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Biosynthesis of Chloro-ß-Hydroxytyrosine, a Nonproteinogenic Amino Acid of the Peptidic Backbone of Glycopeptide Antibiotics. Oliver Puk, 2004.The role of the putative P450 monooxygenase OxyD and the chlorination time point in the biosynthesis of the glycopeptide antibiotic balhimycin produced by Amycolatopsis balhimycina were analyzed. The oxyD gene is located directly downstream of the bhp [perhydrolase]and bpsD [nonribosomal peptide synthetase D] genes, which areinvolved in the synthesis of the balhimycin building block ß-hydroxytyrosine[ß-HT] . Reverse transcriptase experiments revealedthat bhp, bpsD, and oxyD form an operon . oxyD was inactivatedby an in-frame deletion, and the resulting mutant was unableto produce an active compound . Balhimycin production could berestored [i] by complementation with an oxyD gene, [ii] in cross-feedingstudies using A . balhimycina JR1 [a null mutant with a blockin the biosynthesis pathway of the building blocks hydroxy-and dihydroxyphenylglycine] as an excretor of the missing precursor,and [iii] by supplementation of ß-HT in the growthmedium . These data demonstrated an essential role of OxyD in the formation pathway of this amino acid . Liquid chromatography-electrosprayionization-mass spectrometry analysis indicated the biosynthesisof completely chlorinated balhimycin by the oxyD mutant whenculture filtrates were supplemented with nonchlorinated ß-HT.In contrast, supplementation with 3-chloro-ß-HT didnot restore balhimycin production . These results indicated that the chlorination time point was later than the stage of free ß-HT, most likely during heptapeptide synthesis. Population Pharmacokinetics of Pyrimethamine and Sulfadoxine in Children Treated for Congenital Toxoplasmosis. Stéphane Corvaisier, 2004.The population pharmacokinetics of pyrimethamine (PYR) and sulfadoxine (SDX) for a group of 32 children with congenital toxoplasmosis was investigated by nonparametric modeling analysis . A one-compartment model was used as the structural model, and individual pharmacokinetic parameters were estimated by Bayesian modeling . PYR (1.25 mg/kg of body weight) and SDX (25 mg/kg) were administered orally every 10 days for 1 year, with adjustment of the dose to body weight every 3 months . Drug concentrations were measured by high-performance liquid chromatography . A total of 101 measurements in serum were available for both drugs . Mean absorption rate constants, volumes of distribution, elimination rate constants, and half-lives were 0.915 h–1, 4.379 liters/kg, 0.00839 h–1, and 5.5 days for PYR and 1.659 h–1, 0.392 liters/kg, 0.00526 h–1, and 6.6 days for SDX, respectively . Wide interindividual variability was observed . The estimated minimum and maximum concentrations of PYR in serum differed 8- and 25-fold among patients, respectively, and those of SDX differed 4- and 5-fold, respectively . Increases in the concentration of PYR were observed for eight children, and increases in the SDX concentration were observed for seven children . Serum PYR-SDX concentrations are unpredictable even when the dose is standardized for body weight . The concentrations of the PYR-SDX combination that are most efficacious for children have not yet been established . A model such as ours, associated with long-term follow-up, is needed to study the correlation between exposure to these two drugs and clinical outcome in children .
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