RGD Reference Report - 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. - Rat Genome Database

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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.
RGD ID: 14995311
Pubmed: PMID:16617161   (View Abstract at PubMed)
DOI: DOI:10.1124/mol.106.023275   (Journal Full-text)

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.




Biological Process

  
Object Symbol
Species
Term
Qualifier
Evidence
With
Notes
Source
Original Reference(s)
Cyp24a1Ratvitamin D catabolic process involved_inIDA PMID:16617161UniProt 

Molecular Function

  
Object Symbol
Species
Term
Qualifier
Evidence
With
Notes
Source
Original Reference(s)
Cyp24a1Rat1-alpha,25-dihydroxyvitamin D3 24-hydroxylase activity enablesIDA PMID:16617161UniProt 


Genes (Rattus norvegicus)
Cyp24a1  (cytochrome P450, family 24, subfamily a, polypeptide 1)