25-Hydroxyvitamin D<sub>3</sub>-24-hydroxylase. Subcellular location and properties

Knutson, Joyce C.; DeLuca, Hector F.

doi:10.1021/bi00704a034

Cited by 187 publications

(56 citation statements)

References 24 publications

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“…Radioactivity in the fractions was measured using a liquid scintillation spectrometer model SL30 (Intertechnique, Plaisir, France). The putative 24,25(OH)2D3 metabolite, when detected, was further characterized by co-chromatography with synthetic 24,25(OH)2D3 on high performance liquid chromatography (HPLC) using the above system and a straight-phase system in which samples were eluted with dichloromethane-isopropanol (95:5, vol/vol), and by a periodate cleavage procedure (24) BGPproduction. Cells were incubated for 18 h in serum-free medium supplemented either with 1,25(OH)2D3 (10-9 M) or its ethanol solvent.…”

Section: Methodsmentioning

confidence: 99%

Long-term nocturnal calcium infusions can cure rickets and promote normal mineralization in hereditary resistance to 1,25-dihydroxyvitamin D.

Balsan¹,

Garabédian²,

Larchet³

et al. 1986

J. Clin. Invest.

253

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We report the beneficial effects of calcium infusions in a child with hereditary resistance to 1,25(OH)2D and alopecia. This patient after transient responsiveness to vitamin D derivatives became unresponsive to all therapy despite serum 1,25(OH)2D concentrations maintained at levels -100-fold normal. A 7-mo trial with calcium infusions led to correction of biochemical abnormalities and healing of rickets. Bone biopsies (n = 3) showed a normal mineralization and the disappearance of the osteomalacia. Cultures of bone-derived cells demonstrated a lack of activation of 25-hydroxyvitamin D 24-hydroxylase and osteocalcin synthesis by 1,25(0H)2D3 (10-' and 10' M). These results demonstrate that (a) even in the absence of a normal 1,25(OH)2D3 receptor-effector system in bone cells, normal mineralization can be achieved in humans if adequate serum calcium and phosphorus concentrations are maintained; and (b) calcium infusions may be an efficient alternative for the management of patients with this condition who are unresponsive to large doses of vitamin D derivatives.

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Section: Methodsmentioning

confidence: 99%

Long-term nocturnal calcium infusions can cure rickets and promote normal mineralization in hereditary resistance to 1,25-dihydroxyvitamin D.

Balsan¹,

Garabédian²,

Larchet³

et al. 1986

J. Clin. Invest.

253

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“…Though, CYP24A1 was initially referred to as the 25-hydroxyvitamin D 3 -24-hydroxylase, work with the recombinant enzyme has shown that it is able to catalyze multiple hydroxylation reactions at carbons C-24 and C-23 of the side chain of both 25-OH-D 3 and its hormonal form, 1,25-(OH) 2 D 3 ( 13,14 ). Indeed, our view of the role of CYP24A1 has expanded greatly to suggest that this single P450 alone is responsible for the fi ve-step, 24-oxidation pathway from 1,25-(OH) 2 D 3 to produce calcitroic acid, a known biliary catabolite ( 119,120 ), as well as catalyzing a similar pathway which starts with 23-hydroxylation and culminates in the 1,25-(OH) 2 D 3 -26,23-lactone ( Fig.…”

Section: -Hydroxylase (Cyp24a1)mentioning

confidence: 99%

Cytochrome P450-mediated metabolism of vitamin D

Jones

Prosser

Kaufmann

2014

Journal of Lipid Research

384

292

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signal transduction system, the DBP-knockout mouse is normocalcemic and exhibits normal tissue distribution of vitamin D metabolites and vitamin D action despite exhibiting very low blood levels of 1,25-(OH) 2 D 3 . This unexpected phenotype raised questions about DBP's exact role: essential transporter or buffer against toxicity ( 7,8 ). Work performed on the 25-hydroxylases over the past four decades in humans and a variety of animal species has revealed that several cytochrome P450 enzymes 2 (CYP), such as CYP2R1, CYP27A1, CYP3A4, CYP2D25, and perhaps others, are capable of 25-hydroxylation of vitamin D 3 or related compounds. These CYPs can be referred to as vitamin D 3 -25-hydroxylases, and it is CYP2R1 that is emerging as the physiologically relevant enzyme ( 9 ). On the other hand, there is no ambiguity over the second step of 1 ␣ -hydroxylation or the 25-OH-D 3 -1 ␣ -hydroxylase enzyme responsible, which is carried by a single cytochrome P450 2 named CYP27B1 ( 10-12 ). The inactivation of vitamin D is carried out by the mitochondrial enzyme, 25-hydroxyvitamin D 3 -24-hydroxylase, fi rst described in the early 1970s and initially believed to be involved solely in the renal 24-hydroxylation of 25-OH-D 3 ( 13 ). Work performed over the last 35 years has shown that 24-hydroxylase enzyme activity is the result of CYP24A1 ( 5, 14 ). CYP24A1 catalyzes the conversion of both 25-OH-D 3 and 1,25-(OH) 2 D 3 into a series of 24-and 23-hydroxylated products targeted for excretion along well-established pathways culminating in the water-soluble biliary metabolite calcitroic acid or a 26,23-lactone.This article assembles the most currently pertinent literature on the activating and inactivating enzymes of vitamin D metabolism and highlights protein structure and enzymatic properties, crystal structures, gene organization, and The activation of vitamin D 3 is accomplished by sequential steps of 25-hydroxylation to produce the main circulating form, 25-hydroxyvitamin D (25-OH-D 3 ), followed by 1 ␣ -hydroxylation to the hormonal form, 1 ␣ ,25-dihydroxyvitamin D 3 (1,25-(OH) 2 D 3 ) ( 1 ) ( Fig. 1 ). The initial step of 25-hydroxylation occurs in the liver ( 2 ), and the second step occurs both in the kidney and extrarenal sites ( 3, 4 ). The fat-soluble vitamin D and its metabolites are transported from one tissue to another on the vitamin D-binding protein (DBP), which shows different affi nity for the individual metabolites ( 5 ). The cell-surface receptor megalin-cubilin is thought to facilitate the endocytosis of a DBP-bound 25-OH-D 3 into a number of cell types, especially kidney cells ( 6 ). While it is widely believed that DBP is an essential component of the vitamin D

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“…We examined our RNA-Seq dataset for possible alternative targets of hand2 during regeneration, with a focus on genes known to be involved in bone formation or homeostasis. A significant AP asymmetry was observed for cyp24a1, which encodes a vitamin D-inactivating enzyme (Knutson and DeLuca, 1974), which was expressed at higher levels in posterior rays, like hand2 (Table 1, Fig. 5A).…”

Section: Hand2 Effects On Vitamin D Metabolism In Zebrafish Finsmentioning

confidence: 99%

Transcriptional components of anteroposterior positional information during zebrafish fin regeneration

et al. 2013

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SUMMARYMany fish and salamander species regenerate amputated fins or limbs, restoring the size and shape of the original appendage. Regeneration requires that spared cells retain or recall information encoding pattern, a phenomenon termed positional memory. Few factors have been implicated in positional memory during vertebrate appendage regeneration. Here, we investigated potential regulators of anteroposterior (AP) pattern during fin regeneration in adult zebrafish. Sequence-based profiling from tissues along the AP axis of uninjured pectoral fins identified many genes with region-specific expression, several of which encoded transcription factors with known AP-specific expression or function in developing embryonic pectoral appendages. Transgenic reporter strains revealed that regulatory sequences of the transcription factor gene alx4a activated expression in fibroblasts and osteoblasts within anterior fin rays, whereas hand2 regulatory sequences activated expression in these same cell types within posterior rays. Transgenic overexpression of hand2 in all pectoral fin rays did not affect formation of the proliferative regeneration blastema, yet modified the lengths and widths of regenerating bones. Hand2 influenced the character of regenerated rays in part by elevation of the vitamin D-inactivating enzyme encoded by cyp24a1, contributing to region-specific regulation of bone metabolism. Systemic administration of vitamin D during regeneration partially rescued bone defects resulting from hand2 overexpression. Thus, bone-forming cells in a regenerating appendage maintain expression throughout life of transcription factor genes that can influence AP pattern, and differ across the AP axis in their expression signatures of these and other genes. These findings have implications for mechanisms of positional memory in vertebrate tissues.

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25-Hydroxyvitamin D₃-24-hydroxylase. Subcellular location and properties

Cited by 187 publications

References 24 publications

Long-term nocturnal calcium infusions can cure rickets and promote normal mineralization in hereditary resistance to 1,25-dihydroxyvitamin D.

Long-term nocturnal calcium infusions can cure rickets and promote normal mineralization in hereditary resistance to 1,25-dihydroxyvitamin D.

Cytochrome P450-mediated metabolism of vitamin D

Transcriptional components of anteroposterior positional information during zebrafish fin regeneration

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25-Hydroxyvitamin D3-24-hydroxylase. Subcellular location and properties

Cited by 187 publications

References 24 publications

Long-term nocturnal calcium infusions can cure rickets and promote normal mineralization in hereditary resistance to 1,25-dihydroxyvitamin D.

Long-term nocturnal calcium infusions can cure rickets and promote normal mineralization in hereditary resistance to 1,25-dihydroxyvitamin D.

Cytochrome P450-mediated metabolism of vitamin D

Transcriptional components of anteroposterior positional information during zebrafish fin regeneration

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25-Hydroxyvitamin D₃-24-hydroxylase. Subcellular location and properties