Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The activation of vitamin D to its hormonal form is mediated by cytochrome P450 enzymes. CYP2R1 catalyzes the initial step converting vitamin D into 25-hydroxyvitamin D. A CYP2R1 gene mutation causes an inherited form of rickets due to 25-hydroxylase deficiency. To understand the narrow substrate specificity of CYP2R1 we obtained the hemeprotein in a highly purified state, confirmed the enzyme as a vitamin D 25-hydroxylase, and solved the crystal structure of CYP2R1 in complex with vitamin D3. The CYP2R1 structure adopts a closed conformation with the substrate access channel being covered by the ordered B'-helix and slightly opened to the surface, which defines the substrate entrance point. The active site is lined by conserved, mostly hydrophobic residues. Vitamin D3 is bound in an elongated conformation with the aliphatic side-chain pointing toward the heme. The structure reveals the secosteroid binding mode in an extended active site and allows rationalization of the molecular basis of the inherited rickets associated with CYP2R1.
J Mol Biol 2008 Jun 27
PMID:Structural analysis of CYP2R1 in complex with vitamin D3. 1851 Oct 70

Most of the population receive their nutritional vitamin D requirements through exposure to solar ultraviolet (UV) radiation, with cutaneous synthesis estimated to provide 80-100% of the vitamin D requirements of the body. However, little is understood about the basic interaction of sunlight (UV) exposure and the subsequent photobiology and photochemistry of vitamin D production in humans. Low vitamin D (blood serum 25[OH]D) status has been linked to the development of a surprisingly wide range of diseases. Epidemiological data and animal studies indicate that low vitamin D is linked to rickets, bone mass loss, multiple sclerosis, hypertension, breast cancer, prostate cancer, colorectal cancer, insulin dependent diabetes and schizophrenia. Importantly some this emerging research associates such diseases with location and subsequent ultraviolet radiation exposures. This paper overviews concepts important to consider when assessing the impact of location and UV exposure on vitamin D synthesis.
Mol Aspects Med 2008 Dec
PMID:Geographic location and vitamin D synthesis. 1878 59

The vitamin D endocrine system is essential for calcium and bone homeostasis. Vitamin D deficits are associated with muscle weakness and osteoporosis, whereas vitamin D supplementation may improve muscle function, body sway and frequency of falls, growth and mineral homeostasis of bones. The loss of muscle strength and mass, as well as deficits in bone formation, lead to poor balance. Poor balance is one of the main causes of falls, and may lead to dangerous injuries. Here we examine balance functions in vitamin D receptor deficient (VDR-/-) mice, an animal model of vitamin D-dependent rickets type II, and in 1alpha-hydroxylase deficient (1alpha-OHase-/-) mice, an animal model of pseudovitamin D-deficiency rickets. Recently developed methods (tilting box, rotating tube test), swim test, and modified accelerating rotarod protocol were used to examine whether the absence of functional VDR, or the lack of a key vitamin D-activating enzyme, could lead to mouse vestibular dysfunctions. Overall, VDR-/- mice, but not 1alpha-OHase-/- mice, showed shorter latency to fall from the rotarod, smaller fall angle in the tilting box test, and aberrant poor swimming. These data suggest that VDR deficiency in mice is associated with decreased balance function, and may be relevant to poorer balance/posture control in humans with low levels of vitamin D.
J Steroid Biochem Mol Biol 2009 Apr
PMID:Vestibular dysfunction in vitamin D receptor mutant mice. 1942 46

The rare genetic recessive disease, hereditary vitamin D resistant rickets (HVDRR), is caused by mutations in the vitamin D receptor (VDR) that result in resistance to the active hormone 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3) or calcitriol). In this study, we examined the VDR from a young boy with clinical features of HVDRR including severe rickets, hypocalcemia, hypophosphatemia and partial alopecia. The pattern of alopecia was very unusual with areas of total baldness, adjacent to normal hair and regions of scant hair. The child failed to improve on oral calcium and vitamin D therapy but his abnormal chemistries and his bone X-rays normalized with intravenous calcium therapy. We found that the child was homozygous for a unique missense mutation in the VDR gene that converted valine to methionine at amino acid 26 (V26M) in the VDR DNA-binding domain (DBD). The mutant VDR was studied in the patient's cultured skin fibroblasts and found to exhibit normal [(3)H]1,25(OH)(2)D(3) binding and protein expression. However, the fibroblasts were unresponsive to treatment with high concentrations of 1,25(OH)(2)D(3) as demonstrated by their failure to induce CYP24A1 gene expression, a marker of 1,25(OH)(2)D(3) responsiveness. We recreated the V26M mutation in the WT VDR and showed that in transfected COS-7 cells the mutation abolished 1,25(OH)(2)D(3)-mediated transactivation. The mutant VDR exhibited normal ligand-induced binding to RXRalpha and to the coactivator DRIP205. However, the V26M mutation inhibited VDR binding to a consensus vitamin D response element (VDRE). In summary, we have identified a novel V26M mutation in the VDR DBD as the molecular defect in a patient with HVDRR and an unusual pattern of alopecia.
Mol Genet Metab 2010 Jan
PMID:Hereditary 1,25-dihydroxyvitamin D-resistant rickets with alopecia resulting from a novel missense mutation in the DNA-binding domain of the vitamin D receptor. 1981 38

Hypovitaminosis D is a highly prevalent condition and quantification of serum 25-hydroxyvitamin D3 is accepted to be the most useful marker for the assessment of the individual vitamin D status. Due to the increasing awareness of the prevalence and potential health consequences of hypovitaminosis D, the request numbers for 25-hydroxyvitamin D quantification are growing rapidly in many countries. Automated protein binding assays (based on the use of vitamin D-binding protein or antibodies) for the quantification of 25-hydroxyvitamin D3 are available which enable convenient high-throughput analyses in a routine setting; there is, however, substantial concern about accuracy and analytical reliability of these assays. Several LC-MS/MS methods for the quantification of 25-hydroxyvitamin D3 in serum have been described and in a growing number of clinical laboratories this technology is used routinely for vitamin D monitoring. It is justified to assume that LC-MS/MS enables more reliable analyses of 25-hydroxyvitamin D concentrations compared to protein binding assays. In particular the ability to co-quantify the naturally occurring 25-hydroxyvitamin D3 and 25-hydroxyvitamin D2 which is derived primarily from food fortification is a relevant advantage of LC-MS/MS over protein binding assays. This review describes the background of 25-hydroxyvitamin D measurement, compares published LC-MS/MS methods, discusses problems, strengths and limitations of these assays and compares the application characteristics of LC-MS/MS with those of protein binding assays and HPLC-UV.
J Steroid Biochem Mol Biol 2010 Aug
PMID:Quantification of circulating 25-hydroxyvitamin D by liquid chromatography-tandem mass spectrometry. 2020 93

The nuclear vitamin D receptor (VDR) binds 1,25-dihydroxyvitamin D3 (1,25D), its high affinity renal endocrine ligand, to signal intestinal calcium and phosphate absorption plus bone remodeling, generating a mineralized skeleton free of rickets/osteomalacia with a reduced risk of osteoporotic fractures. 1,25D/VDR signaling regulates the expression of TRPV6, BGP, SPP1, LRP5, RANKL and OPG, while achieving feedback control of mineral ions to prevent age-related ectopic calcification by governing CYP24A1, PTH, FGF23, PHEX, and klotho transcription. Vitamin D also elicits numerous intracrine actions when circulating 25-hydroxyvitamin D3, the metabolite reflecting vitamin D status, is converted to 1,25D locally by extrarenal CYP27B1, and binds VDR to promote immunoregulation, antimicrobial defense, xenobiotic detoxification, anti-inflammatory/anticancer actions and cardiovascular benefits. VDR also affects Wnt signaling through direct interaction with beta-catenin, ligand-dependently blunting beta-catenin mediated transcription in colon cancer cells to attenuate growth, while potentiating beta-catenin signaling via VDR ligand-independent mechanisms in osteoblasts and keratinocytes to function osteogenically and as a pro-hair cycling receptor, respectively. Finally, VDR also drives the mammalian hair cycle in conjunction with the hairless corepressor by repressing SOSTDC1, S100A8/S100A9, and PTHrP. Hair provides a shield against UV-induced skin damage and cancer in terrestrial mammals, illuminating another function of VDR that facilitates healthful aging.
J Steroid Biochem Mol Biol 2010 Jul
PMID:The nuclear vitamin D receptor controls the expression of genes encoding factors which feed the "Fountain of Youth" to mediate healthful aging. 2022 97

Vitamin D was discovered as the preventive agent of nutritional rickets, a defect in bone development due to inadequate uptake of dietary calcium. However, a variety of studies over the last several years has revealed that vitamin D controls much more than calcium homeostasis. For example, recent research has underlined the key role of vitamin D signaling in regulation of innate immunity in humans. Vitamin D is converted to 25-hydroxyvitamin D (25D), its major circulating form, and then to hormonal 1,25-dihydroxyvitamin D (1,25D) in target cells. We now know that when cells of the immune system such a macrophages sense a bacterial infection they acquire the capacity to convert circulating 25D into 1,25D. Moreover, 1,25D thus produced is a direct inducer of expression of genes encoding antimicrobial peptides, in particular cathelicidin antimicrobial peptide (CAMP). Antimicrobial peptides such as CAMP are vanguards of innate immune responses to bacterial infection and can act as signaling molecules to regulate immune system function. This review covers what we have learned in the past few years about the expression and function of CAMP under physiological and pathophysiological conditions, and addresses the potential future applications of vitamin D analogues to therapeutic regulation of CAMP expression.
J Steroid Biochem Mol Biol 2010 Jul
PMID:Vitamin D as an inducer of cathelicidin antimicrobial peptide expression: past, present and future. 2030 31

Vitamin D deficiency is common among patients with myocardial diseases because sun-induced vitamin D production in the skin and dietary intake of vitamin D is often insufficient. Knockout mice for the vitamin D receptor develop myocardial hypertrophy and dysfunction. It has also been shown that children with rickets who suffered from severe heart failure could be successfully treated with supplementation of vitamin D plus calcium. In adults, almost all patients with heart failure exhibit reduced 25-hydroxyvitamin D levels, which are used to classify the vitamin D status. In prospective studies, vitamin D deficiency was an independent risk factor for mortality, deaths due to heart failure and sudden cardiac death. Several vitamin D effects on the electrophysiology, contractility, and structure of the heart suggest that vitamin D deficiency might be a causal factor for myocardial diseases. Data from interventional trials, however, are rare and urgently needed to elucidate whether vitamin D supplementation is useful for the treatment of myocardial diseases. In our opinion, the current knowledge of the beneficial effects of vitamin D on myocardial and overall health strongly argue for vitamin D supplementation in all vitamin D-deficient patients with or at high risk for myocardial diseases.
Mol Nutr Food Res 2010 Aug
PMID:Vitamin D deficiency and myocardial diseases. 2035 23

It has been previously documented that alphacalcidol (1alpha-hydroxyvitamin D3) is inefficient in healing rickets, partly because it results in a suboptimal rise in 1,25-dihydroxyvitamin D (1,25-(OH)2D) and partly because it fails to replenish the store of 25-hydroxyvitamin D (25-OHD). However, very few studies have actually documented this outcome. The aim was to document biochemically the response to alphacalcidol and subsequently the change in response to ergocalciferol. This study was conducted at our institution from January 2005 till December 2008. We included all patients referred to our clinic with active rickets after a failed course of alphacalcidol. At baseline the median (IQR) for PTH l7.1 (4.5-35.3) pmol/L, 25-OHD 29.0 (18-66.2) nmol/L, 1,25-(OH)2D 205 (158.2-311.2) pmol/L and ALP 676 (462.5-1101.7) IU/L. After 3 months treatment with ergocalciferol the concentrations changed markedly with biochemical healing: PTH 4.5 (3.9-7.5), 25-OHD 143.5 (101.5-206.5), 1,25-(OH)(2)D 277 (221.0-572.7), ALP 369 (302.2-438.0). The results confirm the biochemical and physiological basis for using ergocalciferol (or cholecalciferol) in nutritional rickets. Unfortunately these forms are not readily available in many geographic areas. This supply problem together with marketing strategies forces physicians to make an incorrect choice of medication. Treatment with ergocalciferol was either with intramuscular stosstherapy or drops for 3 months. The former ensures compliance and is associated with higher 25-OHD and 1,25-(OH)2D concentrations.
J Steroid Biochem Mol Biol 2010 Jul
PMID:Failure of alphacalcidol (1alpha-hydroxyvitamin D3) in treating nutritional rickets and the biochemical response to ergocalciferol. 2039 60

The primary circulating form of vitamin D, 25-hydroxy-vitamin D [25(OH)D], is associated with multiple medical outcomes, including rickets, osteoporosis, multiple sclerosis and cancer. In a genome-wide association study (GWAS) of 4501 persons of European ancestry drawn from five cohorts, we identified single-nucleotide polymorphisms (SNPs) in the gene encoding group-specific component (vitamin D binding) protein, GC, on chromosome 4q12-13 that were associated with 25(OH)D concentrations: rs2282679 (P=2.0x10(-30)), in linkage disequilibrium (LD) with rs7041, a non-synonymous SNP (D432E; P=4.1x10(-22)) and rs1155563 (P=3.8x10(-25)). Suggestive signals for association with 25(OH)D were also observed for SNPs in or near three other genes involved in vitamin D synthesis or activation: rs3829251 on chromosome 11q13.4 in NADSYN1 [encoding nicotinamide adenine dinucleotide (NAD) synthetase; P=8.8x10(-7)], which was in high LD with rs1790349, located in DHCR7, the gene encoding 7-dehydrocholesterol reductase that synthesizes cholesterol from 7-dehydrocholesterol; rs6599638 in the region harboring the open-reading frame 88 (C10orf88) on chromosome 10q26.13 in the vicinity of ACADSB (acyl-Coenzyme A dehydrogenase), involved in cholesterol and vitamin D synthesis (P=3.3x10(-7)); and rs2060793 on chromosome 11p15.2 in CYP2R1 (cytochrome P450, family 2, subfamily R, polypeptide 1, encoding a key C-25 hydroxylase that converts vitamin D3 to an active vitamin D receptor ligand; P=1.4x10(-5)). We genotyped SNPs in these four regions in 2221 additional samples and confirmed strong genome-wide significant associations with 25(OH)D through meta-analysis with the GWAS data for GC (P=1.8x10(-49)), NADSYN1/DHCR7 (P=3.4x10(-9)) and CYP2R1 (P=2.9x10(-17)), but not C10orf88 (P=2.4x10(-5)).
Hum Mol Genet 2010 Jul 01
PMID:Genome-wide association study of circulating vitamin D levels. 2041 85


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