/Km = 200 mM-1 s-1) esters. It did not hydrolyze other types of esters or numerous di- and tripeptides and aminoacyl-beta-naphthylamides. Hydrolysis of valaciclovir by VACVase was not inhibited by amastatin, antipain, aprotinin, bestatin, chymostatin, E-64, EDTA, ebelactone A, ebelactone B, elastatinal, leupeptin, pepstatin, or phosphoramidon. It was neither inhibited nor activated by Ca2+, Co2+, Mg2+, Mn2+, or Zn2+. Therefore, this enzyme is not a typical esterase or peptidase and, to our knowledge, it has not been described previously. Its physiological function is not known; however, it may play a significant role in the biotransformation of valaciclovir to acyclovir.

UI MeSH Term Description Entries
D008099 Liver A large lobed glandular organ in the abdomen of vertebrates that is responsible for detoxification, metabolism, synthesis and storage of various substances. Livers
D008297 Male Males
D008969 Molecular Sequence Data Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories. Sequence Data, Molecular,Molecular Sequencing Data,Data, Molecular Sequence,Data, Molecular Sequencing,Sequencing Data, Molecular
D011355 Prodrugs A compound that, on administration, must undergo chemical conversion by metabolic processes before becoming the pharmacologically active drug for which it is a prodrug. Drug Precursor,Drug Precursors,Pro-Drug,Prodrug,Pro-Drugs,Precursor, Drug,Precursors, Drug,Pro Drug,Pro Drugs
D006867 Hydrolases Any member of the class of enzymes that catalyze the cleavage of the substrate and the addition of water to the resulting molecules, e.g., ESTERASES, glycosidases (GLYCOSIDE HYDROLASES), lipases, NUCLEOTIDASES, peptidases (PEPTIDE HYDROLASES), and phosphatases (PHOSPHORIC MONOESTER HYDROLASES). EC 3. Hydrolase
D000077483 Valacyclovir A prodrug of acyclovir that is used in the treatment of HERPES ZOSTER and HERPES SIMPLEX VIRUS INFECTION of the skin and mucous membranes, including GENITAL HERPES. 2-((2-Amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy)ethyl L-valinate,256U87,Acyclovir, L-valyl Ester,BW256U87,L-Valylacyclovir,Valaciclovir,Valacyclovir Hydrochloride,Valacyclovir Hydrochloride, (DL)-isomer,Valacyclovir, (D)-isomer,Valacyclovir, (DL)-isomer,Valacyclovir, (L)-isomer,Valacyclovir, D-,Valacyclovir, X-Hydrochloride, (D)-isomer,Valacyclovir, X-Hydrochloride, (DL)-isomer,Valtrex,Acyclovir, L valyl Ester,D- Valacyclovir,L Valylacyclovir,L-valyl Ester Acyclovir
D000212 Acyclovir A GUANOSINE analog that acts as an antimetabolite. Viruses are especially susceptible. Used especially against herpes. Acycloguanosine,9-((2-Hydroxyethoxy)methyl)guanine,Aci-Sanorania,Acic,Aciclobeta,Aciclostad,Aciclovir,Aciclovir Alonga,Aciclovir-Sanorania,Acifur,Acipen Solutab,Acivir,Activir,Acyclo-V,Acyclovir Sodium,Antiherpes Creme,Avirax,Cicloferon,Clonorax,Cusiviral,Genvir,Herpetad,Herpofug,Herpotern,Herpoviric,Isavir,Laciken,Mapox,Maynar,Milavir,Opthavir,Supraviran,Viclovir,Vipral,Virax-Puren,Virherpes,Virmen,Virolex,Virupos,Virzin,Wellcome-248U,Zoliparin,Zovirax,Zyclir,aciclovir von ct,Aci Sanorania,Aciclovir Sanorania,Acyclo V,Alonga, Aciclovir,Sodium, Acyclovir,Solutab, Acipen,Virax Puren,ViraxPuren,Wellcome 248U,Wellcome248U
D000595 Amino Acid Sequence The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION. Protein Structure, Primary,Amino Acid Sequences,Sequence, Amino Acid,Sequences, Amino Acid,Primary Protein Structure,Primary Protein Structures,Protein Structures, Primary,Structure, Primary Protein,Structures, Primary Protein
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D000998 Antiviral Agents Agents used in the prophylaxis or therapy of VIRUS DISEASES. Some of the ways they may act include preventing viral replication by inhibiting viral DNA polymerase; binding to specific cell-surface receptors and inhibiting viral penetration or uncoating; inhibiting viral protein synthesis; or blocking late stages of virus assembly. Antiviral,Antiviral Agent,Antiviral Drug,Antivirals,Antiviral Drugs,Agent, Antiviral,Agents, Antiviral,Drug, Antiviral,Drugs, Antiviral

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