Cellular Retinoid Binding Proteins CRBPs and CRABPs

There are five intracellular retinoid binding proteins that show considerable sequence homology not only with each other, but also with a variety of other intracellular binding proteins for hydrophobic metabolites, including the intracellular fatty acid binding protein (Li and Norris, 1996; Noy, 2000; Vogel et al., 2001).

The two cellular retinol binding proteins bind all-trans- and 13-ci's-retinol, but not 9-cis- or 11-cis-retinol, or retinoic acid. They also bind retinaldehyde, although there is a distinct retinaldehyde binding protein in the eye:

1. 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.

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

3. CRBP(III) occurs in skeletal and cardiac muscle.

There are two cellular retinoic acid binding proteins:

1. CRABP(I) is widely distributed.

2. CRABP(II) occurs primarily in the skin, uterus, ovary, choroid plexus, and in fetal cells.

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

The intracellular retinoid binding proteins function as a passive reservoir of retinoids, permitting accumulation within the cell while both protecting the ligands against oxidative damage and also protecting cells against the membrane lytic effects of retinoids.

They are also important in intracellular trafficking and transport of reti-noids. CRBP(II) interacts directly 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(I) is present in large amounts in cells that synthesize and secrete RBP, suggesting that it also functions to transport retinol into the lumen of the endoplasmic reticulum and present it to apo-RBP.

CRABP(I) and CRABP(II) function to transport retinoic acid into the nucleus for binding to retinoid receptors. CRABP(II), with retinoic acid bound, also interacts directly with the liganded RAR-RXRheterodimer bound to hormone response elements on DNA and enhances the activity of the nuclear receptor (Section2.3.2.1; Delvaetal., 1999).

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

1. In the enterocyte, CRBP(II) regulates

(a) reduction to retinol of the retinaldehyde formed by carotene dioxy-genase;

(b) esterification of retinol by LRAT.

2. In the liver and other tissues, CRBP(I) regulates

(a) esterification of retinol and hydrolysis of retinyl esters;

(b) oxidation of retinol to retinaldehyde; and

(c) oxidation of retinaldehyde to retinoic acid.

3. CRABP is required for the microsomal oxidation of retinoic acid to more polar compounds.

In each case, the binding protein is required for binding of the substrate to the enzyme, and protein binding protects retinol from other enzymes that can act on free, but not protein-bound, substrate. It is likely that this requirement to interact with not only the ligand, but also the catalytic sites of enzymes, explains the very high degree of conservation of the cellular retinoid binding proteins across species (Napoli et al., 1995; Boerman and Napoli, 1996). After relatively large amounts of retinol, there is significant formation of (potentially teratogenic) all-frans-retinoic acid as a result of nonspecific (and hence unregulated) oxidation in enterocytes of excess retinol that is not bound to CRBP(II) (Arnhold et al., 2002).

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 hydrolysis of retinyl esters is regulated to a considerable extent by the ratio of apo-CRBP:holo-CRBP.

2.3 METABOLIC FUNCTIONS OF VITAMIN A

Vitamin A has four metabolic roles:

1. as the prosthetic group of the visual pigments;

2. as a nuclear modulator of gene expression;

3. as a carrier of mannosyl units in the synthesis of hydrophobic glyco-proteins; and

4. in the retinoylation of proteins.

Ahmed and coworkers (1990) suggested that the development of clinical signs of vitamin A deficiency may require the additional stress of infection. They showed that vitamin A-depleted mice were more sensitive to rotavirus infection, and the infected animals showed clinical signs of vitamin A deficiency, whereas uninfected animals that had stopped growing as a result of vitamin A depletion did not. The increased susceptibility to infection was associated with reduced differentiation and formation of a specific subpopulation of intestinal, mucus-secreting goblet cells in the crypts of Leberkuhn, suggesting the importance of retinol in mannosyltransfer reactions in mucopolysaccharide synthesis (Section 2.3.3).

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