id: PW:0000141 rgd_url: https://rgd.mcw.edu/rgdweb/pathway/pathwayRecord.html?processType=view&species=Rat&acc_id=PW:0000141 title: retinol metabolic pathway description_xrefs: - GO:0042572 - KEGG:map00830 description: Animal species cannot synthesize retinol or vitamin A. They derive it from diet as provitamin carotenoids found in plants and best exemplified by beta-carotene or as preformed vitamin such as the retinyl esters found in animal food. The provitamin carotenoid is absorbed into the small intestine by passive absorption or via transport by members of the scavenger receptor family, such as Scrba1, also known as SR-BI, and Cd36. In the lumen, retinyl esters are hydrolyzed by enzymes secreted by the pancreas or associated with intestinal cells. The pancreatic lipases Pnlip and Pnliprp2, known as Ptl and Plrp-2, respectively and the phospholipase B1 located in the brush border membrane of absorptive cells, carry out the reaction. ( PDB entry for the X-ray structure of human PNLIPRP2 ) The unesterifed retinol is believed to be absorbed through passive diffusion. In the cell, beta-carotene is subject to enzymatic cleavage by carotenoid oxygenases; the enzymes require ferrous iron as a cofactor but do not contain a heme ring and as such they belong to the family of non-heme iron oxygenases. The cytosolic Bcmo1 - an enzyme with narrow substrate specificity, cleaves the carotenoid molecule at the central double bond (15, 15') in a reaction referred to as the central cleavage route to produces two molecules of all-trans-retinal. A mitochondrial enzyme with broad specificity - Bco2, is responsible for what is referred to as the eccentric cleavage route carried out at sites different than the central cleavage, such as the 9,10 and 9',10' double bonds of beta-carotene to produce beta-apocarotenals and beta-carotenones. However, the major enzyme responsible for the production of vitamin A and retinol metabolism is Bcmo1 and is the only one shown in the diagram ( PDB entry for the X-ray structure of a bacterial retinal forming carotenoid oxygenase ). A third enzyme in the family - Rpe65 in the retina, does not carry out a cleavage reaction but acts as a trans-to-cis isomerase in a coupled atypical ester hydrolysis-isomerization reaction, essential for the formation and regeneration of the visual chromophore. Retinal is converted to retinol by Akr1b10, the member of the alpha-keto reductase AKR1B subfamily, also known as the small intestine reductase ( PDB entry for the X-ray structure of human AKR1B10 in complex with NADP+ and tolrestat, an aldose reductase inhibitor ). In the cell, free retinol is in complex with Rbp2 retinol binding protein and is re-esterified to retinyl esters (RE) by Lrat or is released into the circulation via Abca1-mediated efflux ( PDB entry for the X-ray structure of human RBP2 ). Retinyl esters along with other dietary lipids are incorporated into chylomicrons and secreted into the lymph. The liver is the the major storage system for retinyl esters. The free retinol in the circulation is complexed with Rbp4, the main vitamin A blood carrier which in turn, is associated with transthyretin. Uptake of retinol by cells is mediated by Stra6 acting as an Rbp4 receptor. In the retinal pigment epithelium, retinol is metabolized to cis-retinal to serve as the chromophore for the visual pigment, as mentioned. In other cells retinal, directly derived from beta-carotene or from the conversion of RE-derived retinol to retinal, is irreversibly converted to all-trans retinoic acid (atRA) and other derivatives. atRA is the ligand for the retinoic acid receptors (RARs) and a subset of peroxisome proliferator-activated receptors (PPARs) that once activated act as transcription factors. Interestingly, an intestine-specific homeobox transcription factor has been identified that controls the expression of Scarb1 and Bcmo1; its own expression may be under the control of RA as its promoter contains retinoic acid response elements. Expression of Isx results in repression of Scarb1 and Bcmo1 genes, providing a negative feedback loop between cellular dietary vitamin A metabolites and its uptake and production. diagram_image: https://rgd.mcw.edu/pathway/PW0000141/retinol%20metabolic%20pathway/pwmap.png pathway_studio_file: https://rgd.mcw.edu/pathway/PW0000141/retinol%20metabolic%20pathway/retinol%20metabolic%20pathway.gpp diagram_pathway_links: [] diagram_gene_links: - id: RGD:631344 label: Abca1 - id: RGD:1308277 label: Akr1b10 - id: RGD:70981 label: Bcmo1 - id: RGD:2301 label: Cd36 - id: RGD:68362 label: Lrat - id: RGD:621565 label: Plb1 - id: RGD:3360 label: Pnlip - id: RGD:620793 label: Pnliprp2 - id: RGD:3544 label: Rbp2 - id: RGD:2302 label: Scarb1 diagram_chemicals: - id: CHEBI:17336 label: all-trans-retinol - id: CHEBI:23044 label: carotenoids/beta-carotene - id: CHEBI:50211 label: circ_retinol - id: CHEBI:18009 label: NADP+ - id: PUBCHEM.COMPOUND:5884 label: NADPH - id: CHEBI:16179 label: re-esterifed retinol - id: CHEBI:15035 label: retinal diagram_edges: - source: NADPH relation: positively_affects target: NADP+ - source: all-trans-retinol relation: positively_affects target: cell_retinol - source: carotenoids relation: positively_affects target: carotenoids/beta-carotene - source: carotenoids/beta-carotene relation: positively_affects target: retinal - source: cell_retinol relation: associated_with target: Rbp2 - source: cell_retinol relation: positively_affects target: circ_retinol - source: cell_retinol relation: positively_affects target: re-esterifed retinol - source: retinal relation: positively_affects target: cell_retinol - source: retinyl esters relation: positively_affects target: all-trans-retinol diagram_labels: - diet - passive diffusion references: - id: RGD:6484678 citation: Schreiber R, etal., Biochim Biophys Acta. 2012 Jan;1821(1):113-23. Epub 2011 May 8. - id: RGD:6484679 citation: Harrison EH Biochim Biophys Acta. 2012 Jan;1821(1):70-7. Epub 2011 Jun 12. - id: RGD:6903956 citation: Lobo GP, etal., Biochim Biophys Acta. 2012 Jan;1821(1):78-87. Epub 2011 May 4. - id: RGD:6903957 citation: Jin Y and Penning TM, Annu Rev Pharmacol Toxicol. 2007;47:263-92. - id: RGD:6904150 citation: Lietz G, etal., Arch Biochem Biophys. 2010 Oct 1;502(1):8-16. Epub 2010 Jul 1. - id: RGD:6904151 citation: Curley RW Jr Biochim Biophys Acta. 2012 Jan;1821(1):3-9. Epub 2011 Apr 30. - id: RGD:6904152 citation: Reboul E and Borel P, Prog Lipid Res. 2011 Oct;50(4):388-402. Epub 2011 Jul 8. - id: RGD:6904153 citation: 'Valacchi G, etal., Ann N Y Acad Sci. 2011 Jul;1229:E1-7. doi: 10.1111/j.1749-6632.2011.06205.x.' - id: RGD:6904154 citation: Lobo GP, etal., FASEB J. 2010 Jun;24(6):1656-66. Epub 2010 Jan 8.