30: Folate and vitamin B12 metabolism - Wilson

Question 1

sources of folate

Answer 1

green leafy vegetables (spinach, lettuce, broccoli)

water-soluble and readily removed by prolonged cooking

also organ meats (liver, kidney, etc)

Question 2

functional form of folate

Answer 2

tetrahydrofolate THF

formed from folate by dihydrofolate reductase

Question 3

what are the actions of dihydrofolate reductase?

Answer 3

converts folate to dihydrofolate and coverts dihydrofolate to THF

Question 4

folate analog that inhibits dihydrofolate reductase

Answer 4

methotrexate

prevents generation of THF

antiproliferative effects

Question 5

major source of one carbon groups

Answer 5

serine hydroxymethyltransferase

converts serine into glycine making a one-carbon

Question 6

which form of folate is taken into the intestinal epithelial cell?

Answer 6

monoglutamate form

reduction and methylation occur in the cell to form N5methyl THF which is released into the blood

Question 7

what is the majority of folate in your body?

Answer 7

N5 methyl THF (most reduced form)

Question 8

method of folate uptake from blood

Answer 8

receptor mediated endocytosis

receptors have high affinity for folate monoglutamates

rapidly metabolized in the cell

Question 9

converts dUMP to dTMP

Answer 9

thymidylate synthase

essential for DNA synthesis

Question 10

methionine synthesis

THF form used:
folate form produced:

Answer 10

N5 methyl THF

THF

Question 11

best dietary sources of vitB12

Answer 11

liver, kidney, other meats, dairy products, shellfish

plant foods do not supply vit B12

ONLY synthesized by certain bacteria

Question 12

cyanocobalamin aka

Answer 12

vit B12

four cobalamins in human metabolism: cyanocobalamin, hydroxycobalamin, adenosylcobalamin, methylcobalamin

• biologically active forms

Question 13

where is dietary B12 absorbed?

Answer 13

ileum - needs intrinsic factor

see slide 13

Question 14

lack of ability to absorb vit B12 from ileum

Answer 14

pernicious anemia

autoimmune disease with gastric atrophy, no intrinsic factor produced

Question 15

how is B12 taken from the blood?

Answer 15

receptor-mediated endocytosis with a transcobalamin recetors

Question 16

B12 is secreted into blood as…

Answer 16

B12/transcobalamin complex

cells of ileal mucosa make TC

Question 17

binding of B12 to TC required for uptake into cells, but most B12 in circulation is bound to ______

Answer 17

haptocorrin

this complex is taken up by liver (B12 secreted into bile, binds to haptocorrin again in bile, degraded in duodenum, binds intrinsic in ileum, etc)

Question 18

describe the schilling test

Answer 18

Part 1: oral load of radioactive B12 and injection of non-radioactive B12. Normal individual excrete at least 7% of radioactivity within 24 hr.
Part 2: oral radioactive B12 and purified intrinsic factor.

abnormal P1 normal P2 = pernicious anemia

abnormal P1 and P2 = defect in B12 absorption independent of intrinsic factor

Question 19

2 metabolic processes requiring vit B12

Answer 19

propionyl-coA metabolism (adenosylcobalamin)

homocysteine metabolism (methylcobalamin)

Question 20

methyl trap hypothesis

Answer 20

folate trapped in N5methyl THF form –> functional folate deficiency

why? lack of b12 prevents sysnthesis of methylcobalamin, only methionin synthase can convert N5methyl THF back to THF

Question 21

neurological consequences of vit B12 deficiency?

Answer 21

vit B12 results in demyelination

more likely failure of methionine synthase rxn, improve with methionine administration

Question 22

functional v. actual folate deficiency

in either case: thymidine synthesis blocked (DNA synthesis blocked**) , purine synthesis also blocked

Answer 22

vit B12 deficiency leads to function folate deficiency with accumulation of N5methyl THF

dietary insufficiency may lead to actual
folate deficiency

Question 23

___ incorporated into DNA instead of DTTP

Answer 23

dUTP

because of thymdiylate synthase

cells grow but can’t divide –> DNA fragmentation and cell death. megaloblastic anemia in RBC too .

Question 24

folate needs increased by

Answer 24

pregnancy
lactation
growth
chronic hemolytic anemia

a deficiency often seen in alcoholism, old age, poverty, celiac disease, malabsorption

Question 25

deficient in B12 and folate?

Answer 25

probably alcoholic

Question 26

vit B12 needs increased by

Answer 26

pregnancy
periods of growth

deficiency seen in:
strict vegans
pernicious anemia
celiac disease
gastric acid insufficiency
ileitis
fish tapeworm infestation
competing intestinal flora

Question 27

acute megaloblastic anemia can be associated with

Answer 27

nitrous oxide anetsthesia

nitrous oxide destroys methylcobalamin**

Question 28

classic B12 deficiency signs

Answer 28

pancytopenia
megaloblastic abnormalities in bone marrow
methylmalonic aciduria
hyperhomosyteinemia