Disease relevance of Cyp27b1

• Although PTH-/- and 1alpha(OH)ase-/- mice displayed only moderate hypocalcemia, PTH-/-1alpha(OH)ase-/- mice died of tetany with severe hypocalcemia by 3 weeks of age [1].
• The inability of hypophosphatemia and PTH to increase 25(OH)D-1alpha-hydroxylase activity and protein expression in hyp-mice was not universal because calcitonin stimulation was normal, suggesting proximal convoluted tubule localization of the defect [2].
• 25-Hydroxyvitamin D3-1alpha-hydroxylase (1alpha-OHase) knockout mice are characterized by hyperparathyroidism, rickets, hypocalcemia, and undetectable levels of 1,25(OH)2D3 and were used to study the 1,25(OH)2D3-dependency of the stimulatory effects of 17beta-E2 [3].
• Enzymatic properties of mouse 25-hydroxyvitamin D3 1 alpha-hydroxylase expressed in Escherichia coli [4].
• However, in human adenocarcinomas expression of the catabolic CYP24 is also enhanced when compared with adjacent normal mucosa [5].

High impact information on Cyp27b1

• BACKGROUND: Pseudovitamin D-deficiency rickets is characterized by the early onset of rickets with hypocalcemia and is thought to be caused by a deficit in renal 25-hydroxyvitamin D3 1alpha-hydroxylase, the key enzyme for the synthesis of 1alpha,25-dihydroxyvitamin D3 [6].
• RESULTS: The gene for 25-hydroxyvitamin D3 1alpha-hydroxylase was mapped to chromosome 12q13.3, which had previously been reported to be the locus for pseudovitamin D-deficiency rickets by linkage analysis [6].
• Renal 25-hydroxyvitamin D3 1alpha-hydroxylase [1alpha(OH)ase] catalyzes metabolic activation of 25-hydroxyvitamin D3 into 1alpha, 25-dihydroxyvitamin D3 [1alpha,25(OH)2D3], an active form of vitamin D, and is inhibited by 1alpha,25(OH)2D3 [7].
• We compared 25(OH)D-1 alpha-hydroxylase activity in the Hyp-mouse kidney to that in normal and phosphate-depleted mouse kidney [8].
• We have previously shown that the novel ATP-dependent chromatin-remodeling complex WINAC is required for the ligand-bound vitamin D receptor (VDR)-mediated transrepression of the 25(OH)D3 1alpha-hydroxylase (1alpha(OH)ase) gene [9].

Chemical compound and disease context of Cyp27b1

• To test if hypercalcemia independent of high levels of 1,25-(OH)2D3 can suppress EAE, we used a 25-hydroxyvitamin D3-1alpha-hydroxylase (1alpha-hydroxylase) knockout mouse strain [10].

Biological context of Cyp27b1

• The mapped negative vitamin D response element (1alphanVDRE) in the human 1alpha(OH)ase gene promoter (around 530 bp) was distinct from those of the reported DR3-like nVDREs, composed of two E-box-like motifs [11].
• To better understand the relative contributions of PTH and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] to skeletal and calcium homeostasis, we compared mice with targeted disruption of the PTH or 1alpha(OH)ase genes to the double null mutants [1].
• Although reduced osteoblastic bone formation was seen in both mutants, PTH deficiency caused only a slight reduction in long bone length but a marked reduction in trabecular bone volume, whereas 1alpha(OH)ase ablation caused a smaller reduction in trabecular bone volume but a significant decrease in bone length [1].
• Mice in which the 25-hydroxyvitamin D3-1alpha-hydroxylase (1alpha-OHase) gene was inactivated presented the same clinical phenotype as patients with PDDR and were used to study renal expression of the epithelial Ca2+ channel (ECaC1), the calbindins, Na+/Ca2+ exchanger (NCX1), and Ca2+-ATPase (PMCA1b) [12].
• Regulation of gene expression by dietary Ca2+ in kidneys of 25-hydroxyvitamin D3-1 alpha-hydroxylase knockout mice [13].

Anatomical context of Cyp27b1

• Expression of 25-hydroxyvitamin D3-1alpha-hydroxylase in pancreatic islets [14].
• Among offspring of Vdr null mothers, Vdr(+/-) and Vdr null fetuses had normal ionized calcium levels and a skeletal ash weight that was appropriate to the lower body weight [15].
• Targeted disruption of the 25-hydroxyvitamin D3 1alpha-hydroxylase gene in ras-transformed keratinocytes demonstrates that locally produced 1alpha,25-dihydroxyvitamin D3 suppresses growth and induces differentiation in an autocrine fashion [16].

Associations of Cyp27b1 with chemical compounds

• The active form of vitamin D, 1alpha,25-dihydroxyvitamin D [1alpha,25(OH)2D], is synthesized from its precursor 25 hydroxyvitamin D [25(OH)D] via the catalytic action of the 25(OH)D-1alpha-hydroxylase [1alpha(OH)ase] enzyme [17].
• The murine homologue of the 25-hydroxyvitamin D [25(OH)D] 1alpha-hydroxylase gene [1alpha(OH)ase; Cyp27bl], which is mutated in humans with vitamin D-dependent rickets type I (VDDR-I; also known as pseudovitamin D-deficiency rickets [PDDR]) was cloned and characterized [18].
• Low-Pi diet, via stimulation of the activity of the renal 25-hydroxyvitamin-D3-1alpha-hydroxylase (1alphaOHase), leads to an increase in the level of 1,25-dihydroxy-vitamin D3 [1,25(OH)2D] [19].
• The role of the VDR in ductal morphogenesis was examined in Vdr knockout mice fed high dietary Ca(2+) which normalizes fertility, serum estrogen and neonatal growth [20].
• Finally, BSPRY expression in kidney was increased in 25-hydroxyvitamin D3-1alpha-hydroxylase knockout mice, suggesting an inverse regulation by vitamin D3 [21].

Regulatory relationships of Cyp27b1

• These results indicate that parathyroid hormone stimulates 25-hydroxyvitamin D3-1alpha-hydroxylase by acting on the promoter of the 1alpha-hydroxylase gene [22].
• Thus, our findings indicate that WINAC associates with chromatin through a physical interaction between the WSTF bromodomain and acetylated his tones, which appears to be indispensable for VDR/promoter association for ligand-induced transrepression of 1alpha(OH)ase gene expression [9].

Other interactions of Cyp27b1

• Parathyroid hormone stimulation of normal mice increased 25(OH)D-1alpha-hydroxylase activity 10-fold, while eliciting only a 2-fold increment in hyp mouse enzyme function [23].
• Positive and negative regulations of the renal 25-hydroxyvitamin D3 1alpha-hydroxylase gene by parathyroid hormone, calcitonin, and 1alpha,25(OH)2D3 in intact animals [24].
• Enzymatic properties of human 25-hydroxyvitamin D3 1alpha-hydroxylase coexpression with adrenodoxin and NADPH-adrenodoxin reductase in Escherichia coli [25].

References