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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.

Authors: Hamamoto, Hiromi  Kusudo, Tatsuya  Urushino, Naoko  Masuno, Hiroyuki  Yamamoto, Keiko  Yamada, Sachiko  Kamakura, Masaki  Ohta, Miho  Inouye, Kuniyo  Sakaki, Toshiyuki 
Citation: Hamamoto H, etal., Mol Pharmacol. 2006 Jul;70(1):120-8. doi: 10.1124/mol.106.023275. Epub 2006 Apr 14.
Pubmed: (View Article at PubMed) PMID:16617161
DOI: Full-text: DOI:10.1124/mol.106.023275

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.

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CRRD Object Information
CRRD ID: 14995311
Created: 2019-10-19
Species: All species
Last Modified: 2019-10-19
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.