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Calcitroic acid


Calcitroic acid (1α-hydroxy-23-carboxy-24,25,26,27-tetranorvitamin D3) is a major metabolite of 1α,25-dihydroxyvitamin D3 (calcitriol). Around 1980, scientists first reported the isolation of calcitroic acid from the aqueous extract of radioactively treated animals' livers and intestines. Subsequent researches confirmed calcitroic acid to be a part of enterohepatic circulation. Often synthesized in the liver and kidneys, calcitroic acid is generated in the body after vitamin D is first converted into calcitriol, an intermediate in the fortification of bone through the formation and regulation of calcium in the body. These pathways managed by calcitriol are thought to be inactivated through its hydroxylation by the enzyme CYP24A1, also called calcitriol 24-hydroxylase. Specifically, It is thought to be the major route to inactivate vitamin D metabolites. The hydroxylation and oxidation reactions will yield either calcitroic acid via the C24 oxidation pathway or 1,25(OH2)D3-26,23-lactone via the C23 lactone pathway. However, the only scientifically known formation of calcitroic acid is through an oxidative reaction of the 1ɑ,25-dihydroxy vitamin D3. The positions of C24 and C23 undergo multiple oxidative reactions. Thus, causing the large and small side chains of 1ɑ,25-dihydroxy vitamin D3 to cleave off and form calcitroic acid.

The compound has been prepared in the laboratory.

Metabolism

Hydroxylation and further metabolism of calcitriol in the liver and the kidneys yields calcitroic acid, a water-soluble compound that is excreted in bile.

In vitro

In case where a higher concentration of this acid is used in vitro, studies determined that calcitroic acid binds to vitamin D receptor (VDR) and induces gene transcription.

Structure

There is an x-ray co-crystal structure of calcitroic acid that justifies that the calcitroic acid and vitamin D receptor have agonistic confirmation properties. Calcitroic acid has two side chains, the smaller side chain consists of a hydrogen bond with His333 and a single water molecule. In addition, the longer side chain consists of His333 and His423 interacting with 1,25(OH)2D3.

References

References

  1. (October 2016). "Calcitroic Acid-A Review". ACS Chemical Biology.
  2. (2014). "Efficient and scalable total synthesis of calcitroic acid and its 13C-labeled derivative". RSC Adv..
  3. (January 2014). "Cytochrome P450-mediated metabolism of vitamin D". Journal of Lipid Research.
  4. (January 2005). "Metabolism of vitamin D3 by cytochromes P450". Frontiers in Bioscience.
  5. (November 2017). "Biochemistry, physiology and diagnostics". Elsevier Academic Press.
  6. (2001). "Calcitroic Acid Is a Major Catabolic Metabolite in the Metabolism of 1α-Dihydroxyvitamin D2". Archives of Biochemistry and Biophysics.
  7. (2021). "Biological evaluation and synthesis of calcitroic acid". Bioorganic Chemistry.
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