PMID: 11901100Mar 20, 2002Paper

CYP3A4 active site volume modification by mutagenesis of leucine 211

Drug Metabolism and Disposition : the Biological Fate of Chemicals
S M FowlerR J Riley

Abstract

The leucine 211 --> phenylalanine (L211F) and leucine 211 --> tyrosine (L211Y) mutant forms of cytochrome P450 3A4 have been generated by site-directed mutagenesis and expressed functionally in Escherichia coli. Substrate binding affinities (S50 values) for testosterone and 7-benzyloxy-4-trifluoromethylcoumarin (BFC) were similar for the mutants and wild-type CYP3A4 (49 and 21 microM for L211F, 35 and 20 microM for L211Y, and 33 and 20 microM for the wild type, respectively). For erythromycin, however, the K(m) values determined for the L211F and L211Y mutants were 2.4- and 10.5-fold higher than for the wild type. Furthermore, IC50 values for the inhibition of testosterone 6 beta-hydroxylation by erythromycin and troleandomycin for L211F were 2.4- and 3.7-fold higher, and those for L211Y were 3.4- and 9.2-fold higher than those measured for the wild type. Conversely, small inhibitors, such as diazepam, exhibited no significant difference in IC50 values between the wild type and the L211F and L211Y mutants. It is proposed that large substrates bound in the catalytic center of CYP3A4 with molecular volumes greater than approximately 600 A(3) were less well accommodated in the altered active sites, resulting in lower association e...Continue Reading

References

Jan 1, 1985·Proceedings of the National Academy of Sciences of the United States of America·T A Kunkel
Oct 23, 1974·Biochemical and Biophysical Research Communications·J L Vermilion, M J Coon
Apr 1, 1993·Trends in Pharmacological Sciences·P Leff, I G Dougall
May 1, 1997·Journal of Computer-aided Molecular Design·G D Szklarz, J R Halpert
Mar 26, 1998·European Journal of Drug Metabolism and Pharmacokinetics·R C HallidayD A Smith
Jun 17, 1998·Proceedings of the National Academy of Sciences of the United States of America·G R Harlow, J R Halpert
Jan 6, 2000·Archives of Biochemistry and Biophysics·K K Khan, J R Halpert
Apr 12, 2000·Biochemistry·S M FowlerC R Wolf

❮ Previous
Next ❯

Citations

Nov 17, 2010·Journal of Molecular Modeling·Jayakanthan MannuPremendu P Mathur
Oct 25, 2008·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Yusuke OkadaHiroshi Yamazaki
Mar 22, 2013·Drug Metabolism and Pharmacokinetics·Takeshi AkiyoshiHisakazu Ohtani
Sep 29, 2012·Dalton Transactions : an International Journal of Inorganic Chemistry·Irina F Sevrioukova, Thomas L Poulos
Nov 30, 2016·Chembiochem : a European Journal of Chemical Biology·Paolo SchiaviniKarine Auclair
Nov 9, 2016·The Journal of Pharmacology and Experimental Therapeutics·Stephen FowlerNavita L Mallalieu
Jul 25, 2006·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Vikash Rajnikant DodhiaGianfranco Gilardi
Feb 16, 2017·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Shotaro UeharaHiroshi Yamazaki
Sep 13, 2019·International Journal of Molecular Sciences·Yusra Sajid KianiAdrian J Mulholland
Dec 1, 2004·Therapeutic Drug Monitoring·Nicolas PicardPierre Marquet
Jul 23, 2008·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Yury KapelyukhGordon C K Roberts
Aug 21, 2019·Drug Metabolism and Disposition : the Biological Fate of Chemicals·F Peter Guengerich
Jul 20, 2004·The Journal of Biological Chemistry·Jason K YanoEric F Johnson
Sep 26, 2006·Journal of Chemical Information and Modeling·Boryeu MaoNicolas Froloff
Feb 21, 2019·Biochemistry·Ilia G DenisovStephen G Sligar

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.