Disease relevance of BPHL

• The Bph-rp cDNA was expressed in Escherichia coli, and after purification, the recombinant protein was able to degrade p-nitrophenylbutyrate, a water-soluble substrate commonly used for assaying serine hydrolases [1].

High impact information on BPHL

• We conclude that BPHL may be an important enzyme activating valacyclovir and valganciclovir in humans and an important new target for prodrug design [2].
• Using a non-redundant data base search, the N-terminal 19-amino acid sequence of the purified 27-kDa, basic protein revealed a perfect match within the N terminus of a serine hydrolase, Biphenyl hydrolase-like (BPHL, gi:4757862) protein, previously cloned from human breast carcinoma [2].
• According to structural characteristics, hydrolytic activity and tissue distribution of Bph-rp, a potential role of this enzyme in detoxification processes is proposed [1].
• The gene, whose HGM-approved nomenclature is BPHL, spans more than 30 kb and is composed of eight exons and seven introns [3].
• Nucleotide sequence analysis of the 5'-flanking region of BPHL revealed a high GC content, a ratio CpG/GpC close to unity, and the absence of consensus transcriptional sequences such as a TATA box or a CCAAT box [3].

Biological context of BPHL

• Chromosomal localization of BPHL revealed that it maps to chromosome 6p25, a unique location for all serine hydrolases mapped to date [3].
• 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 [4].
• The homology model of BPHL provides a basis for further investigation of the catalytic and active site residues, can account for the observed structure activity profile of BPHL, and will be useful in the design of nucleoside prodrugs [5].
• The hydrolysis of typical esterase and aminopeptidase substrates by BPHL was also investigated [4].

Associations of BPHL with chemical compounds

• Recombinant BPHL exhibited significant hydrolytic activity for both valacyclovir and valganciclovir with specificity constants (kcat/Km), 420 and 53.2 mm-1.s-1, respectively [2].
• BPHL exhibited stereoselectivity with an L/D specificity ratio of 32 for 5'-valyl floxuridine and 1.5 for 5'-phenylalanyl floxuridine [4].
• For all nucleoside parent drugs, BPHL preferred the hydrophobic amino acids valine, phenylalanine, and proline over the charged amino acids lysine and aspartic acid [4].
• Biphenyl hydrolase-like (BPHL) protein is a novel serine hydrolase which has been identified as human valacyclovirase (VACVase), catalyzing the hydrolytic activation of valine ester prodrugs of the antiviral drugs acyclovir and ganciclovir as well as other amino acid ester prodrugs of therapeutic nucleoside analogues [5].

Other interactions of BPHL

• The BPHL model has residues S122, H255, and D227 comprising the putative catalytic triad in proximity and potential charge-charge interaction sites, M52 or D123 for the alpha-amino group [5].

Analytical, diagnostic and therapeutic context of BPHL

• Northern blot analysis of poly(A)+ RNAs isolated from a variety of human tissues revealed that Bph-rp is mainly expressed in liver and kidney, which was also confirmed at the protein level by Western blot analysis with antibodies raised against purified recombinant Bph-rp [1].

References