ncreas 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. To see the ontology report for annotations, Gviewer and download, click here . [Click to see associated GO term - GO:0042572 and KEGG map map00830]...(less)