CRBP

Nematodes provide exceptions to the rule that members of the FABP/ P2/CRBP/CRABP family of proteins are universally intracellular. Some of those secreted by nematodes may be involved in specialized functions, such as the protection of developing embryos within shelled eggs. Nematodes also provide examples of where the highly conserved tertiary structure of these proteins has been modified. 

Within the enterocyte, retinol is bound to cellular retinol binding protein (CRBP 11) and is esterified by lecithin retinol acyltransferase (LRAT), which uses phosphatidylcholine as the fatty acid donor, mainly yielding retinyl palmitate, although small amounts of stearate and oleate are also formed. At unphysiologically high levels of retinol, when CRBP 11 is saturated, acyl coenzyme A (CoA) retinol acyltransferase (ARAT) esterifies the free retinol that accumulates in intracellular membranes. Then the retinyl esters enter the lymphatic circulation and then the bloodstream (in chylomicrons), together with dietary lipid and carotenoids (Norum et al., 1986 Olson, 1986 Blomhoff et al., 1991 Green et al., 1993 Harrison and Hussain, 2001). 

Cytosolic alcohol dehydrogenases only act on free retinol, not retinol bound to CRBP, so they are unlikely to he involved in formation of retinaldehyde and retinoic acid. Furthermore, inhihition of cytosolic alcohol dehydrogenases does not inhibit the oxidation of retinol to retinoic acid (Boerman and Napoli, 1996). CRBP-bound retinol is a substrate for atleast three microsomal NADP+-dependent dehydrogenases hut, given the intracellular NADP+ NADPH ratio (0.01, compared with an NAD+ NADH ratio of the order of 10 ), it is likely that these microsomal enzymes wiU act mainly to reduce retinaldehyde to retinol and not to oxidize retinol. 

A microsomal retinol dehydrogenase catalyzes the oxidation of CRBP-hound all-trans-retinol to retinaldehyde it also acts as a 3a-hydroxysteroid dehydrogenase. A similar enzyme catalyzes the oxidation of 9-cis- and 11-ds-retinol, but not all-trans-retinol again, it has 3a-hydroxysteroid dehydrogenase activity. In the eye, the major product of this enzyme is 11-cts-retinaldehyde, whereas in other tissues it is 9-cts-retinaldehyde, which is then oxidized to 9-cis-retinoic acid (Section 2.3.2.1 Chen et al., 2000 Duester, 2000, 2001 Gamble et al., 2000 NapoU, 2001). Although there is known to be an isomerase in the eye for the formation of 11-cts-retinaldehyde as a... 

Cellular Retinoid Binding Proteins CRBPs and CRABPs... 

CRBP(I) occurs in almost all tissues, apart from skeletal and cardiac muscle it is especially abundant in tissues that contain large amounts of retinol. 

CRBP(II) occurs only in the small intestinal mucosal cells. 

M five proteins have a high affinity and are present in excess of their ligands, with CRBP 1.4-fold higher than intracellular retinol, and CRABP 20-fold higher than intracellular retinoic acid. This means that, under normal conditions, essentially all of the intracellular retinoids will be protein-bound. 

They are also important in intracellular trafficking and transport of retinoids. CRBP(II) interacts direcdy with the enterocyte membrane retinol transporter, and CRBP(I) with the cell surface RBP receptor, thus permitting direct uptake and accumulation of retinol from the intestinal lumen and circulation respectively. CRBP(l) is present in large amounts in cells that synthesize and... 

Both CRBP and CRABP are also important in regulating the metabolism of retinoids ... 

In most tissues, apo-CRBP does not bind to enzymes only the holo-CRBP binds. However, in the liver, apo-CRBP(I) does bind to LRAT and acts to reduce the rate of esterification of retinol when there is a significant excess of apo-CRBP. This serves to reduce the esterification of retinol for storage at times of low retinol availability and will presumable direct retinol into the endoplasmic reticulum for binding to apo-RBP for export. Apo-CRBP(II) in the intestinal mucosa does not bind to LRAT. 

Apo-CRBP(I) stimulates the hydrolysis of retinyl esters, thus releasing retinol from stores for transfer to RBP. This means that the esterification and... 

Retinoic acid may either enter the target cell from the circulation or may be formed intraceUularly by oxidation of retinol. A number of tissues - but not muscle, kidneys, small intestines, liver, lungs, or spleen - have a cellular retinoic acid binding protein (CRABP) that is distinct from CRBP. Testis and... 

The role of these intracellular binding proteins seems to be to transport retinoic acid into the nucleus. Unlike receptor proteins, which bind their ligand in the nucleus and then interact with regulatory elements on DNA, the CRBPs do not enter the nucleus or interact with DNA and nucleoproteins. 

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