Structure-function analysis of vitamin D 24-hydroxylase (CYP24A1) by site-directed mutagenesis: amino acid residues responsible for species-based difference of CYP24A1 between humans and rats

Molecular Pharmacology
Hiromi HamamotoToshiyuki Sakaki

Abstract

Our previous studies revealed the species-based difference of CYP24A1-dependent vitamin D metabolism. Although human CYP24A1 catalyzes both C-23 and C-24 oxidation pathways, rat CYP24A1 shows almost no C-23 oxidation pathway. We tried to identify amino acid residues that cause the species-based difference by site-directed mutagenesis. In the putative substrate-binding regions, amino acid residue of rat CYP24A1 was converted to the corresponding residue of human CYP24A1. Among eight mutants examined, T416M and I500T showed C-23 oxidation pathway. In addition, the mutant I500F showed quite a different metabolism of 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3] from both human and rat CYP24A1. These results strongly suggest that the amino acid residues at positions 416 and 500 play a crucial role in substrate binding and greatly affect substrate orientation. A three-dimensional model of CYP24A1 indicated that the A-ring and triene part of 1alpha,25(OH)2D3 could be located close to amino acid residues at positions 416 and 500, respectively. Our findings provide useful information for the development of new vitamin D analogs for clinical use.

References

May 8, 1992·Biochemical Pharmacology·L Binderup
Apr 1, 1971·Proceedings of the National Academy of Sciences of the United States of America·M F HolickH F DeLuca
Sep 1, 1971·Proceedings of the National Academy of Sciences of the United States of America·I T BoyleH F DeLuca
Mar 15, 1982·Biochemical and Biophysical Research Communications·A HiwatashiY Ichikawa
Apr 1, 1995·Endocrine Reviews·R BouillonA W Norman
Jun 25, 1996·Biochemistry·M J BeckmanH F DeLuca
Jul 27, 2000·Pediatric Nephrology : Journal of the International Pediatric Nephrology Association·A A Portale, W L Miller
Sep 30, 2000·European Journal of Biochemistry·T SakakiK Inouye
Jan 10, 2003·Journal of Cellular Biochemistry·J L OmdahlR Serda
Jan 10, 2003·Journal of Cellular Biochemistry·Inge SchusterRomano T Kroemer
Jul 16, 2003·Nature·Pamela A WilliamsHarren Jhoti
Sep 19, 2003·Biochemical and Biophysical Research Communications·Tatsuya KusudoKuniyo Inouye
Oct 18, 2003·Proceedings of the National Academy of Sciences of the United States of America·Emily E ScottC David Stout
Dec 17, 2003·The Journal of Biological Chemistry·Guillaume A SchochEric F Johnson
Apr 28, 2004·Archives of Biochemistry and Biophysics·Andrew AnnaloraJohn L Omdahl
Sep 11, 2004·Biochemical and Biophysical Research Communications·Tatsuya KusudoKuniyo Inouye
Sep 17, 2004·Biochemical and Biophysical Research Communications·Eriko UchidaKuniyo Inouye
Mar 15, 2005·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Daisuke AbeKuniyo Inouye
Aug 9, 2005·Nature Structural & Molecular Biology·Jason K YanoEric F Johnson
Dec 15, 2005·The Journal of Biological Chemistry·Paul RowlandAngela M Bridges

❮ Previous
Next ❯

Citations

Feb 27, 2009·Toxicological Sciences : an Official Journal of the Society of Toxicology·Manabu MatsunawaMakoto Makishima
Jan 25, 2012·Journal of Toxicologic Pathology·Robert A EttlinDavid E Prentice
Jul 25, 2007·Proceedings of the National Academy of Sciences of the United States of America·David E ProsserGlenville Jones
Feb 13, 2007·Biochemical and Biophysical Research Communications·Natsumi SawadaToshiyuki Sakaki
Jun 1, 2010·Endocrinology and Metabolism Clinics of North America·Glenville Jones
Apr 9, 2013·Journal of Lipid Research·Glenville JonesMartin Kaufmann
Jul 11, 2019·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Amit Kumar, D Fernando Estrada
Jun 24, 2010·Behavioural Pharmacology·Adam StewartAllan V Kalueff
Jun 17, 2011·The New England Journal of Medicine·Karl P SchlingmannMartin Konrad
Jun 5, 2014·The FEBS Journal·Elaine W TieuRobert C Tuckey
Jun 8, 2007·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Naoko UrushinoToshiyuki Sakaki
Sep 19, 2020·Metabolites·Emma A HurstRichard J Mellanby
Apr 28, 2009·Biochemical and Biophysical Research Communications·Naoko UrushinoToshiyuki Sakaki
Dec 8, 2009·Journal of Molecular Biology·Andrew J AnnaloraC David Stout
Feb 23, 2011·Archives of Biochemistry and Biophysics·Steve Y RhieuG Satyanarayana Reddy
Nov 22, 2011·Archives of Biochemistry and Biophysics·Glenville JonesMartin Kaufmann
Apr 25, 2012·Rheumatic Diseases Clinics of North America·Glenville Jones

❮ 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.

Related Papers

Biochemical and Biophysical Research Communications
Tatsuya KusudoKuniyo Inouye
Frontiers in Bioscience : a Journal and Virtual Library
Toshiyuki SakakiKuniyo Inouye
Biochemical and Biophysical Research Communications
Naoko UrushinoToshiyuki Sakaki
© 2022 Meta ULC. All rights reserved