Flashcards in EXAM #1: FOLATE & VITAMIN B12 METABOLSIM Deck (42)
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1
List the major dietary sources of folate.
Spinach
Lettuce
Broccoli
****Think FOLATE i.e. FOLIAGE. Also, remember that folate is removed from vegetables by prolonged cooking/ boiling.*****
2
What structural feature distinguishes dietary folate from folate found in supplements?
- Dietary= polyglutamate
- Supplement= monoglutamate
3
What enzyme converts folate to tetrahydrofolate (THF)? What drug inhibits this enzyme?
- Diydrofolate reductase
- Methotrexate
*****Remember that THF and THF derivatives of THF are the active forms of THF in the body.*****
4
What is the most oxidized form of THF?
N10-formyl THF
5
What is the most reduced form?
N5-methyl THF
6
What is the one-carbon pool?
One carbon groups attached to THF that can be oxidized or reduced while bound to THF
7
Which reaction is the source of most of the carbon in the one-carbon pool?
Serine hydroxymethyltransferase reaction.
Serine + THF = Glycine + N5,N10 methylene-THF + H20
8
How is dietary folate absorbed in the intestine?
1) Hydrolysis of polyglutamate to monoglutamate
2) Monoglutamate form is absorbed
3) Reduction
4) Methylation
*****Product is N5-methyl THF, the most abundant form of folate in the circulation*****
9
How is folate released into the circulation?
Monoglutamate form of folate is eventually methylated to form "N5-methyl THF" that enters the circulation
10
What is the major form of THF in the circulation?
N5-methyl THF
11
How is folate taken up from the circulation?
Receptor-mediated endocytosis
- Receptors have high affinity for folate monoglutamate
- Receptors/N5-methyl THF are taken up
- Recycling of the receptor
12
What happens to folate inside the cell? Why is this modification important?
1) Conversion from monoglutamate to polyglutamate
*****Polyglutamate form keeps folate IN the cell i.e. prevents diffusion through the cell membrane*****
13
Which reaction requiring folate derivatives appears to be of greatest clinical importance?
Thymidylate synthase
- dUMP to dTMP, which is essential for DNA synthesis
14
What is the ultimate source of all vitamin B12?
Only synthesized by certain BACTERIA
****Note that B12 is also referred to as cyanocobalamin b/c of a cobalt group in the center--this is the form that is contained in supplements for vegans****
15
What are some important dietary sources?
- Liver
- Kidney
- Meat
- Dairy
- Shellfish
*****Though it is made by BACTERIA, B12 is stored in these organs*****
PLANTS DO NOT CONTAIN B12
16
Describe how vitamin B12 is liberated from food?
1) HCl and pepsin liberate B12 from food
2) B12 binds R-proteins
3) B12-R-proteins travel to the intestine
17
How is B12 absorbed in the intestine?
1) Pancreatic proteases remove R-proteins
2) B12 binds intrinsic factor
3) B12/IF undergoes receptor mediated endocytosis in the ILEUM
18
Describe how vitamin B12 is transported in the blood.
- Cells of the ileal mucosa make TRANSCOBALAMIN
- B12 is secreted into the blood as B12/transcobalamin
*****Note that most of the B12 in the blood is bound to HAPTACORRIN*****
19
How is B12 taken up by tissues?
Receptor mediated endocytosis of B12/transcobalamin
20
What are the metabolically active forms of vitamin B12?
Adenosylcobalamin
Methycobalamin
21
Describe how Part 1 and Part 2 of the Schilling test are performed.
Schilling test is a way of evaluating a patient's ability to absorb B12.
Part1=
- oral load of radioactive B12
- injection of non-radioactive B12
- 24 hour urine collection
- Radioactive excreted in urine, normal = 7%
Part2=
- oral radioactive B12
- oral purified IF
- same processing
22
What does an abnormal Part 1 but normal Part 2 tell you?
Pernicious anemia
- Not getting into the blood b/c of lack of IF
- Normal part 2 b/c of supplemented IF
23
How about abnormal Part 1 and Part 2?
NOT pernicious anemia b/c it was not fixed by IF administration
24
Describe the role of adenosylcobalamin in propionate metabolism. What does a deficiency in adenosylcobalamin result in?
methylmalonyl-CoA mutase in propionyl-CoA metabolism require ADENOSYLCOBALAMIN
Deficiency= methylmaloyl acidemia
25
Describe the role of methylcobalamin in homocysteine metabolism.
Methylcobalamin is required for Methionine synthase
26
What is meant by the ‘methyl trap hypothesis’?
- Methionine synthase converts N5, N10-mehtyl THF back to THF (requires methylcobalamin)
- Without B12, Folate becomes trapped in N5-methyl THF form
*****A FUNCTIONAL folate deficiency exists b/c this form cannot participate in the necessary biochemical reactions*****
27
What is megaloblastic anemia?
Anemia characterized by overgrowth of RBCs and RBC destruction
28
Why does deficiency of either folate or vitamin B12 result in a megaloblastic anemia?
- Vitamin B12 deficiency leads to functional folate deficiency (trapped as N5-methyl THF)
- Dietary insufficency may lead to actual folate deficiency
1) Thymidylate synthase is impaired dUMP-->dTTP
2) dUTP is incorporated into DNA instead
3) Cells GROW but CANNOT DIVIDE
****Eventually leads to DNA fragmentation and cell death and appears in rapidly dividing cells i.e. RBCs*****
29
What circumstances might increase folate needs?
1) Pregnancy
2) Lactation
3) Growth
4) Chronic hemolytic anemia
30
