Vitamin D 1α-Hydroxylase

doi:10.1016/S1043-2760(00)00287-3

Trends in Endocrinology & Metabolism

Volume 11, Issue 8, 1 October 2000, Pages 315-319

https://doi.org/10.1016/S1043-2760(00)00287-3 Get rights and content

Abstract

The rate-limiting, hormonally regulated step in the bioactivation of vitamin D is renal 1α-hydroxylation by P450c1α. In late 1997, we reported the cloning of the human cDNA and gene from keratinocytes, and established that P450c1α mutations cause vitamin D-dependent rickets, type I, while three other groups reported the cloning of the rodent enzyme. The genetics of P450c1α are well established, with studies of over 30 patients, but the molecular mechanisms for the hormonal regulation of P450c1α are still under investigation.

Section snippets

The Vitamin D Biosynthetic Enzymes are Mitochondrial Forms of Cytochrome P450

The vitamin D 25-hydroxylase, the 1α-hydroxylase and the 24-hydroxylase are all type I (mitochondrial) cytochrome P450 enzymes, which function as oxidases and use electrons from NADPH and molecular oxygen3, 4. For catalysis by a type I P450 enzyme, electrons from NADPH are first taken up by a flavoprotein, ferredoxin reductase, which is bound to the inner mitochondrial membrane. Ferredoxin reductase passes the electrons to ferredoxin, an iron–sulfur protein that is either loosely associated

Vitamin D 25-Hydroxylase

The hepatic 25-hydroxylase was initially thought to be a microsomal enzyme, and it was not until it was cloned that its subcellular location was agreed upon. Studies of bile acid 26-hydroxylation led to the cloning of vitamin D 25-hydroxylase. A mitochondrial P450 enzyme that had bile acid 26-hydroxylase activity was isolated from rabbit liver and cloned. Three groups used similar techniques to purify rat liver mitochondrial vitamin D 25-hydroxylase6, 7, 8, 9, 10. Screening of

Vitamin D 24-Hydroxylase

Vitamin D 24-hydroxylase was cloned by purifying P450c24 from renal mitochondria, raising a polyclonal antiserum, and screening a rat kidney cDNA expression library¹⁸. This facilitated the cloning of the rat gene¹⁹ and the human cDNA and gene20, 21. Studies with the purified rat renal enzyme¹⁸ and with cells expressing the transfected human cDNA²⁰ show that P450c24 can catalyze the 24-hydroxylation of either 25OHD or 1,25(OH)₂D. The conversion of 1,25(OH)₂D to 1,24,25(OH)₃D, which is inducible

Vitamin D 1α-Hydroxylase

Although the 25- and 24-hydroxylases were cloned in 1990 and 1991, the 1α-hydroxylase was not cloned until the second half of 1997, when four independent groups using different approaches reported the cloning of the mouse, rat and human vitamin D 1α-hydroxylase, P450c1α (25, 26, 27, 28, 29, 30). This work has been reviewed in greater detail elsewhere³¹. The cloning of P450c1α was very difficult, primarily because there is very little P450c1α protein in the kidney. Although physiological

The Molecular Genetics of 1α-Hydroxylase deficiency

We then studied the P450c1α genes in 19 more patients from 17 families from multiple ethnic groups⁴⁰. These patients all had the typical findings of 1α-hydroxylase deficiency: hypocalcemia, hypophosphatemia, high serum alkaline phosphatase and PTH concentrations, normal 25OHD concentrations, low 1,25(OH)₂ D concentrations, radiographic evidence of rickets and a therapeutic response to physiological replacement doses of 1,25(OH)₂D. Because the P450c1α gene is small, we could PCR amplify the

Regulation of P450c1α

Renal 1α-hydroxylase activity and P450c1α mRNA are stimulated by PTH, insulin-like growth factor I (IGF-I), hypocalcemia and hypophosphatemia, and suppressed by hypercalcemia, hyperphosphatemia and 1,25(OH)₂D (28, 29, 45). The stimulatory effect of PTH on 1α-hydroxylase activity appears to require both the cAMP-dependent protein kinase A (PKA) and protein kinase C (PKC) pathways. The induction by PTH (and cAMP) occurs, at least in part, at the transcriptional level and the suppression by

Acknowledgements

The work discussed here was supported by National Institute of Health grants DK37922 (to WLM), DK42154 (to WLM), DK/AR54433 (to AAP), and by grants from the March of Dimes Birth Defects Foundation (to WLM and AAP).

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The activating enzymes convert the pro-hormone, vitamin D, into the major circulating form, 25-hydroxyvitamin D and then the hormonal form, 1,25-dihydroxyvitamin D. The two enzymes involved, known as the vitamin D₃-25-hydroxylase and the 25(OH)D₃-1α-hydroxylase, are located primarily in liver and kidney. Both enzymes are cytochrome P450s, and the bulk of the evidence suggests that the principal P450 isoforms are CYP2R1 and CYP27B1, respectively. The two CYPs have been cloned, shown to hydroxylate vitamin D metabolites in vitro, and there are crystal structures or molecular models of their structure. Human mutations of CYP2R1 and CYP27B1 are known which cause deficiency of circulating 25(OH)D₃ and/or 1,25(OH)₂D₃ and result in rickets, and there are mouse models in which the two CYPs have been knocked out. While CYP2R1 appears to be poorly regulated; renal CYP27B1 is tightly regulated by calcium and phosphate ions through their regulatory hormones: PTH, FGF23, and through its product, 1,25(OH)₂D₃.
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Citation Excerpt :
VDDR-1A is the classic and most prevalent form of pseudovitamin D deficiency rickets or hereditary vitamin D–resistant rickets. It is caused by recessive loss-of-function mutations in the CYP27B1 gene encoding 25-(OH)D3-1α-hydroxylase.21,47–51 Numerous patients and CYP27B1 mutations have been reported (see Fig. 2C).

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Trends in Endocrinology & Metabolism

ReviewVitamin D 1α-Hydroxylase

Abstract

Section snippets

The Vitamin D Biosynthetic Enzymes are Mitochondrial Forms of Cytochrome P450

Vitamin D 25-Hydroxylase

Vitamin D 24-Hydroxylase

Vitamin D 1α-Hydroxylase

The Molecular Genetics of 1α-Hydroxylase deficiency

Regulation of P450c1α

Acknowledgements

Am. J. Med. Sci.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

FEBS Lett.

J. Biol. Chem.

J. Lipid Res.

J. Pediatr.

Biochem. Biophys. Res. Commun.

FEBS Lett.

Biochim. Biophys. Acta

Biochem. Biophys. Res. Commun.

Endocrinol. Metab. Clin. North Am.

Am. J. Hum. Genet.

Kidney Int.

Biochem. Biophys. Res. Commun.

Metabolism of 1,25-dihyroxy vitamin D3

Physiol. Rev.

P450 genesstructure, evolution and regulation

Annu. Rev. Biochem.

P-450 cytochromesstructure and function

Adv. Enzymol. Relat. Areas Mol. Biol.

25-Hydroxylation of vitamin D by a cytochrome P-450 from rabbit liver mitochondria

J. Biochem.

Purification and characterization of a hepatic mitochondrial cytochrome P450 active in aflatoxin B1 metabolism

Biochemistry

A cDNA encoding a rat mitochondrial cytochrome P450 catalysing both the 26-hydroxylations of cholesterol and 25-hydroxylation of vitamin D3gonadotropic regulation of the cognate mRNA in ovaries

DNA Cell Biol.

Inborn errors in bile acid biosynthesis and storage of sterols other than cholesterol

Review
Vitamin D 1α-Hydroxylase

Metabolism of 1,25-dihyroxy vitamin D₃

A cDNA encoding a rat mitochondrial cytochrome P450 catalysing both the 26-hydroxylations of cholesterol and 25-hydroxylation of vitamin D₃gonadotropic regulation of the cognate mRNA in ovaries