PMID: 9546661Apr 18, 1998Paper

Conferring aldosterone synthesis to human CYP11B1 by replacing key amino acid residues with CYP11B2-specific ones

European Journal of Biochemistry
B BöttnerR Bernhardt

Abstract

Performing residue-swapping experiments between the highly conserved human steroidogenic proteins CYP11B1 and CYP11B2 we recently demonstrated that replacement of specific residues at position 301, 302 and 320 in the aldosterone-producing CYP11B2 protein for such residues that were specific for the highly similar cortisol-producing CYP11B1 protein elevated the 11beta-hydroxylase activity dramatically. Conversely, aldosterone synthesis in the triple mutant was severely impaired. Here we provide evidence that in a reciprocal experiment, CYP11B2-specific amino acids at position 320 and 335 endowed CYP11B1 with an 18-oxidase function amounting to 20% of the CYP11B2 wild-type activity, thus changing the specificity of steroid hydroxylation by only one point mutation. Combining substitutions at positions 296, 301, 302, 320, 335 and 339 did, however, not result in further enhancement. Paradoxically, 11beta-hydroxylation was not or only marginally affected in CYP11B1 mutants, indicating an alternative structural basis for this activity in CYP11B1 compared with the engineered CYP11B2 variant. Our results suggest that the sequence spanned by amino acids 301 and 335 constitutes part of the substrate-binding site in CYP11B1 and CYP11B2 as ...Continue Reading

Citations

Nov 24, 2007·Archives of Toxicology·Veronica LindströmOrjan Lindhe
Jul 16, 2008·Analytical and Bioanalytical Chemistry·Kersten S RabeChristof M Niemeyer
Nov 1, 2005·Current Cardiology Reports·Richard J Auchus
Apr 6, 2004·Molecular and Cellular Endocrinology·Jérôme NicodPaolo Ferrari
Mar 18, 2004·Molecular and Cellular Endocrinology·Michael Lisurek, Rita Bernhardt
Feb 22, 2002·European Journal of Biochemistry·Stephanie BechtelRita Bernhardt
Jan 9, 2013·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·Daniel W NebertWalter L Miller
Aug 14, 2013·Reproductive Biology and Endocrinology : RB&E·Andrea VecchiolaCarlos E Fardella
Nov 6, 2010·Endocrine Reviews·Walter L Miller, Richard J Auchus
Nov 28, 2002·Biological Chemistry·Matthias BureikRita Bernhardt
Oct 26, 2000·Proceedings of the National Academy of Sciences of the United States of America·M Schalk, R Croteau
Jul 25, 2007·Journal of Computer-aided Molecular Design·Luc RoumenJ J R Hermans
Sep 6, 2007·Drug Metabolism Reviews·Inge Schuster, Rita Bernhardt
Mar 7, 2006·Journal of Biotechnology·Rita Bernhardt
Jan 24, 2006·Pharmacology & Therapeutics·Tarek Hakki, Rita Bernhardt
Jan 17, 2013·Molecular Endocrinology·Natallia StrushkevichHee-Won Park
Sep 11, 2001·The Journal of Clinical Endocrinology and Metabolism·M HampfR Bernhardt
Jun 6, 2003·The Journal of Clinical Endocrinology and Metabolism·Felicity M DunlopKathleen M Curnow
Apr 26, 2012·Chembiochem : a European Journal of Chemical Biology·Kim Thoa NguyenRita Bernhardt
Mar 12, 2005·Arquivos brasileiros de endocrinologia e metabologia·Maricilda Palandi MelloMargaret de Castro

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