Tetrahydrofolate, Vitamin B12, SAM

Question 1

Structural features of folate

Answer 1

Peteridine ring- site of oxidation/reduction
Para-aminobenzoic acid (PABA)
Polyglutamate tail- cleaved to n=1 in brush border of lumen

Question 2

Sulfa drugs

Answer 2

Analogs of PABA, anti-microbial drugs that inhibit folate synthesis

Question 3

Folate in the body

Answer 3

Most is in the reduced form- tetrahydrofolate (FH4), oxidized by the enzyme dihydrofolate reductase

Question 4

Conditions inhibiting folate absorption

Answer 4

Absorption can be inhibited by damage to intestinal mucosa as in Crohn’s disease, alcohol, and Celiac disease

Question 5

Folate one carbon groups

Answer 5

One carbon units are attached to N5 or N10 on FH4, can be oxidized or reduced

Question 6

Most oxidized form of FH4

Answer 6

N10-formyl-FH4

Question 7

Most reduced form of FH4

Answer 7

N5-methyl-FH4, once the reduced form is produced it is difficult to oxidize it again

Question 8

Source of one carbon pool

Answer 8

Serine is the major source of carbon for the one carbon pool, can be produced from a glycolysis intermediate

Question 9

Transfer of one carbon

Answer 9

Deoxythymidine monophosphate (dTMP) is produced from deoxyuridine monophosphate (dUMP) by thymidylate synthase, requires N5N10-methylene-FH4

Question 10

5-Fluorouracil

Answer 10

Inhibitor of thymidylate synthase

Question 11

Methotrexate

Answer 11

Inhibits dihydrofolate reductase which forms FH4, used as a cancer drug because folate is important for cell division

Question 12

Trimethoprim

Answer 12

Inhibitor of dihydrofolate reductase, mimics folate

Question 13

Forms of vitamin B12

Answer 13

In the body- methylcobalamin, 5’-deoxyadenosylcobalamin

Commercial- cyanocobalamin

Question 14

Sources of vitamin B12

Answer 14

Meat, dairy, fish, other animal products

Question 15

Major reactions of vitamin B12

Answer 15

Homocystine to methionine- requires B12 and folate

Methylmalonyl-CoA to succinyl CoA- only requires B12, can use both to determine deficiency in one

Question 16

Absorption of vitamin B12

Answer 16

Free B12 must bind to R-binders, protein bound B12 is released and binds to R-binders, R-binders are degraded and B12 binds to intrinsic factor, binds to a receptor in the small intestine and is absorbed

Question 17

Intrinsic factor

Answer 17

Secreted by gastric parietal cells, deficiency of intrinsic factor is called pernicious anemia

Question 18

Schilling test

Answer 18

If any stage has abnormal results, move to the next
Stage 1- two doses of B12, one regular, one labeled, collect urine
Stage 2- given dose of labeled B12 with intrinsic factor
Stage 3- two weeks of antibiotics, test levels again
Stage 4- take pancreatic enzymes for several days then labeled B12

Question 19

S-adenosylmethionine (SAM)

Answer 19

Adds methyl groups to nitrogen or oxygen atoms, made from methionine and ATP (B12 is used to make methionine)

Question 20

SAM reactions

Answer 20

SAM is converted to S-adenosylhomocysteine (SAH) when it donates a methyl group, homocysteine is generated, used to make cysteine

Question 21

Choline pathway

Answer 21

Can be oxidized to form betaine, which can be used to add a one carbon unit to homocysteine, producing methionine, minor pathway only expressed in the liver

Question 22

Hyperhomocysteinemia

Answer 22

Elevated levels of homocysteine can be caused by problems with B12, folic acid, or PLP, different products will accumulate depending on the problem

Question 23

Neural tube defects

Answer 23

Folate deficiency in pregnancy is a risk factor for neural tube defects, deficiency leads to inhibition of DNA synthesis, high levels of homocysteine indicates folate deficiency

Question 24

Folate supplements

Answer 24

Difficult for pregnant women to consume recommended levels of folate, less than 50% of dietary folate is absorbed, almost all of the supplement is absorbed

Question 25

Megaloblastic anemia

Answer 25

Caused by decreased synthesis of thymine and purine bases, limits DNA synthesis, cells become large, red blood cells do not function properly, causing anemia, caused by both folate and B12 deficiency