Enzymatic hydrolysis of pantetheine.
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Amidohydrolases↗
Biomedical subjects
C T Wittwer
Publications and source records attributed to C T Wittwer.
Metabolism of pantethine in cystinosis.
D-Pantethine is a conjugate of the vitamin pantothenic acid and the low-molecular-weight aminothiol cysteamine. Pantethine is an experimental hypolipemic agent and has been suggested as a source of cysteamine in the treatment of nephropathic cystinosis. We treated four cystinotic children with 70-1,000 mg/kg per d oral D-pantethine and studied its metabolism. Pantethine was rapidly hydrolyzed to pantothenic acid and cysteamine; we could not detect pantethine in plasma after oral administration. The responsible enzyme, "pantetheinase," was highly active in homogenates of small intestinal mucosa and plasma. The Michaelis constant of the rat intestinal enzyme was 4.6 microM and its pH profile showed a broad plateau between 4 and 9. Pantothenate pharmacokinetics after orally administered pantethine followed an open two-compartment model with slow vitamin elimination (t1/2 = 28 h). Peak plasma pantothenate occurred at 2.5 h and levels over 250 microM were seen at 300 times normal. Apparent total body storage of pantothenate was significant (25 mg/kg), and plasma levels were elevated threefold for months after pantethine therapy. Plasma cysteamine concentrations after pantethine were similar to those reported after equivalent doses of cysteamine. However, at best only 80% white blood cell cystine depletion occurred. We conclude that pantethine is probably less effective than cysteamine in the treatment of nephropathic cystinosis and should only be considered in cases of cysteamine intolerance. Serum cholesterol was decreased an average of 14%, which supports the potential clinical significance of pantethine as a hypolipemic agent. Rapid in vivo hydrolysis of pantethine suggests that pantothenate or cysteamine may be the effectors of its hypolipemic action.
Adolescent↗
Purification and properties of a pantetheine-hydrolyzing enzyme from pig kidney.
A microsomal glycoprotein that catalyzes the hydrolysis of pantetheine to pantothenate and cysteamine was solubilized and purified to homogeneity as determined by sodium dodecyl sulfate electrophoresis. The enzyme from pig kidney cortex was solubilized on exposure to butanol and purified by heat treatment, ammonium sulfate fractionation, hydrophobic chromatography, and hydroxyapatite chromatography. The purified enzyme (Mr = 57,000) has a specific activity of 14 mumol of pantothenate produced per min/mg of protein, a value 35 times that previously reported. A method for localizing enzymatic activity on polyacrylamide gels is presented, and enzyme activity, protein, and carbohydrate are shown to migrate identically by electrophoresis on nondenaturing polyacrylamide gels. Amino acid analysis indicated an absorbance index E1%1cm (280 nm) of 11.3, and carbohydrate analysis revealed the presence of galactose, mannose, fucose, glucose, galactosamine, and sialic acid for a total carbohydrate composition of 11.8%. The enzymatic hydrolysis of various pantetheine analogs indicated the enzyme had a high specificity for the pantothenate moiety but a low specificity for the cysteamine portion.
Amino Acids↗
Sensitization to OKT3 monoclonal antibody in heart transplantation: correlation with early allograft loss.
Because administration of murine monoclonal anti-CD3 antibody (OKT3) may result in the formation of human antimouse antibody, which complexes with OKT3, we conducted this study to assess the incidence and effect of human antimouse antibody formation during prophylactic administration of OKT3 in heart transplantation. Human antimouse antibody developed in eight of 55 (14%) cardiac allograft recipients receiving OKT3 prophylaxis as measured by enzyme-linked immunosorbent assay. Additionally, two recipients had an inexplicable rise in CD3+ lymphocytes during therapy without detectable antibody. The outcome of these 10 sensitized recipients was compared with that of 45 nonsensitized recipients. Age, preoperative diagnosis, hemodynamics, and the need for intravenous inotropes or mechanical assistance before transplantation were similar in both groups. No female patients were in the sensitized group, whereas 33% of the nonsensitized group were female patients. A trend toward greater sensitization when prophylaxis was extended to 21 days (28%) compared with the more conventional 14-day administration (10%) was not statistically significant. Retransplantation because of rejection was required in a single patient in each group. Allograft survival was significantly lower by 3 months in the sensitized group, and allograft loss caused by rejection selectively accounted for that difference. In survivors, rejection frequency and infectious complications were similar. These findings suggest that sensitization to OKT3 occurs at low frequency after prophylactic administration in heart transplantation but is associated with an increased frequency of graft loss because of rejection.
Animals↗