Journal Article

Human Valacyclovir Hydrolase/Biphenyl Hydrolase-Like Protein Is a Highly Efficient Homocysteine Thiolactonase

Suzuki, Stephanie M., Rettie, Allan E., MacCoss, Michael J., Marsillach, Judit, McDonald, Matthew G., Rademacher, Peter M., Hsieh, Edward J., Furlong, Clement E., Richter, Rebecca J.

2014

Overview

Homocysteinylation of lysine residues by homocysteine thiolactone (HCTL), a reactive homocysteine metabolite, results in protein aggregation and malfunction, and is a well-known risk factor for cardiovascular, autoimmune and neurological diseases. Human plasma paraoxonase-1 (PON1) and bleomycin hydrolase (Blmh) have been reported as the physiological HCTL detoxifying enzymes. However, the catalytic efficiency of HCTL hydrolysis by Blmh is low and not saturated at 20 mM HCTL. The catalytic efficiency of PON1 for HCTL hydrolysis is 100-fold lower than that of Blmh. A homocysteine thiolactonase (HCTLase) was purified from human liver and identified by mass spectrometry (MS) as the previously described human biphenyl hydrolase-like protein (BPHL). To further characterize this newly described HCTLase activity, BPHL was expressed in Escherichia coli and purified. The sequence of the recombinant BPHL (rBPHL) and hydrolytic products of the substrates HCTL and valacyclovir were verified by MS. We found that the catalytic efficiency (kcat/Km) of rBPHL for HCTL hydrolysis was 7.7 × 10(4) M(-1)s(-1), orders of magnitude higher than that of PON1 or Blmh, indicating a more significant physiological role for BPHL in detoxifying HCTL.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Amino acids / Antiviral drugs / Arteriosclerosis / Aryldialkylphosphatase - genetics / Aryldialkylphosphatase - metabolism / Biology and Life Sciences / Biphenyl / Bleomycin / Blood plasma / Carboxylic Ester Hydrolases - genetics / Carboxylic Ester Hydrolases - metabolism / Cardiovascular diseases / Catalysis / Chemistry / Diabetic retinopathy / Disease / E coli / Efficiency / Enzymes / Genomes / Health risks / Homocysteine / Humans / Hydrolase / Hydrolases / Hydrolysis / Kidneys / Liver / Liver - enzymology / Lysine / Mass spectrometry / Mass spectroscopy / Medicine / Medicine and Health Sciences / Metabolism / Metabolites / Multiple sclerosis / Neurological diseases / Neurotoxicity / Paraoxonase / Pharmaceutical sciences / Physiology / Protein interaction / Proteins / Risk factors / Substrates / Thiolactone / Valacyclovir / Yeast