Vitamin D (calciferol) metabolism (Homo sapiens)

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cytosol endoplasmic reticulum lumen cytosol cytosol lysosomal lumen mitochondrial matrix endoplasmic reticulum lumen mitochondrial intermembrane space nucleoplasm cytosol SKIN LIVER KIDNEY TARGET CELL GC CYP2R1 NADPH H+ O2 NADP+ GC:CDL CUBN CUBN:GC:CDL CUBN:GC:CDL LRP2 CUBN:GC:CDL CDL LGMN H2O CTL CYP27B1(?-508) NADP+ H+ NADPH O2 CTA H2O CYP24A1 O2 H+ NADPH NADP+ CDL 7-dehydroCHOL VD3 VD3 VD3 VD3 CUBN:CDL Cholesterol biosynthesis CDL H2O CDL CDL GC CUBN CDL GC CUBN CDL GC GC CUBN CDL CUBN CDL Name: Vitamin D (calciferol) metabolism Organism: Homo sapiens


Vitamin D3 (VD3, cholecalciferol) is a steroid hormone that principally plays roles in regulating intestinal calcium absorption and in bone metabolism. It is obtained from the diet and produced in the skin by photolysis of 7-dehydrocholesterol and released into the bloodstream. Only a few food sources have significant amounts of vitamins D2 and D3 but many foodstuffs nowadays are fortified with vitamin D. The metabolites of vitamin D3 are carried in the circulation bound to a plasma protein called vitamin D binding protein (GC) (for review see Delanghe et al. 2015, Chun 2012). VD3 undergoes two subsequent hydroxylations to form the active form of the vitamin, 1,25(OH)2 vitamin D3 (CTL, calcitriol). The first hydroxylation takes place in the liver followed by subsequent transport to the kidney where the second hydroxylation takes place. CTL acts by binding to nuclear vitamin D receptors and regulates over 60 genes involved in calcium homeostasis, immune responses, cellular growth, differentiation and apoptosis. Inactivation of CTL occurs via C23/C24 oxidation catalysed by cytochrome CYP24A1 enzyme (Christakos et al. 2016).

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  1. Cheng JB, Motola DL, Mangelsdorf DJ, Russell DW.; ''De-orphanization of cytochrome P450 2R1: a microsomal vitamin D 25-hydroxilase.''; PubMed
  2. Nykjaer A, Dragun D, Walther D, Vorum H, Jacobsen C, Herz J, Melsen F, Christensen EI, Willnow TE.; ''An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3.''; PubMed
  3. Christakos S, Dhawan P, Verstuyf A, Verlinden L, Carmeliet G.; ''Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects.''; PubMed
  4. Shinkyo R, Sakaki T, Kamakura M, Ohta M, Inouye K.; ''Metabolism of vitamin D by human microsomal CYP2R1.''; PubMed
  5. Chen JM, Fortunato M, Barrett AJ.; ''Activation of human prolegumain by cleavage at a C-terminal asparagine residue.''; PubMed
  6. Herman GE.; ''Disorders of cholesterol biosynthesis: prototypic metabolic malformation syndromes.''; PubMed
  7. Fritsche J, Mondal K, Ehrnsperger A, Andreesen R, Kreutz M.; ''Regulation of 25-hydroxyvitamin D3-1 alpha-hydroxylase and production of 1 alpha,25-dihydroxyvitamin D3 by human dendritic cells.''; PubMed
  8. Rudney H, Sexton RC.; ''Regulation of cholesterol biosynthesis.''; PubMed
  9. Kaseda R, Hosojima M, Sato H, Saito A.; ''Role of megalin and cubilin in the metabolism of vitamin D(3).''; PubMed
  10. Russell DW.; ''Cholesterol biosynthesis and metabolism.''; PubMed
  11. Nykjaer A, Fyfe JC, Kozyraki R, Leheste JR, Jacobsen C, Nielsen MS, Verroust PJ, Aminoff M, de la Chapelle A, Moestrup SK, Ray R, Gliemann J, Willnow TE, Christensen EI.; ''Cubilin dysfunction causes abnormal metabolism of the steroid hormone 25(OH) vitamin D(3).''; PubMed
  12. Kounnas MZ, Loukinova EB, Stefansson S, Harmony JA, Brewer BH, Strickland DK, Argraves WS.; ''Identification of glycoprotein 330 as an endocytic receptor for apolipoprotein J/clusterin.''; PubMed
  13. Chen KS, Prahl JM, DeLuca HF.; ''Isolation and expression of human 1,25-dihydroxyvitamin D3 24-hydroxylase cDNA.''; PubMed
  14. Radons J.; ''The human HSP70 family of chaperones: where do we stand?''; PubMed
  15. Gaylor JL.; ''Membrane-bound enzymes of cholesterol synthesis from lanosterol.''; PubMed
  16. Hjälm G, Murray E, Crumley G, Harazim W, Lundgren S, Onyango I, Ek B, Larsson M, Juhlin C, Hellman P, Davis H, Akerström G, Rask L, Morse B.; ''Cloning and sequencing of human gp330, a Ca(2+)-binding receptor with potential intracellular signaling properties.''; PubMed
  17. Halfon S, Patel S, Vega F, Zurawski S, Zurawski G.; ''Autocatalytic activation of human legumain at aspartic acid residues.''; PubMed
  18. Sawada N, Sakaki T, Kitanaka S, Takeyama K, Kato S, Inouye K.; ''Enzymatic properties of human 25-hydroxyvitamin D3 1alpha-hydroxylase coexpression with adrenodoxin and NADPH-adrenodoxin reductase in Escherichia coli.''; PubMed
  19. Song BL, Javitt NB, DeBose-Boyd RA.; ''Insig-mediated degradation of HMG CoA reductase stimulated by lanosterol, an intermediate in the synthesis of cholesterol.''; PubMed
  20. Zehnder D, Bland R, Chana RS, Wheeler DC, Howie AJ, Williams MC, Stewart PM, Hewison M.; ''Synthesis of 1,25-dihydroxyvitamin D(3) by human endothelial cells is regulated by inflammatory cytokines: a novel autocrine determinant of vascular cell adhesion.''; PubMed
  21. Verboven C, Rabijns A, De Maeyer M, Van Baelen H, Bouillon R, De Ranter C.; ''A structural basis for the unique binding features of the human vitamin D-binding protein.''; PubMed
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93749view 06:33, 16 August 2017ReactomeTeamreactome version 61
93268view 04:18, 9 August 2017ReactomeTeamreactome version 61
86977view 07:30, 15 July 2016MkutmonOntology Term : 'vitamin D metabolic pathway' added !
86345view 02:15, 11 July 2016ReactomeTeamreactome version 56
86215view 04:11, 7 July 2016ReactomeTeamNew pathway

External references


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NameTypeDatabase referenceComment
7-dehydroCHOLMetaboliteCHEBI:17759 (ChEBI)
CDL MetaboliteCHEBI:17933 (ChEBI)
CDLMetaboliteCHEBI:17933 (ChEBI)
CTAMetaboliteCHEBI:47828 (ChEBI)
CTLMetaboliteCHEBI:17823 (ChEBI)
CUBN ProteinO60494 (Uniprot-TrEMBL)
CUBN:CDLComplexR-HSA-8963847 (Reactome)
CUBN:GC:CDLComplexR-HSA-350085 (Reactome)
CUBN:GC:CDLComplexR-HSA-350092 (Reactome)
CUBN:GC:CDLComplexR-HSA-350115 (Reactome)
CUBNProteinO60494 (Uniprot-TrEMBL)
CYP24A1ProteinQ07973 (Uniprot-TrEMBL)
CYP27B1(?-508)ProteinO15528 (Uniprot-TrEMBL)The start coordinate is not yet known
CYP2R1ProteinQ6VVX0 (Uniprot-TrEMBL)
Cholesterol biosynthesisPathwayR-HSA-191273 (Reactome)Cholesterol is synthesized de novo from acetyl CoA. The overall synthetic process is outlined in the attached illustration. Enzymes whose regulation plays a major role in determining the rate of cholesterol synthesis in the body are highlighted in red, and connections to other metabolic processes are indicated. The transformation of zymosterol into cholesterol can follow either of routes, one in which reduction of the double bond in the isooctyl side chain is the final step (cholesterol synthesis via desmosterol, also known as the Bloch pathway) and one in which this reduction is the first step (cholesterol biosynthesis via lathosterol, also known as the Kandutsch-Russell pathway). The former pathway is prominent in the liver and many other tissues while the latter is prominent in skin, where it may serve as the source of the 7-dehydrocholesterol that is the starting point for the synthesis of D vitamins. Defects in several of the enzymes involved in this process are associated with human disease and have provided useful insights into the regulatory roles of cholesterol and its synthetic intermediates in human development (Gaylor 2002; Herman 2003; Kandutsch & Russell 1960; Mitsche et al. 2015; Song et al. 2005).
GC ProteinP02774 (Uniprot-TrEMBL)
GC:CDLComplexR-HSA-209892 (Reactome)
GCProteinP02774 (Uniprot-TrEMBL)
H+MetaboliteCHEBI:15378 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
LGMNProteinQ99538 (Uniprot-TrEMBL)
LRP2ProteinP98164 (Uniprot-TrEMBL)
NADP+MetaboliteCHEBI:18009 (ChEBI)
NADPHMetaboliteCHEBI:16474 (ChEBI)
O2MetaboliteCHEBI:15379 (ChEBI)
VD3MetaboliteCHEBI:28940 (ChEBI)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
7-dehydroCHOLR-HSA-209754 (Reactome)
CDLArrowR-HSA-209766 (Reactome)
CDLArrowR-HSA-209845 (Reactome)
CDLArrowR-HSA-6807242 (Reactome)
CDLR-HSA-209766 (Reactome)
CDLR-HSA-209868 (Reactome)
CDLR-HSA-209944 (Reactome)
CDLR-HSA-6807242 (Reactome)
CTAArrowR-HSA-209765 (Reactome)
CTLArrowR-HSA-209868 (Reactome)
CTLR-HSA-209765 (Reactome)
CUBN:CDLArrowR-HSA-350158 (Reactome)
CUBN:GC:CDLArrowR-HSA-209760 (Reactome)
CUBN:GC:CDLArrowR-HSA-350168 (Reactome)
CUBN:GC:CDLArrowR-HSA-350186 (Reactome)
CUBN:GC:CDLR-HSA-209760 (Reactome)
CUBN:GC:CDLR-HSA-350158 (Reactome)
CUBN:GC:CDLR-HSA-350168 (Reactome)
CUBNR-HSA-350186 (Reactome)
CYP24A1mim-catalysisR-HSA-209765 (Reactome)
CYP27B1(?-508)mim-catalysisR-HSA-209868 (Reactome)
CYP2R1mim-catalysisR-HSA-209845 (Reactome)
GC:CDLArrowR-HSA-209944 (Reactome)
GC:CDLR-HSA-350186 (Reactome)
GCR-HSA-209944 (Reactome)
H+R-HSA-209765 (Reactome)
H+R-HSA-209845 (Reactome)
H+R-HSA-209868 (Reactome)
H2OArrowR-HSA-209765 (Reactome)
H2OArrowR-HSA-209845 (Reactome)
H2OArrowR-HSA-209868 (Reactome)
LGMNmim-catalysisR-HSA-350158 (Reactome)
LRP2mim-catalysisR-HSA-350168 (Reactome)
NADP+ArrowR-HSA-209765 (Reactome)
NADP+ArrowR-HSA-209845 (Reactome)
NADP+ArrowR-HSA-209868 (Reactome)
NADPHR-HSA-209765 (Reactome)
NADPHR-HSA-209845 (Reactome)
NADPHR-HSA-209868 (Reactome)
O2R-HSA-209765 (Reactome)
O2R-HSA-209845 (Reactome)
O2R-HSA-209868 (Reactome)
R-HSA-209754 (Reactome)The skin's exposure to UV rays from sunlight induces the photolytic cleavage of 7-dehydrocholesterol to previtamin D3. This is followed by thermal isomerization to form vitamin D3 (VD3, cholecalciferol) (Holick et al. 1977).
R-HSA-209760 (Reactome)The internalized complex enters the lysosome where it can be acted upon the protease legumain.
R-HSA-209765 (Reactome)Calcitriol (1,25(OH)2-D3) is biologically inactivated through a series of reactions beginning with 24-hydroxylation and is most likely a mechanism of elimination. 24-Hydroxylation of the vitamin D metabolites is largely regulated inversely to 1-hydroxylation, the initial step towards activation.
R-HSA-209766 (Reactome)Once out of the lysosome, calcidiol (CDL) translocates to the mitochondion where it is made available to the mitochondrial membrane-resident protein CYP27B1 for further hydroxylation. The mechanism of mitochondrial targeting is unknown but may involve some kind of intracellular vitamin D binding protein (IDBP). IDBPs are related to the hsc-70 family of heat shock proteins and may function to localise vitamin D metabolites to specific areas. No human IDBP has yet been characterised (Radons 2016).
R-HSA-209845 (Reactome)To be functionally active, vitamin D3 (VD3) needs to be dihydroxylated. The first hydroxylation at position 25 is carried out by ER membrane-located vitamin D 25-hydroxylase (CYP2R1) in the liver, forming calcidiol (CDL) (Shinkyo et al. 2004, Cheng et al. 2003).
R-HSA-209868 (Reactome)The second step in vitamin D3 activation requires hydroxylation of 25-hydroxyvitamin D3 (calcidiol, CDL) to 1alpha-25-dihydroxyvitamin D3 (calcitriol, CTL). This conversion is mediated by 25-hydroxyvitamin D-1alpha hydroxylase (CYP27B1), an outer mitochondrial membrane-resident protein (Zehnder et al. 2002, Fritsche et al. 2003, Sawada et al. 1999).
R-HSA-209944 (Reactome)Vitamin D binding protein (GC aka DBP), a plasma protein, carries the vitamin D metabolites in the circulation. Calcidiol (CDL) translocates to the extracellular region where it binds with GC and is transported to the kidney (Verboven et al. 2002).
R-HSA-350147 (Reactome)Once vitamin D3 (VD3) is released from vitamin D binding protein (GC, DBP), it translocates from the extracellular region to the ER membrane, becoming available for hydroxylation by the microsomal enzyme CYP2R1 (Shinkyo et al. 2004).
R-HSA-350158 (Reactome)Mammalian legumain (LGMN, asparagine-specific endoprotease) is a subfamily of cysteine proteases with no homology to other known proteases and is found in a wide range of organisms from parasites to plants and animals. LGMN requires acidic conditions for its degradative activity. Cubilin (CUBN), once released from the complex, cycles back to the cell surface. Free calcidiol (CDL) becomes available for further processing (Nykjaer et al. 1999).
R-HSA-350168 (Reactome)Megalin (LRP2, glycoprotein 330) is a member of the low density lipoprotein receptor family and is abundant in kidney proximal tubules (Kounnas et al. 1995, Hjalm et al. 1996). LRP2 mediates the endocytic uptake of GC:CDL complexes, thereby preventing the loss of CDL in urine (Nykjaer et al. 1999, Kaseda et al. 2011).
R-HSA-350186 (Reactome)Cubilin (CUBN) is a membrane-associated protein colocalising with megalin (LRP2). Its function is to sequester steroid carrier complexes such as vitamin D binding protein:calcidiol (GC:CDL) on the cell surface before LRP2 mediates their internalisation (Nykjaer et al. 2001).
R-HSA-6807242 (Reactome)Calcidiol (CDL) translocates to the extracellular region (Verboven et al. 2002).
R-HSA-8963872 (Reactome)Vitamin D metabolites such as VD3 are lipophilic and must be transported in the circulation bound to plasma proteins. VD3 translocates to the extracellular region where it binds GC, a vitamin D binding protein (Verboven et al. 2002).
VD3ArrowR-HSA-209754 (Reactome)
VD3ArrowR-HSA-350147 (Reactome)
VD3ArrowR-HSA-8963872 (Reactome)
VD3R-HSA-209845 (Reactome)
VD3R-HSA-350147 (Reactome)
VD3R-HSA-8963872 (Reactome)