Vitamin D (calciferol) metabolism (Homo sapiens)

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Bibliography

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2. Herman GE.; ''Disorders of cholesterol biosynthesis: prototypic metabolic malformation syndromes.''; PubMed Europe PMC Scholia
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4. Du C, Yang S, Zhao X, Dong H.; ''Pathogenic roles of alterations in vitamin D and vitamin D receptor in gastric tumorigenesis.''; PubMed Europe PMC Scholia
5. Shinkyo R, Sakaki T, Kamakura M, Ohta M, Inouye K.; ''Metabolism of vitamin D by human microsomal CYP2R1.''; PubMed Europe PMC Scholia
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11. Cheng JB, Motola DL, Mangelsdorf DJ, Russell DW.; ''De-orphanization of cytochrome P450 2R1: a microsomal vitamin D 25-hydroxilase.''; PubMed Europe PMC Scholia
12. Eelen G, Verlinden L, Rochel N, Claessens F, De Clercq P, Vandewalle M, Tocchini-Valentini G, Moras D, Bouillon R, Verstuyf A.; ''Superagonistic action of 14-epi-analogs of 1,25-dihydroxyvitamin D explained by vitamin D receptor-coactivator interaction.''; PubMed Europe PMC Scholia
13. Prietl B, Treiber G, Pieber TR, Amrein K.; ''Vitamin D and immune function.''; PubMed Europe PMC Scholia
14. 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 Europe PMC Scholia
15. Chen JM, Fortunato M, Barrett AJ.; ''Activation of human prolegumain by cleavage at a C-terminal asparagine residue.''; PubMed Europe PMC Scholia
16. Russell DW.; ''Cholesterol biosynthesis and metabolism.''; PubMed Europe PMC Scholia
17. HERS HG.; ''[The mechanism of the formation of seminal fructose and fetal fructose].''; PubMed Europe PMC Scholia
18. Christakos S, Dhawan P, Verstuyf A, Verlinden L, Carmeliet G.; ''Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects.''; PubMed Europe PMC Scholia
19. Bandera Merchan B, Morcillo S, Martin-Nuñez G, Tinahones FJ, Macías-González M.; ''The role of vitamin D and VDR in carcinogenesis: Through epidemiology and basic sciences.''; PubMed Europe PMC Scholia
20. DiNicolantonio JJ, O'Keefe JH, Lucan SC.; ''Added fructose: a principal driver of type 2 diabetes mellitus and its consequences.''; PubMed Europe PMC Scholia
21. 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 Europe PMC Scholia
22. 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 Europe PMC Scholia
23. Jena S, Lee WP, Doherty D, Thompson PD.; ''PIAS4 represses vitamin D receptor-mediated signaling and acts as an E3-SUMO ligase towards vitamin D receptor.''; PubMed Europe PMC Scholia
24. Wolden-Kirk H, Gysemans C, Verstuyf A, Mathieu C.; ''Extraskeletal effects of vitamin D.''; PubMed Europe PMC Scholia
25. Radons J.; ''The human HSP70 family of chaperones: where do we stand?''; PubMed Europe PMC Scholia
26. Kolderup A, Svihus B.; ''Fructose Metabolism and Relation to Atherosclerosis, Type 2 Diabetes, and Obesity.''; PubMed Europe PMC Scholia
27. Gaylor JL.; ''Membrane-bound enzymes of cholesterol synthesis from lanosterol.''; PubMed Europe PMC Scholia
28. Kim S, Shevde NK, Pike JW.; ''1,25-Dihydroxyvitamin D3 stimulates cyclic vitamin D receptor/retinoid X receptor DNA-binding, co-activator recruitment, and histone acetylation in intact osteoblasts.''; PubMed Europe PMC Scholia
29. Oates PJ.; ''Aldose reductase, still a compelling target for diabetic neuropathy.''; PubMed Europe PMC Scholia
30. Rudney H, Sexton RC.; ''Regulation of cholesterol biosynthesis.''; PubMed Europe PMC Scholia
31. 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 Europe PMC Scholia
32. Kaseda R, Hosojima M, Sato H, Saito A.; ''Role of megalin and cubilin in the metabolism of vitamin D(3).''; PubMed Europe PMC Scholia
33. 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 Europe PMC Scholia
34. Kamitani T, Kito K, Nguyen HP, Fukuda-Kamitani T, Yeh ET.; ''Characterization of a second member of the sentrin family of ubiquitin-like proteins.''; PubMed Europe PMC Scholia
35. Su HL, Li SS.; ''Molecular features of human ubiquitin-like SUMO genes and their encoded proteins.''; PubMed Europe PMC Scholia
36. HERS HG, KUSAKA T.; ''[The metabolism of fructose-1-phosphate in the liver].''; PubMed Europe PMC Scholia
37. Bray GA.; ''Energy and fructose from beverages sweetened with sugar or high-fructose corn syrup pose a health risk for some people.''; PubMed Europe PMC Scholia
38. Denburg MR, Hoofnagle AN, Sayed S, Gupta J, de Boer IH, Appel LJ, Durazo-Arvizu R, Whitehead K, Feldman HI, Leonard MB, Chronic Renal Insufficiency Cohort study investigators.; ''Comparison of Two ELISA Methods and Mass Spectrometry for Measurement of Vitamin D-Binding Protein: Implications for the Assessment of Bioavailable Vitamin D Concentrations Across Genotypes.''; PubMed Europe PMC Scholia
39. 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 Europe PMC Scholia
40. 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 Europe PMC Scholia
41. Hewison M.; ''Vitamin D and immune function: an overview.''; PubMed Europe PMC Scholia

History

External references

DataNodes

Name	Type	Database reference	Comment
1,25(OH)2D	Metabolite	CHEBI:17823 (ChEBI)
1,25(OH)2D:VDR	Complex	R-HSA-8963916 (Reactome)
1,25(OH)2D	Metabolite	CHEBI:17823 (ChEBI)
25(OH)D	Metabolite	CHEBI:17933 (ChEBI)
25(OH)D	Metabolite	CHEBI:17933 (ChEBI)
7-dehydroCHOL	Metabolite	CHEBI:17759 (ChEBI)
CTA	Metabolite	CHEBI:47828 (ChEBI)
CUBN	Protein	O60494 (Uniprot-TrEMBL)
CUBN:25(OH)D	Complex	R-HSA-8963847 (Reactome)
CUBN:GC:25(OH)D	Complex	R-HSA-350085 (Reactome)
CUBN:GC:25(OH)D	Complex	R-HSA-350092 (Reactome)
CUBN:GC:25(OH)D	Complex	R-HSA-350115 (Reactome)
CUBN	Protein	O60494 (Uniprot-TrEMBL)
CYP24A1	Protein	Q07973 (Uniprot-TrEMBL)
CYP27B1(?-508)	Protein	O15528 (Uniprot-TrEMBL)	The start coordinate is not yet known
CYP2R1	Protein	Q6VVX0 (Uniprot-TrEMBL)
Cholesterol biosynthesis	Pathway	R-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).
Fru	Metabolite	CHEBI:15824 (ChEBI)
Fructose metabolism	Pathway	R-HSA-5652084 (Reactome)	Fructose is found in fruits, is one of the components of the disaccharide sucrose, and is a widely used sweetener in processed foods. Dietary fructose is catabolized in the liver via fructose 1-phosphate to yield dihydroxyacetone phosphate and glyceraldehyde 3-phosphate, which then are converted to pyruvate via steps of canonical glycolysis (Hers & Kusaka 1953; Sillero et al. 1969). Excessive dietary intake of fructose and its metabolism have been associated with major disease risks in humans, although this issue remains controversial (Kolderup & Svihus 2015; DiNicolantonio et al. 2015; Bray 2013; Mayes 1993; Rippe & Angelopoulos 2013; van Buul et al. 2013). Fructose can also be synthesized from glucose via the polyol pathway (Hers 1960; Oates 2008). This synthetic process provides the fructose found in seminal fluid and, in other tissues, can contribute to pathologies of diabetes.
GC	Protein	P02774 (Uniprot-TrEMBL)
GC:25(OH)D	Complex	R-HSA-209892 (Reactome)
GC:VD3	Complex	R-HSA-352339 (Reactome)
GC	Protein	P02774 (Uniprot-TrEMBL)
H+	Metabolite	CHEBI:15378 (ChEBI)
H2O	Metabolite	CHEBI:15377 (ChEBI)
LGMN	Protein	Q99538 (Uniprot-TrEMBL)
LRP2	Protein	P98164 (Uniprot-TrEMBL)
NADP+	Metabolite	CHEBI:18009 (ChEBI)
NADPH	Metabolite	CHEBI:16474 (ChEBI)
O2	Metabolite	CHEBI:15379 (ChEBI)
PIAS4	Protein	Q8N2W9 (Uniprot-TrEMBL)
SUMO2-C93-UBE2I	Protein	P63279 (Uniprot-TrEMBL)
SUMO2-VDR	Protein	P11473 (Uniprot-TrEMBL)
SUMO2:UBE2I	Complex	R-HSA-2993778 (Reactome)
UBE2I-G93-SUMO2	Protein	P61956 (Uniprot-TrEMBL)
UBE2I	Protein	P63279 (Uniprot-TrEMBL)
VD3	Metabolite	CHEBI:28940 (ChEBI)
VD3	Metabolite	CHEBI:28940 (ChEBI)
VDR	Protein	P11473 (Uniprot-TrEMBL)
VDR	Protein	P11473 (Uniprot-TrEMBL)

Annotated Interactions

Source	Target	Type	Database reference	Comment
	1,25(OH)2D:VDR	Arrow	R-HSA-8963915 (Reactome)
	1,25(OH)2D	Arrow	R-HSA-209868 (Reactome)
	1,25(OH)2D	Arrow	R-HSA-8963913 (Reactome)
1,25(OH)2D			R-HSA-209765 (Reactome)
1,25(OH)2D			R-HSA-8963913 (Reactome)
1,25(OH)2D			R-HSA-8963915 (Reactome)
	25(OH)D	Arrow	R-HSA-209766 (Reactome)
	25(OH)D	Arrow	R-HSA-209845 (Reactome)
	25(OH)D	Arrow	R-HSA-6807242 (Reactome)
	25(OH)D	Arrow	R-HSA-8963864 (Reactome)
25(OH)D			R-HSA-209766 (Reactome)
25(OH)D			R-HSA-209868 (Reactome)
25(OH)D			R-HSA-209944 (Reactome)
25(OH)D			R-HSA-6807242 (Reactome)
7-dehydroCHOL			R-HSA-209754 (Reactome)
	CTA	Arrow	R-HSA-209765 (Reactome)
	CUBN:25(OH)D	Arrow	R-HSA-350158 (Reactome)
CUBN:25(OH)D			R-HSA-8963864 (Reactome)
	CUBN:GC:25(OH)D	Arrow	R-HSA-209760 (Reactome)
	CUBN:GC:25(OH)D	Arrow	R-HSA-350168 (Reactome)
	CUBN:GC:25(OH)D	Arrow	R-HSA-350186 (Reactome)
CUBN:GC:25(OH)D			R-HSA-209760 (Reactome)
CUBN:GC:25(OH)D			R-HSA-350158 (Reactome)
CUBN:GC:25(OH)D			R-HSA-350168 (Reactome)
	CUBN	Arrow	R-HSA-8963864 (Reactome)
CUBN			R-HSA-350186 (Reactome)
CYP24A1		mim-catalysis	R-HSA-209765 (Reactome)
CYP27B1(?-508)		mim-catalysis	R-HSA-209868 (Reactome)
CYP2R1		mim-catalysis	R-HSA-209845 (Reactome)
Fru		Arrow	R-HSA-209765 (Reactome)
Fru		TBar	R-HSA-209868 (Reactome)
	GC:25(OH)D	Arrow	R-HSA-209944 (Reactome)
GC:25(OH)D			R-HSA-350186 (Reactome)
	GC:VD3	Arrow	R-HSA-209738 (Reactome)
GC:VD3			R-HSA-8963851 (Reactome)
	GC	Arrow	R-HSA-8963851 (Reactome)
GC			R-HSA-209738 (Reactome)
GC			R-HSA-209944 (Reactome)
H+			R-HSA-209765 (Reactome)
H+			R-HSA-209845 (Reactome)
H+			R-HSA-209868 (Reactome)
	H2O	Arrow	R-HSA-209765 (Reactome)
	H2O	Arrow	R-HSA-209845 (Reactome)
	H2O	Arrow	R-HSA-209868 (Reactome)
LGMN		mim-catalysis	R-HSA-350158 (Reactome)
LRP2		mim-catalysis	R-HSA-350168 (Reactome)
	NADP+	Arrow	R-HSA-209765 (Reactome)
	NADP+	Arrow	R-HSA-209845 (Reactome)
	NADP+	Arrow	R-HSA-209868 (Reactome)
NADPH			R-HSA-209765 (Reactome)
NADPH			R-HSA-209845 (Reactome)
NADPH			R-HSA-209868 (Reactome)
O2			R-HSA-209765 (Reactome)
O2			R-HSA-209845 (Reactome)
O2			R-HSA-209868 (Reactome)
PIAS4		mim-catalysis	R-HSA-4546387 (Reactome)
			R-HSA-209738 (Reactome)	Vitamin D metabolites such as VD3 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 (GC aka DBP) (Verboven et al. 2002). GC is a 58 kDa circulating glycoprotein that transports vitamin D metabolites. The vast majority of vitamin D metabolites circulate bound to GC (85–90%), some bound to albumin (10–15%), with the remainder (<1%) circulating in the free form. GC has more than 1000-fold stronger binding affinity for vitamin D metabolites than albumin. Thus, the albumin-bound and free fractions of vitamin D metabolites are considered bioavailable (Denburg et al. 2016).
			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 CUBN:GC:25(OH)D complex enters the lysosome where it can be acted upon the protease legumain (Halfon et al. 1998, Chen et al. 2000).
			R-HSA-209765 (Reactome)	1-alpha, 25-dihydroxyvitamin D (1,25(OH)2D) is biologically inactivated through a series of reactions beginning with 24-hydroxylation and is most likely a mechanism of elimination. 24-Hydroxylation of vitamin D metabolites is largely regulated inversely to 1-hydroxylation, the initial step towards activation. Human cDNA encoding CYP24A1 was isolated in 1993 (Chen et al. 1993). Studies with expressed human CYP24A1 in Sf21 insect cells indicated that the enzyme could catalyze most, if not all, of the steps in the C23 and C24 oxidation pathways of 25(OH)D and 1,25(OH)2D metabolism (Beckman et al. 1996). Sakaki et al observed that the ratio of initial hydroxylation products at C24 to C23 was 4:1, indicating that the C24-oxidation pathway predominates in humans (Sakaki et al. 2000).
			R-HSA-209766 (Reactome)	Once out of the lysosome, 25-hydroxyvitamin D (calcidiol, 25(OH)D) 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 25-hydroxyvitamin D (calcidiol, 25(OH)D) (Shinkyo et al. 2004, Cheng et al. 2003).
			R-HSA-209868 (Reactome)	The second step in vitamin D activation requires hydroxylation of 25-hydroxyvitamin D (calcidiol, 25(OH)D) to 1-alpha, 25-dihydroxyvitamin D (1,25(OH)2D). This conversion is mediated by 25-hydroxyvitamin D-1-alpha 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 vitamin D metabolites in the circulation. 25-hydroxyvitamin D (25(OH)D) 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 25-hydroxyvitamin D (calcidiol, 25(OH)D) 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:25(OH)D complexes, thereby preventing the loss of 25-hydroxyvitamin D (calcidiol, 25(OH)D) 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:25-hydroxyvitamin D (GC:25(OH)D) on the cell surface before LRP2 mediates their internalisation (Nykjaer et al. 2001).
			R-HSA-4546387 (Reactome)	E3 SUMO-protein ligase (PIAS4) SUMOylates Vitamin D3 receptor (VDR) with SUMO2 (Jena et al. 2012). SUMOylation inhibits transcriptional activation by VDR in response to vitamin D.
			R-HSA-6807242 (Reactome)	25-hydroxyvitamin D (calcidiol, 25(OH)D) translocates to the extracellular region (Verboven et al. 2002).
			R-HSA-8963851 (Reactome)	Vitamin D3 (VD3) is transported to the liver bound to a plasma protein called vitamin D binding protein (GC aka DBP) (Verboven et al. 2002). Before uptake by the liver, VD3 must dissociate from GC.
			R-HSA-8963864 (Reactome)	Cubilin (CUBN), once released from the complex, cycles back to the cell surface. Free 25-hydroxyvitamin D (calcidiol, 25(OH)D) becomes available for further processing (Nykjaer et al. 1999).
			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).
			R-HSA-8963913 (Reactome)	The biologically active form of vitamin D, 1-alpha, 25-dihydroxyvitamin D (1,25(OH)2D), can be transported to any target tissue where it enters the nucleoplasm to interact with vitamin D receptor (VDR) to exert its effects. The mechanism of translocation from cytosol to nucleoplasm is unknown (see review for general description - Christakos et al. 2016).
			R-HSA-8963915 (Reactome)	The biologically active form of vitamin D, 1-alpha, 25-dihydroxyvitamin D (1,25(OH)2D), interacts with the nuclear hormone receptor vitamin D receptor (VDR) in the nucleoplasm of any target tissue (Neme et al. 2017). VDR regulates the actions of 1,25(OH)2D and their binding recruits coactivators (Eelen et al. 2005, Kim et al. 2005, Du et al. 2017) to initiate a signaling response that regulates an estimated upwards of 2000 genes involved in calcium homeostasis, immune responses, cellular growth, differentiation and apoptosis (Hossein-nezhad et al. 2013, Hossein-nezhad & Holick 2013, Wolden-Kirk et al. 2012, Prietl et al. 2013, Hewison 2012, Christakos et al. 2016, Bandera Merchan et al. 2017).
	SUMO2-VDR	Arrow	R-HSA-4546387 (Reactome)
SUMO2:UBE2I			R-HSA-4546387 (Reactome)
	UBE2I	Arrow	R-HSA-4546387 (Reactome)
	VD3	Arrow	R-HSA-209754 (Reactome)
	VD3	Arrow	R-HSA-350147 (Reactome)
	VD3	Arrow	R-HSA-8963851 (Reactome)
	VD3	Arrow	R-HSA-8963872 (Reactome)
VD3			R-HSA-209738 (Reactome)
VD3			R-HSA-209845 (Reactome)
VD3			R-HSA-350147 (Reactome)
VD3			R-HSA-8963872 (Reactome)
VDR			R-HSA-4546387 (Reactome)
VDR			R-HSA-8963915 (Reactome)