Vitamin D (calciferol) metabolism (Homo sapiens)

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421, 695, 7991, 68, 10312111mitochondrial matrixcytosolcytosolcytosollysosomal lumenendoplasmic reticulum lumenCYP27B1(?-508)VD3H+CDLGC GCNADPHGC H+CUBN:GC:CDLCDL NADP+VD3 GC CUBN CYP2R1CUBNH+LRP2CDL NADP+CUBN CDLCUBNCDLNADP+7-dehydrocholesterolGC:CDLCUBN H2OH2OGC O2Cubilin:DBP:CalcidiolO2CTLLGMNCTACYP24A1CDLNADPHCubilin:DBP:CalcidiolO2CDL VD3NADPHH2OCDL GC DBP:vitamin D3


Description

Vitamin D3 (cholecalciferol) is a steroid hormone that plays a role in regulating calcium and 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 (VDBP). Vitamin D3 undergoes two subsequent hydroxylations to form the active form of the vitamin, 1,25(OH)2 vitamin D3 (calcitriol). The first hydroxylation takes place in the liver and subsequent transport to the kidney allows the second hydroxylation. Calciferol acts by binding to nuclear vitamin D receptors. View original pathway at:Reactome.

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Bibliography

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History

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CompareRevisionActionTimeUserComment
114746view16:23, 25 January 2021ReactomeTeamReactome version 75
113190view11:25, 2 November 2020ReactomeTeamReactome version 74
112418view15:36, 9 October 2020ReactomeTeamReactome version 73
101322view11:21, 1 November 2018ReactomeTeamreactome version 66
100859view20:53, 31 October 2018ReactomeTeamreactome version 65
100400view19:27, 31 October 2018ReactomeTeamreactome version 64
99948view16:11, 31 October 2018ReactomeTeamreactome version 63
99504view14:44, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99150view12:41, 31 October 2018ReactomeTeamreactome version 62
93749view13:33, 16 August 2017ReactomeTeamreactome version 61
93268view11:18, 9 August 2017ReactomeTeamreactome version 61
86977view14:30, 15 July 2016MkutmonOntology Term : 'vitamin D metabolic pathway' added !
86345view09:15, 11 July 2016ReactomeTeamreactome version 56
86215view11:11, 7 July 2016ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
7-dehydrocholesterolMetaboliteCHEBI:17759 (ChEBI)
CDL MetaboliteCHEBI:17933 (ChEBI)
CDLMetaboliteCHEBI:17933 (ChEBI)
CTAMetaboliteCHEBI:47828 (ChEBI)
CTLMetaboliteCHEBI:17823 (ChEBI)
CUBN ProteinO60494 (Uniprot-TrEMBL)
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)
Cubilin:DBP:CalcidiolComplexR-HSA-350085 (Reactome)
Cubilin:DBP:CalcidiolComplexR-HSA-350092 (Reactome)
DBP:vitamin D3ComplexR-HSA-352339 (Reactome)
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)
VD3 MetaboliteCHEBI:28940 (ChEBI)
VD3MetaboliteCHEBI:28940 (ChEBI)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
7-dehydrocholesterolR-HSA-209754 (Reactome)
CDLArrowR-HSA-209766 (Reactome)
CDLArrowR-HSA-209845 (Reactome)
CDLArrowR-HSA-350158 (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:GC:CDLArrowR-HSA-350186 (Reactome)
CUBN:GC:CDLR-HSA-350168 (Reactome)
CUBNArrowR-HSA-350158 (Reactome)
CUBNR-HSA-350186 (Reactome)
CYP24A1mim-catalysisR-HSA-209765 (Reactome)
CYP27B1(?-508)mim-catalysisR-HSA-209868 (Reactome)
CYP2R1mim-catalysisR-HSA-209845 (Reactome)
Cubilin:DBP:CalcidiolArrowR-HSA-209760 (Reactome)
Cubilin:DBP:CalcidiolArrowR-HSA-350168 (Reactome)
Cubilin:DBP:CalcidiolR-HSA-209760 (Reactome)
Cubilin:DBP:CalcidiolR-HSA-350158 (Reactome)
DBP:vitamin D3ArrowR-HSA-209738 (Reactome)
DBP:vitamin D3R-HSA-350147 (Reactome)
GC:CDLArrowR-HSA-209944 (Reactome)
GC:CDLR-HSA-350186 (Reactome)
GCArrowR-HSA-350147 (Reactome)
GCR-HSA-209738 (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-209738 (Reactome) Vitamin D metabolites are lipophilic and must be transported in the circulation bound to plasma proteins. Vitamin D3 is transported to the liver bound to a plasma protein called vitamin D binding protein (DBP).
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 (Cholecalciferol).
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 binds to intracellular vitamin D binding protein (IDBP) which facilitates the localization of vitamin D metabolites in the cell. IDBPs are related to the hsc-70 family of heat shock proteins and demonstrate a high nucleotide homology to that family. No IDBP protein has been documented yet so IDBP has not been annotated.
R-HSA-209845 (Reactome) To be functionally active, vitamin D is required to be dihydroxylated. The first hydroxylation at position 25 is carried out by vitamin D 25-hydroxylase (CYP2R1) in the liver, forming calcidiol (CDL) (Shinkyo et al. 2004).
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) (Zehnder et al. 2002, Fritsche et al. 2003).
R-HSA-209944 (Reactome) Vitamin D binding protein (DBP), a plasma protein, carries the vitamin D metabolites in the circulation. Calcidiol (CDL) translocates to the extracellular region where it binds with DBP and is transported to the kidney.
R-HSA-350147 (Reactome) Once vitamin D3 is released from DBP, it becomes available for hydroxylation.
R-HSA-350158 (Reactome) Mammalian legumain (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. Legumain requires acidic conditions for its degradative activity and has strict specificity for cleavage with an asparagine residue in the P1 site. Cubilin, once released from the complex, cycles back to the cell surface. Calcidiol also becomes available for further processing.
R-HSA-350168 (Reactome) Megalin (glycoprotein 330) is a member of the low density lipoprotein receptor family and is abundant in kidney proximal tubules. Megalin mediates the endocytic uptake of DBP:Calcidiol complexes to prevent loss of calcidiol in urine.
R-HSA-350186 (Reactome) Cubilin (CUBN) is a membrane-associated protein colocalizing with megalin. Its function is to sequester steroid carrier complexes such as vitamin D binding protein:calcidiol (GC:CDL) on the cell surface before megalin mediates their internalization (Nykjaer et al. 2001).
R-HSA-6807242 (Reactome) Calcidiol (CDL) translocates to the extracellular region (Verboven et al. 2002).
VD3ArrowR-HSA-209754 (Reactome)
VD3ArrowR-HSA-350147 (Reactome)
VD3R-HSA-209738 (Reactome)
VD3R-HSA-209845 (Reactome)
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