GMM Klinge et al (Exam 2)

Question 1

How do we make Vitamin A from beta-carotene?

Answer 1

We cleave beta carotene (enzyme = beta-carotene dioxygenase) into two molecules of retinal. Retinal (RAH) can then be interconverted to Retinol (ROH) via retinol dehydrogenases. Then Retinal can either be isomerized to 11-cis-retinal OR irreversibly converted to Retinoic acid by retinaldehyde dehydrogenase.

Question 2

Which enzyme catalyzes conversion from retinal (aka retinaldehyde) to retinol? What kind of rxn is this?

Answer 2

Retinol dehydrogenases. This is a reversible interconversion.

Question 3

How does retinal (aka retinaldehyde) get to all-trans-retinoic acid (ATRA) and its isomers? What kind of rxn is this?

Answer 3

conversion catalyzed by Retinaldehyde dehydrogenase. Is an irreversible rxn. So once you go to retinoic acid, you can’t go back to retinal.

Question 4

What kind of activity to carotenoids have? Name a clinical relevance of this.

Answer 4

antioxidant activity. Age-related macular degeneration (AMD) has increasing evidence for dietary carotenoids protecting against AMD by filtering out blue light and quenching free radicals.

Question 5

Describe the transport and storage of Vitamin A. How is Vitamin A stored in the liver?

Answer 5

Since retinoids are not water-soluble, their absorption depends on the amount of fat in the diet. Inside enterocytes, ROH and RAH bind to CRBP , which protects them from being oxidixed to retinoid acid (RA). Then the CRBP-retinol complex acts as a substrate for conversion of retinol into retinyl esters (RE). The RE are then incorporated into chylomicrons and go out into circulation. Then liver takes up chylomicron remnants and most of the retinol is stored as RE, called Retinyl Palmitate.

Question 6

Why do retinoids need carrier proteins? List (3) retinol binding proteins and their function

Answer 6

retinoids are not water-soluble, so need carrier proteins.
-CRBP (cellular retinol binding protein) = intestinal protein that protects ROH and RAH from being oxidized to RA inside the enterocyte
Then to get retinol that is stored in liver (as retinyl palmitate CE) to extrahepatic tissues, need RBP + TTR:
-RBP (retinol binding protein) = made by liver and secreted into circulation carrying 1 molecule of retinol per molecule of RBP.
-TTR (transthyretin) = one of the T3/T4 binding proteins. It binds to both RBP + retinol and protects RBP from filtration by the kidney

Question 7

Which form of Vitamin A is important in the visual cycle?

Answer 7

11-cis-retinal, which binds to Opsin = the photoreceptor, Rhodopsin (i.e. visual pigment). Light-induced activation of rhodopsin leads ultimately to an action potential.

Question 8

What tissue has the highest concentration of retinyl-palmitate?

Answer 8

the liver! This is major form of Vitamin A storage in liver

Question 9

Describe how all-trans-retinoic acid works through RAR.

Answer 9

RAR = retinoid acid receptor. This is an INTRA-nuclear receptor that is activated upon RA binding. The retinoic acid receptor complex then binds to chromatin activating the transcription of specific genes, such as cellular differentiation into nervous, immune systems, etc.

Question 10

What is RXR? What is an important clinical function?

Answer 10

RXR = retinoid X receptor. RXR and RAR are two nuclear receptors that bind RA. RXR binds only 9-cis-RA.
RXR heterodimerizes with certain other nuclear receptors, such as VitD receptor (VDR) or thyroid hormone receptor (TR) to form complexes (e.g. RXR-VDR). It’s the binding of the RA ligand of RXR that contributes to activation of Vit D and other gene expressions. Clinical relevance b/c these NRs that heterodimerize w/ RXR = drug targets!

Question 11

Name (4) sx of Vitamin A deficiency

Answer 11

• night blindness;
• xeropthalmia (eye dryness);
• dry, scaly skin; and
• kertinization of epithelium in GI, respiratory, and GU tract (diarrhea, trouble breathing)

Question 12

When does toxicity due to Vitamin A overdose occur? Name (5) sx of CHRONIC overdose of Vitamin A.

Answer 12

toxicity occurs when the capacity of RBP is exceeded. Thus, it is the free (unbound) retinol that causes problems. Chronic ingestion of 10x RDA for Vitamin A can result in:

• neuro sx
• damage to eyes
• anorexia
• drying and cracking of skin, and
• hepatosplenomegaly

Question 13

What is APL? What form of Vitamin A is used to treat it?

Answer 13

APL = acute promyelocytic leukemia. Caused by translocation that fuses the PML (promyelocytic leukemia) gene with the RAR-alpha gene. The PML/RAR-alpha binds to the same DNA sequences that are normally bound by RAR/RXR. This blocks the normal differentiation function regulated by RAR/RXR.
Tx = pharmacological doses of all-trans-RA causes a dissociation of the PML/RAR-alpha fusion.