Retinoid metabolism and transport (Homo sapiens)

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33, 434920, 37, 454810, 21, 422512, 255, 7, 822, 30, 5024, 475, 7, 8491526, 293240, 531, 6533, 1316404, 5327, 35, 38, 41, 51493618, 5226, 293911, 31early endosomeEnterocyteHSCLymphatic circulationParenchymalendoplasmic reticulum lumenlipid particlemitochondrial matrixcytosolendoplasmic reticulum lumenendoplasmic reticulum lumencytosolcytosolAPOA4 atR-OLEA VisualphototransductionSTEAL OLEA APOEatROL PALML atR-STEA PL PL atRA APOA4 atROLLINA atR-LINA HS(3)-PGs HS(2)-PGs TTR CHOL atR-STEA betaCFAsTTR nascent CMatR-LINA spherical HDLH+retinoidsLINA HS/HPIN-PGs HS(1)-PGs atR-PALM atR-LINA LRP8 APOA2(24-100) atR-PALM RBP2HS/HPIN-PGs APOE CR:atREs:HSPG:apoEHS(1)-PGs APOB(28-2179) CHEST APOC2 atROLCHOL APOA1(25-267) HS(3)-PGs APOB(28-2179) APOA4 atREsAPOB(28-2179) TAGs atR-PALM HS(5)-PGs atROL Fe2+ H2OH2OAPOA1(25-266) LRP1 APOC2 RBP1HS(4)-PGs CHOL PALM TAGs APOA4 CLPS BCO2 APOA4 CHOL Fe2+ CHEST atR-OLEA CR:atREsAKR1B10 atROLRBP1:atROLO2APOE RBP2 HS(5)-PGs APOB(28-2179) APOA1(25-266) atROLLRP2 LCFAsatRA atR-LINA CHOL LRATCHOL APOC3 H+atR-LINA APOA2(24-100) HS(2)-PGs CHEST HS(2)-PGs atR-STEA PLB1TAGs APOA4 atR-STEA CHEST HS(3)-PGs AKR1C4 RBP2:atRALPL APOA1(25-266) AKR1C1 atROL PALM APOE APOC2 GPIHBP1:HSPG:LPLdimerAPOA1(25-267) APOC3 HS(5)-PGs atROL TAGs APOE APOA1(25-267) RBP4(19-201)GPIHBP1 APOB(28-2179) HS(4)-PGs atR-OLEA 9cRA atR-PALM FAssphericalHDL:apoC-II:apoC-III:apoENADPHH+RBP1atREsCR:atREsCHEST PNLIP CHOL APOA1(25-267) APOC2 APOC3 CR:atREs:HSPG:apoEAPOA1(25-266) TAGs RETSATAPOMSTEA atR-STEA PL OLEL nascent CM:atREsatR-OLEA FACYLsat-13,14-dhROLHS(1)-PGs RBP1 TAGs 9cRA RBP2LRPsDAGsAKR1C3 APOM:retinoidsHS(4)-PGs PL CHEST PL CHEST APOC3 HSPG APOB(28-2179) atR-PALM CRAPOA2(24-100) CHEST atR-OLEA RDH11APOA2(24-100) APOA2(24-100) APOE TAG STEA TTR:RBP4:atROLPL RBP1:atROLAPO10alAPOC2 APOA2(24-100) bIONAPOB(28-2179) atR-PALM atROL OLEA RBP4(19-201) APOB(28-2179) CHEST PALML APOE LRP10 TAGs APOC2 TAG mature CM:atREsFACYLsatR-STEA H2OLINL LINL APOE atRALRBP2:atROLSTEAL RBP2 atR-STEA AKRsPL PALMBCMO1 RBP4:atROLatR-STEA betaCatR-OLEA atR-PALM LDLRAPOM OLEL RBP1atR-PALM HSPGsatRAL APOC2 PL APOC3 APOA2(24-100) CHOL BCMO1:Fe2+NADHLRATTAGs RBP4(19-201) atR-OLEA atR-LINA LRP12 APOC3 CHOL atR-PALM atR-LINA atR-STEA CHEST atROL APOA4 BCO2:Fe2+APOA1(25-266) PL CHOL APOC3 NAD+APOA2(24-100) atR-OLEA atR-OLEA RPALMAPOA2(24-100) LPL NREHPNLIP:CLPSTTR tetrameratROL NADP+CHEST CHOL APOB(28-2179) APOA1(25-267) APOA4 O2APOEnascent CM:atREsHS/HPIN-PGs atR-LINA APOA4 RBP1 REHatR-LINA PL APOA1(25-266) TAGs 2, 9, 14, 17, 19...4646


Description

Vitamin A (all-trans-retinol) must be taken up, either as carotenes from plants, or as retinyl esters from animal food. The most prominent carotenes are alpha-carotene, lycopene, lutein, beta-cryptoxanthine, and especially beta-carotene. After uptake they are mostly broken down to retinal. Retinyl esters are hydrolysed like other fats. In enterocytes, retinoids bind to retinol-binding protein (RBP). Transport from enterocytes to the liver happens via chylomicrons (Harrison & Hussain 2001, Harrison 2005). View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 975634
Reactome-version 
Reactome version: 61
Reactome Author 
Reactome Author: Stephan, Ralf

Quality Tags

Ontology Terms

 

Bibliography

View all...
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History

View all...
CompareRevisionActionTimeUserComment
101259view11:15, 1 November 2018ReactomeTeamreactome version 66
100797view20:43, 31 October 2018ReactomeTeamreactome version 65
100339view19:20, 31 October 2018ReactomeTeamreactome version 64
99884view16:03, 31 October 2018ReactomeTeamreactome version 63
99441view14:37, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99112view12:40, 31 October 2018ReactomeTeamreactome version 62
94039view13:53, 16 August 2017ReactomeTeamreactome version 61
93662view11:30, 9 August 2017ReactomeTeamreactome version 61
89077view15:51, 21 August 2016EgonwOntology Term : 'classic metabolic pathway' added !
89076view15:51, 21 August 2016EgonwOntology Term : 'retinoid metabolic pathway' added !
86783view09:26, 11 July 2016ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
9cRA MetaboliteCHEBI:50648 (ChEBI)
AKR1B10 ProteinO60218 (Uniprot-TrEMBL)
AKR1C1 ProteinQ04828 (Uniprot-TrEMBL)
AKR1C3 ProteinP42330 (Uniprot-TrEMBL)
AKR1C4 ProteinP17516 (Uniprot-TrEMBL)
AKRsComplexR-HSA-2855241 (Reactome)
APO10alMetaboliteCHEBI:53153 (ChEBI)
APOA1(25-266) ProteinP02647 (Uniprot-TrEMBL)
APOA1(25-267) ProteinP02647 (Uniprot-TrEMBL)
APOA2(24-100) ProteinP02652 (Uniprot-TrEMBL)
APOA4 ProteinP06727 (Uniprot-TrEMBL)
APOB(28-2179) ProteinP04114 (Uniprot-TrEMBL)
APOC2 ProteinP02655 (Uniprot-TrEMBL)
APOC3 ProteinP02656 (Uniprot-TrEMBL)
APOE ProteinP02649 (Uniprot-TrEMBL)
APOEProteinP02649 (Uniprot-TrEMBL)
APOM ProteinO95445 (Uniprot-TrEMBL)
APOM:retinoidsComplexR-HSA-5246486 (Reactome)
APOMProteinO95445 (Uniprot-TrEMBL)
BCMO1 ProteinQ9HAY6 (Uniprot-TrEMBL)
BCMO1:Fe2+ComplexR-HSA-975642 (Reactome)
BCO2 ProteinQ9BYV7 (Uniprot-TrEMBL)
BCO2:Fe2+ComplexR-HSA-5164400 (Reactome)
CHEST MetaboliteCHEBI:17002 (ChEBI)
CHOL MetaboliteCHEBI:16113 (ChEBI)
CLPS ProteinP04118 (Uniprot-TrEMBL)
CR:atREs:HSPG:apoEComplexR-HSA-2423794 (Reactome)
CR:atREs:HSPG:apoEComplexR-HSA-2429682 (Reactome)
CR:atREsComplexR-HSA-2429667 (Reactome)
CR:atREsComplexR-HSA-2569093 (Reactome)
CRComplexR-HSA-2429649 (Reactome)
DAGsMetaboliteCHEBI:18035 (ChEBI)
FACYLsComplexR-ALL-2859065 (Reactome)
FAsComplexR-ALL-2534426 (Reactome)
FAsComplexR-ALL-2864103 (Reactome)
Fe2+ MetaboliteCHEBI:18248 (ChEBI)
GPIHBP1 ProteinQ8IV16 (Uniprot-TrEMBL)
GPIHBP1:HSPG:LPL dimerComplexR-HSA-8857969 (Reactome)
H+MetaboliteCHEBI:15378 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HS(1)-PGs R-HSA-2076647 (Reactome)
HS(2)-PGs R-HSA-2076620 (Reactome)
HS(3)-PGs R-HSA-2076690 (Reactome)
HS(4)-PGs R-HSA-2076655 (Reactome)
HS(5)-PGs R-HSA-2076688 (Reactome)
HS/HPIN-PGs R-HSA-2076639 (Reactome)
HSPG MetaboliteCHEBI:24499 (ChEBI)
HSPGsComplexR-HSA-2076618 (Reactome)
LCFAsMetaboliteCHEBI:15904 (ChEBI)
LDLRProteinP01130 (Uniprot-TrEMBL)
LINA MetaboliteCHEBI:17351 (ChEBI)
LINL MetaboliteCHEBI:32386 (ChEBI)
LPL ProteinP06858 (Uniprot-TrEMBL)
LRATProteinO95237 (Uniprot-TrEMBL)
LRP1 ProteinQ07954 (Uniprot-TrEMBL)
LRP10 ProteinQ7Z4F1 (Uniprot-TrEMBL)
LRP12 ProteinQ9Y561 (Uniprot-TrEMBL)
LRP2 ProteinP98164 (Uniprot-TrEMBL)
LRP8 ProteinQ14114 (Uniprot-TrEMBL)
LRPsComplexR-HSA-2424258 (Reactome)
NAD+MetaboliteCHEBI:15846 (ChEBI)
NADHMetaboliteCHEBI:16908 (ChEBI)
NADP+MetaboliteCHEBI:18009 (ChEBI)
NADPHMetaboliteCHEBI:16474 (ChEBI)
NREHR-HSA-2470277 (Reactome)
O2MetaboliteCHEBI:15379 (ChEBI)
OLEA MetaboliteCHEBI:16196 (ChEBI)
OLEL MetaboliteCHEBI:25667 (ChEBI)
PALM MetaboliteCHEBI:15756 (ChEBI)
PALMMetaboliteCHEBI:15756 (ChEBI)
PALML MetaboliteCHEBI:45021 (ChEBI)
PL MetaboliteCHEBI:16247 (ChEBI)
PLB1ProteinQ6P1J6 (Uniprot-TrEMBL)
PNLIP ProteinP16233 (Uniprot-TrEMBL)
PNLIP:CLPSComplexR-HSA-192466 (Reactome)
RBP1 ProteinP09455 (Uniprot-TrEMBL)
RBP1:atROLComplexR-HSA-2855242 (Reactome)
RBP1:atROLComplexR-HSA-74842 (Reactome)
RBP1ProteinP09455 (Uniprot-TrEMBL)
RBP2 ProteinP50120 (Uniprot-TrEMBL)
RBP2:atRALComplexR-HSA-975639 (Reactome)
RBP2:atROLComplexR-HSA-975626 (Reactome)
RBP2ProteinP50120 (Uniprot-TrEMBL)
RBP4(19-201) ProteinP02753 (Uniprot-TrEMBL)
RBP4(19-201)ProteinP02753 (Uniprot-TrEMBL)
RBP4:atROLComplexR-HSA-2453678 (Reactome)
RDH11ProteinQ8TC12 (Uniprot-TrEMBL)
REHR-HSA-2453687 (Reactome)
RETSATProteinQ6NUM9 (Uniprot-TrEMBL)
RPALMMetaboliteCHEBI:17616 (ChEBI)
STEA MetaboliteCHEBI:9254 (ChEBI)
STEAL MetaboliteCHEBI:26753 (ChEBI)
TAG MetaboliteCHEBI:17855 (ChEBI)
TAGs MetaboliteCHEBI:17855 (ChEBI)
TTR ProteinP02766 (Uniprot-TrEMBL)
TTR tetramerComplexR-HSA-2453680 (Reactome)
TTR:RBP4:atROLComplexR-HSA-2453705 (Reactome)
Visual phototransductionPathwayR-HSA-2187338 (Reactome) Visual phototransduction is the process by which photon absorption by visual pigment molecules in photoreceptor cells is converted to an electrical cellular response. The events in this process are photochemical, biochemical and electrophysiological and are highly conserved across many species. This process occurs in two types of photoreceptors in the retina, rods and cones. Each type consists of two parts, the outer segment which detects a photon signal and the inner segment which contains the necessary machinery for cell metabolism. Each type of cell functions differently. Rods are very light sensitive but their flash response is slow so they work best in twilight conditions but are not good at detecting objects moving quickly. Cones are less light-sensitive and have a fast flash response so they work best in daylight conditions and are better at detecting fast moving objects than rods.

The visual pigment consists of a chromophore (11-cis-retinal, 11cRAL, A1) covalently attached to a GPCR opsin family member. The linkage is via a Schiff base forming retinylidene protein. Upon photon absorption, 11cRAL isomerises to all-trans retinal (atRAL), changing the conformation of opsin to an activated form which can activate the regulatory G protein transducin (Gt). The alpha subunit of Gt activates phosphodiesterase which hydrolyses cGMP to 5'-GMP. As high level of cGMP keep cGMP-gated sodium channels open, the lowering of cGMP levels closes these channels which causes hyperpolarization of the cell and subsequently, closure of voltage-gated calcium channels. As calcium levels drop, the level of the neurotransmitter glutamate also drops causing depolarization of the cell. This effectively relays the light signal to postsynaptic neurons as electrical signal (Burns & Pugh 2010, Korenbrot 2012, Pugh & Lamb 1993).

11cRAL cannot be synthesised in vertebrates. Vitamin A from many dietary sources is the precursor for 11cRAL. It is taken from food in the form of esters such as retinyl acetate or palmitate or one of four caretenoids (alpha-carotene, beta-carotene, gamma-carotene and beta-cryptoxanthin). Retinoids are transported from the gut to be stored in liver, until required by target organs such as the eye (Harrison & Hussain 2001, Harrison 2005). In the eye, in the form 11cRAL, it is used in the retinoid (visual) cycle to initiate phototransduction and for visual pigment regeneration to ready the photoreceptor for the next phototransduction event (von Lintig 2012, Blomhoff & Blomhoff 2006, von Lintig et al. 2010, D'Ambrosio et al. 2011, Wang & Kefalov 2011, Kefalov 2012, Wolf 2004).
at-13,14-dhROLMetaboliteCHEBI:52075 (ChEBI)
atR-LINA MetaboliteCHEBI:70762 (ChEBI)
atR-OLEA MetaboliteCHEBI:70760 (ChEBI)
atR-PALM MetaboliteCHEBI:17616 (ChEBI)
atR-STEA MetaboliteCHEBI:70761 (ChEBI)
atRA MetaboliteCHEBI:15367 (ChEBI)
atRAL MetaboliteCHEBI:17898 (ChEBI)
atRALMetaboliteCHEBI:17898 (ChEBI)
atREsComplexR-ALL-2534423 (Reactome)
atREsComplexR-ALL-2864099 (Reactome)
atROL MetaboliteCHEBI:17336 (ChEBI)
atROLMetaboliteCHEBI:17336 (ChEBI)
bIONMetaboliteCHEBI:32325 (ChEBI)
betaCMetaboliteCHEBI:17579 (ChEBI)
mature CM:atREsComplexR-HSA-2395771 (Reactome)
nascent CM:atREsComplexR-HSA-2395763 (Reactome)
nascent CM:atREsComplexR-HSA-2395765 (Reactome)
nascent CMComplexR-HSA-2395787 (Reactome)
retinoidsComplexR-ALL-5246487 (Reactome)
spherical HDL:apoC-II:apoC-III:apoEComplexR-HSA-174643 (Reactome)
spherical HDLComplexR-HSA-265523 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
AKRsmim-catalysisR-HSA-2855252 (Reactome)
APO10alArrowR-HSA-5164399 (Reactome)
APOEArrowR-HSA-2429643 (Reactome)
APOER-HSA-2423785 (Reactome)
APOM:retinoidsArrowR-HSA-5246478 (Reactome)
APOMR-HSA-5246478 (Reactome)
BCMO1:Fe2+mim-catalysisR-HSA-975635 (Reactome)
BCO2:Fe2+mim-catalysisR-HSA-5164399 (Reactome)
CR:atREs:HSPG:apoEArrowR-HSA-2404131 (Reactome)
CR:atREs:HSPG:apoEArrowR-HSA-2423785 (Reactome)
CR:atREs:HSPG:apoER-HSA-2404131 (Reactome)
CR:atREs:HSPG:apoER-HSA-2429643 (Reactome)
CR:atREsArrowR-HSA-2395768 (Reactome)
CR:atREsArrowR-HSA-2424254 (Reactome)
CR:atREsR-HSA-2404140 (Reactome)
CR:atREsR-HSA-2423785 (Reactome)
CR:atREsR-HSA-2424254 (Reactome)
CRArrowR-HSA-2404140 (Reactome)
CRArrowR-HSA-2429643 (Reactome)
DAGsArrowR-HSA-2395768 (Reactome)
FACYLsR-HSA-2404137 (Reactome)
FACYLsR-HSA-975608 (Reactome)
FAsArrowR-HSA-2404133 (Reactome)
FAsArrowR-HSA-2404140 (Reactome)
FAsArrowR-HSA-2429643 (Reactome)
GPIHBP1:HSPG:LPL dimermim-catalysisR-HSA-2395768 (Reactome)
H+ArrowR-HSA-2404140 (Reactome)
H+ArrowR-HSA-2429643 (Reactome)
H+ArrowR-HSA-8956427 (Reactome)
H+R-HSA-2855252 (Reactome)
H+R-HSA-975629 (Reactome)
H2OR-HSA-2404133 (Reactome)
H2OR-HSA-2404140 (Reactome)
H2OR-HSA-2429643 (Reactome)
H2OR-HSA-975593 (Reactome)
H2OR-HSA-975594 (Reactome)
HSPGsArrowR-HSA-2429643 (Reactome)
HSPGsR-HSA-2423785 (Reactome)
LCFAsArrowR-HSA-2395768 (Reactome)
LDLRmim-catalysisR-HSA-2424254 (Reactome)
LRATmim-catalysisR-HSA-2404137 (Reactome)
LRATmim-catalysisR-HSA-975608 (Reactome)
LRPsmim-catalysisR-HSA-2404131 (Reactome)
NAD+R-HSA-8956427 (Reactome)
NADHArrowR-HSA-8956427 (Reactome)
NADP+ArrowR-HSA-2855252 (Reactome)
NADP+ArrowR-HSA-975629 (Reactome)
NADPHR-HSA-2855252 (Reactome)
NADPHR-HSA-975629 (Reactome)
NREHmim-catalysisR-HSA-2404140 (Reactome)
NREHmim-catalysisR-HSA-2429643 (Reactome)
O2R-HSA-5164399 (Reactome)
O2R-HSA-975635 (Reactome)
PALMArrowR-HSA-975593 (Reactome)
PALMArrowR-HSA-975594 (Reactome)
PLB1mim-catalysisR-HSA-975594 (Reactome)
PNLIP:CLPSmim-catalysisR-HSA-975593 (Reactome)
R-HSA-2187332 (Reactome) Nascent chylomicrons (CM) containing all-trans-retinyl esters (atREs) are secreted from intestinal cells and transported to the liver via the lymphatic system (Nayak et al. 2001, During & Harrison 2007).
R-HSA-2395764 (Reactome) Chylomicrons (CM) are large (75–450 nm), spherical lipoprotein particles secreted by intestinal cells postprandially and transport dietary fat and fat-soluble vitamins in the lymphatic system (Nayak et al. 2001, During & Harrison 2007). All-trans-retinyl esters (atREs) are packaged into nascent chylomicrons.
R-HSA-2395768 (Reactome) Lipoprotein lipase dimers (LPL:LPL) are tethered to heparan sulfate proteoglycans (HSPG) at endothelial cell surfaces (Fernandez-Borja et al. 1996; Peterson et al. 1992). Both syndecan 1 (Rosenberg et al. 1997) and perlecan (Goldberg 1996) HSPG molecules are capable of tethering LPL. The LPL enzyme catalyzes the hydrolysis and release of triacylglycerols (TG) associated with circulating chylomicrons to leave a CM remnant (CR). This reaction is annotated here as causing the hydrolysis and release of 50 molecules of TG. In vivo, the number is much larger, and TG depletion probably occurs in the course of multiple encounters between a chylomicron and endothelial LPL. This reaction is strongly activated by chylomicron-associated apo C-II protein both in vivo and in vitro (Jackson et al. 1986). Chylomicron-associated apoC-II protein inhibits LPL activity in vitro (Brown and Baginsky 1972), and recent studies have indicated a positive regulatory role for apoA-5 protein, though its molecular mechanism of action remains unclear (Marcais et al. 2005; Merkel and Heeren 2005). CRs can then be taken up by liver parenchymal cells in two ways; 1) directly by the LDL receptor or 2) apoE/HSPG-directed uptake by LDL receptor-related proteins.
R-HSA-2395784 (Reactome) Nascent chylomicrons (CMs) acquire copies of apolipoproteins C-II, C-III, and E from circulating spherical (mature) high-density lipoprotein particles, becoming mature chylomicrons (Havel et al. 1973, Bisgaier & Glickman 1983). Here, this interaction is annotated to involve the transfer of a single copy of each lipoprotein, but a mature chylomicron in fact contains approximately 25 copies of apolipoprotein E and 180 copies of C apolipoproteins (Bhattacharya & Redgrave 1981).
R-HSA-2399913 (Reactome) In enterocytes, all-trans-retinal (atRAL) binds to RBP2 (CRBPII) for stabilisation, metabolism and transport (Fierce et al. 2008).
R-HSA-2404131 (Reactome) When the low-density lipoprotein receptor (LDLR) is missing, saturated or inhibited, chylomicron remnants (CRs) containing all-trans-retinyl esters (atREs) can be cleared from circulation by interaction with cell-surface heparan sulfate proteoglycan (HSPG) and secreted apolipoprotein E (apoE). This complex is then presented to LDL receptor-related proteins (LRPs; reviews May et al. 2007, Li et al. 2001, Hussain 2001) for internalization (Ji et al. 1993).
R-HSA-2404133 (Reactome) Retinyl esters (REs) are stored in lipid droplets (LDs) in hepatic stellate cells (HSCs) until there is a demand for retinoid by the body. Mobilization of atREs stores require lipases with retinyl ester hydrolase (REH) activity. At present, the identity of the REH mediating atRE mobilization is unknown (see reviews Shirakami et al. 2012, Schreiber et al. 2012). In studies performed with rat livers, Mello et al. found that the carboxylesterases ES4 and ES10 possessed REH activity and were localised to HSCs (Mello et al. 2008) but it's not confirmed that these are the actual REHs involved in retinoid mobilization. The human orthologue to these rat enzymes is presently unknown.
R-HSA-2404134 (Reactome) In the bloodstream, circulating retinol binding protein 4 (RBP4, in complex with atROL), binds transthyretin (TTR, a 51 kDa protein) in a 1:1 molar complex (Naylor & Newcomer, 1999). The resultant TTR:RBP4:atROL complex is larger and therefore less susceptible to glomerular filtration, maintaining normal levels of retinoid and RBP4 in the circulation. In TTR-deficient mice, plasma levels of atROL and RBP