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1.
ACS Chem Biol ; 11(8): 2304-11, 2016 08 19.
Article in English | MEDLINE | ID: mdl-27294475

ABSTRACT

DUF1537 is a novel family of kinases identified by comparative genomic approaches. The family is widespread and found in all sequenced plant genomes and 16% of sequenced bacterial genomes. DUF1537 is not a monofunctional family and contains subgroups that can be separated by phylogenetic and genome neighborhood context analyses. A subset of the DUF1537 proteins is strongly associated by physical clustering and gene fusion with the PdxA2 family, demonstrated here to be a functional paralog of the 4-phosphohydroxy-l-threonine dehydrogenase enzyme (PdxA), a central enzyme in the synthesis of pyridoxal-5'-phosphate (PLP) in proteobacteria. Some members of this DUF1537 subgroup phosphorylate l-4-hydroxythreonine (4HT) into 4-phosphohydroxy-l-threonine (4PHT), the substrate of PdxA, in vitro and in vivo. This provides an alternative route to PLP from the toxic antimetabolite 4HT that can be directly generated from the toxic intermediate glycolaldehyde. Although the kinetic and physical clustering data indicate that these functions in PLP synthesis are not the main roles of the DUF1537-PdxA2 enzymes, genetic and physiological data suggest these side activities function has been maintained in diverse sets of organisms.


Subject(s)
Phosphotransferases/metabolism , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Genes, Bacterial , Phosphotransferases/genetics
2.
Br J Clin Pharmacol ; 72(3): 434-41, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21501216

ABSTRACT

AIM: To determine whether customary exposure to grapefruit juice (GFJ) alters serum concentrations, effectiveness, and potential adverse effects of atorvastatin in patients requiring the medication. METHODS: Patients receiving extended treatment with atorvastatin (10, 20 or 40 mg day(-1)) at a stable dose received 300 ml day(-1) of 100% GFJ for a period of 90 days. One cohort of patients (arm A, n= 60) continued on their current dose of atorvastatin; the second cohort (arm B, n= 70) reduced the daily dose by 50%. Serum atorvastatin, lipid profile, liver functions, and creatine phosphokinase (CPK) were measured at baseline and at 30, 60, and 90 days after starting GFJ. RESULTS: In Arm A patients, co-ingestion of GFJ significantly elevated serum atorvastatin by 19% to 26% compared with baseline. Changes in lipid profile relative to baseline were negligible. There were no adverse effects on liver function tests or CPK. In arm B patients, serum atorvastatin declined by 12% to 25% compared to baseline, with a small but significant unfavourable effect in serum lipid profile. There were no adverse effects on liver function tests or CPK. CONCLUSION: In patients on extended stable atorvastatin treatment, addition of daily GFJ in typical quantities slightly elevates serum atorvastatin concentrations, but has no meaningful effect on the serum lipid profile, and causes no detectable adverse liver or muscle effects. Reduction of atorvastatin dosage when moderate amounts of GFJ are co-ingested does not appear to be necessary.


Subject(s)
Anticholesteremic Agents/blood , Beverages , Citrus paradisi/metabolism , Food-Drug Interactions , Heptanoic Acids/blood , Lipid Metabolism Disorders/drug therapy , Pyrroles/blood , Aged , Analysis of Variance , Anticholesteremic Agents/therapeutic use , Atorvastatin , Cohort Studies , Dose-Response Relationship, Drug , Female , Heptanoic Acids/therapeutic use , Humans , Lipid Metabolism/drug effects , Lipid Metabolism Disorders/blood , Male , Middle Aged , Pyrroles/therapeutic use , Time Factors
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