FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W3017594920> ?p ?o ?g. }

• W3017594920 endingPage "1" @default.
• W3017594920 startingPage "1" @default.
• W3017594920 abstract "A broad spectrum of human diseases, including abnormalities in steroidogenesis, is caused by mutations in the NADPH cytochrome P450 oxidoreductase (POR) [1, 2]. Cytochrome P450 proteins perform several reactions, including the metabolism of steroids, drugs, and other xenobiotics. Therefore, genetic variations in POR can impact many different metabolic pathways by changing the activities of cytochromes P450. In 2004 the first human patients with defects in POR were reported with symptoms of ambiguous genitalia and bone malformations, and over 200 variations in POR are known. By analyzing the POR sequences from genomics databases, we focused on the common variant in POR A503V, which is often present in heterozygous form in many PORD patients. We expressed the A503V variant of POR in bacteria and characterized it by functional studies using purified recombinant proteins. The POR, as well as P450 Proteins, were expressed in E. coli BL21(DE3) and purified by ion-exchange, affinity, and metal chelate chromatography for activity assays as described in our earlier publications [3, 4]. Activities of cytochrome P450 enzymes were tested with lipids into which P450 and P450 reductase proteins were embedded and assayed using fluorogenic substrates on a microplate spectrofluorometer. We found a positive effect on many drug-metabolizing enzyme activities due to the A503V variant in POR. The activity of CYP2C9 was increased to 180% of the WT POR, and CYP2C19 showed 243% of WT activity with the A503V variant of POR. Most remarkable was the impact of the A503V variant on CYP3A5 activity, which was increased by 421% compared to WT POR. Effect on drug metabolism in patients with PORD requires careful considerations of cytochrome P450 mediated activities. While many PORD patients have low or reduced drug metabolism due to defects in POR, the presence of the A503V allele can alter the overall effect on drug metabolism. Significantly, tacrolimus, a drug given during organ transplant, can be metabolized several folds faster due to the presence of the A503V variant of POR. The presence of the A503V allele is likely beneficial in patients with POR deficiency. Support or Funding Information This work was supported by the Swiss National Science Foundation (31003A-134926), the Novartis Foundation for Medical-Biological Research (18A053), and a grant from Burgergemeiende Bern to AP." @default.
• W3017594920 created "2020-05-01" @default.
• W3017594920 creator A5024262855 @default.
• W3017594920 creator A5031721914 @default.
• W3017594920 creator A5078344831 @default.
• W3017594920 date "2020-04-01" @default.
• W3017594920 modified "2023-09-25" @default.
• W3017594920 title "Impact of Common Polymorphic Variant A503V in POR on Drug Metabolism: Implications for POR Deficiency" @default.
• W3017594920 cites W2083768732 @default.
• W3017594920 cites W2749799165 @default.
• W3017594920 cites W2793569235 @default.
• W3017594920 cites W2949473644 @default.
• W3017594920 doi "https://doi.org/10.1096/fasebj.2020.34.s1.03983" @default.
• W3017594920 hasPublicationYear "2020" @default.
• W3017594920 type Work @default.
• W3017594920 sameAs 3017594920 @default.
• W3017594920 citedByCount "0" @default.
• W3017594920 crossrefType "journal-article" @default.
• W3017594920 hasAuthorship W3017594920A5024262855 @default.
• W3017594920 hasAuthorship W3017594920A5031721914 @default.
• W3017594920 hasAuthorship W3017594920A5078344831 @default.
• W3017594920 hasBestOaLocation W30175949201 @default.
• W3017594920 hasConcept C104317684 @default.
• W3017594920 hasConcept C115448650 @default.
• W3017594920 hasConcept C119795356 @default.
• W3017594920 hasConcept C134651460 @default.
• W3017594920 hasConcept C140840227 @default.
• W3017594920 hasConcept C181199279 @default.
• W3017594920 hasConcept C185592680 @default.
• W3017594920 hasConcept C2779384962 @default.
• W3017594920 hasConcept C3946865 @default.
• W3017594920 hasConcept C40767141 @default.
• W3017594920 hasConcept C526171541 @default.
• W3017594920 hasConcept C55493867 @default.
• W3017594920 hasConcept C86803240 @default.
• W3017594920 hasConcept C89311334 @default.
• W3017594920 hasConceptScore W3017594920C104317684 @default.
• W3017594920 hasConceptScore W3017594920C115448650 @default.
• W3017594920 hasConceptScore W3017594920C119795356 @default.
• W3017594920 hasConceptScore W3017594920C134651460 @default.
• W3017594920 hasConceptScore W3017594920C140840227 @default.
• W3017594920 hasConceptScore W3017594920C181199279 @default.
• W3017594920 hasConceptScore W3017594920C185592680 @default.
• W3017594920 hasConceptScore W3017594920C2779384962 @default.
• W3017594920 hasConceptScore W3017594920C3946865 @default.
• W3017594920 hasConceptScore W3017594920C40767141 @default.
• W3017594920 hasConceptScore W3017594920C526171541 @default.
• W3017594920 hasConceptScore W3017594920C55493867 @default.
• W3017594920 hasConceptScore W3017594920C86803240 @default.
• W3017594920 hasConceptScore W3017594920C89311334 @default.
• W3017594920 hasIssue "S1" @default.
• W3017594920 hasLocation W30175949201 @default.
• W3017594920 hasOpenAccess W3017594920 @default.
• W3017594920 hasPrimaryLocation W30175949201 @default.
• W3017594920 hasRelatedWork W1975591667 @default.
• W3017594920 hasRelatedWork W1978392142 @default.
• W3017594920 hasRelatedWork W2079104442 @default.
• W3017594920 hasRelatedWork W2316137577 @default.
• W3017594920 hasRelatedWork W2316563089 @default.
• W3017594920 hasRelatedWork W2399165565 @default.
• W3017594920 hasRelatedWork W2478188498 @default.
• W3017594920 hasRelatedWork W2614119380 @default.
• W3017594920 hasRelatedWork W2799509613 @default.
• W3017594920 hasRelatedWork W3114647638 @default.
• W3017594920 hasVolume "34" @default.
• W3017594920 isParatext "false" @default.
• W3017594920 isRetracted "false" @default.
• W3017594920 magId "3017594920" @default.
• W3017594920 workType "article" @default.