Tetrahydrofolate, Vitamin B12, SAM Flashcards
Structural features of folate
Peteridine ring- site of oxidation/reduction
Para-aminobenzoic acid (PABA)
Polyglutamate tail- cleaved to n=1 in brush border of lumen
Sulfa drugs
Analogs of PABA, anti-microbial drugs that inhibit folate synthesis
Folate in the body
Most is in the reduced form- tetrahydrofolate (FH4), oxidized by the enzyme dihydrofolate reductase
Conditions inhibiting folate absorption
Absorption can be inhibited by damage to intestinal mucosa as in Crohn’s disease, alcohol, and Celiac disease
Folate one carbon groups
One carbon units are attached to N5 or N10 on FH4, can be oxidized or reduced
Most oxidized form of FH4
N10-formyl-FH4
Most reduced form of FH4
N5-methyl-FH4, once the reduced form is produced it is difficult to oxidize it again
Source of one carbon pool
Serine is the major source of carbon for the one carbon pool, can be produced from a glycolysis intermediate
Transfer of one carbon
Deoxythymidine monophosphate (dTMP) is produced from deoxyuridine monophosphate (dUMP) by thymidylate synthase, requires N5N10-methylene-FH4
5-Fluorouracil
Inhibitor of thymidylate synthase
Methotrexate
Inhibits dihydrofolate reductase which forms FH4, used as a cancer drug because folate is important for cell division
Trimethoprim
Inhibitor of dihydrofolate reductase, mimics folate
Forms of vitamin B12
In the body- methylcobalamin, 5’-deoxyadenosylcobalamin
Commercial- cyanocobalamin
Sources of vitamin B12
Meat, dairy, fish, other animal products
Major reactions of vitamin B12
Homocystine to methionine- requires B12 and folate
Methylmalonyl-CoA to succinyl CoA- only requires B12, can use both to determine deficiency in one
Absorption of vitamin B12
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
Intrinsic factor
Secreted by gastric parietal cells, deficiency of intrinsic factor is called pernicious anemia
Schilling test
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
S-adenosylmethionine (SAM)
Adds methyl groups to nitrogen or oxygen atoms, made from methionine and ATP (B12 is used to make methionine)
SAM reactions
SAM is converted to S-adenosylhomocysteine (SAH) when it donates a methyl group, homocysteine is generated, used to make cysteine
Choline pathway
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
Hyperhomocysteinemia
Elevated levels of homocysteine can be caused by problems with B12, folic acid, or PLP, different products will accumulate depending on the problem
Neural tube defects
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
Folate supplements
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
