Folate, Vitamin B12 and Inhibitors Flashcards
What are the two ways we synthesize tetrahydrofolate in our bodies?
- folate is converted to dihydrofolate and then to tetrahydrofolate by DHFR
- methyltetrathydrofolate from liver stores in converted to tetrahydrofolate (requires vitamin B12)
What reactions use tetrahydrofolate as a carbon donor?
- thymidilate and purine synthesis
- methionine synthesis
- amino acid metabolism
What is the rate limiting step in DNA synthesis? What enzyme?
conversion of UMP to TMP with thymidylate synthase (in pyrimidine synthesis)
What reactions in pyrimidine synthesis is important for the development of resistance of 5-FU?
UMP to UDP by pyrimidine monophosphate kinase
An inherited deficiency in what enzyme responsible for thymidine nucleotide degradation causes greately increased sensitivity to 5;FU?
dihydropyrimidine dehydrogenase
What two kinds of cells particularly need folate and vitamin B12 for maintenance/
RBCs and neurons
B12 is necessary for a reaction that converts methylTH4 to TH4, converting homocysteine to what?
methionine (that’s why homocysteine levels are diagnostic of B12 deficiency)
B12 is also necessary for the conversion of methylmalonyl CoA to what?
succinyl CoA
What’s the synthetic form of folate typically used in supplements?
folic acid
What’s the naturally occurring form of folate that’s used to replace folate in rescue therapy?
leucovorin
What about leucovorin makes it better for folate rescue than just folic acid?
It doesn’t require dihydrofolate reductase for its conversion to tetrahydrofolate
What are the two naturally occurring forms of B12?
adenosylcobalamin, methylcobalamin
What are the two medicinal forms of B12?
hydroxocobalamin, cyanocobalamin
Where in the body is folate absorbed?
small intestine
Why is there a high daily requirement for folate?
a relatively small quantity is stored in the liver - only 1-6 month supply
What is required for absorption of B12?
acidic pH and intrinsic factor made in the stomach
Where in the body does absopriton of B12 occur?
small intestine
Why is B12 deiciency rare except in the elderly?
there’s about a 5 year supply stored in the liver
Reduced expression or mutation of what causes a primary resistance to low doses of folate inhibitors like methotrexate?
reduced folate carrier
What do we give to overcome resistance from mutated reduced folate carrier?
HIGH doses of methotrexate (forces uptake via folate receptor), followed by leucovorin to rescue healthy cells (since leukocovorin won’t be taken up by the mutant form - haha sucker)
Comparing the reduced folate carrier and the folate receptor…Which has higher affinity? which has higher capacity?
reduced folate carrier has low affinity but high capacity
folate receptor has high affinity but low capacity and is only in specific tissues
Overexpression of the folate receptor (as seen in some leukemias, gynecological cancers and epithelial cancers) will conver a higher or lower sensitivity to folate inhibitors?
high sensitivity
What does polyglutamation do for the folates inside the cell?
It occurs through the enzyme folylpolyglutamate synthase
It is required for biological activity and facilitates retention and icnreases affinity for folate-dependent enzymes like TS
How does polyglutamation confer selective toxicity for the folate inhibitors?
Cancer cells are more capable of polyglutamation, so they’re more likely to retain the folate inhibitors once they’re in
What’s usually the first clinical sign of a folate or B12 deficiency?
megaloblastic anemia
What can cause a folate deficiency?
insufficient dieary intake (rare), high demand (pregnancy), alcoholism, intestinal disease like celiacs, inhibitors
Why do we fortify with folate now?
to avoid neural tube defects
What’s the most common cuase of B12 deficiency?
intrinsic factor deficiency (so you can’t treat it with oral supplementation)
Why does B12 deficiency cause a flate deficiency as well?
Without B12 you can’t access the stored TH4
IF the B12 deficiency is caused by lack of IF, what type of anemia occurs?
pernicious anemia
Which can cause neurological deficits in adults: folate or B12 deficiency
B12
Why is it critical that B12 stats be checked before beginning folate supplementaiton?
Because once B12 deficiency reaches neurological stages, it really can’t be reversed
What’s the dilemma with folate fortification?
It decreases incidence of neural tube defects, but it masks B12 deficiencies, making it more difficult in millions of elderly people - common cause of senile dementia
What does methotrexate inhibit?
DHFR
What are the four therapeutic uses of MTX?
- cancer
- immunosuppressant (RA, IBS, etc)
- antibiotic
- abortifacient
Trimethoprim is usually combined with what other antibiotic to work synergistically against bacteria?
sulfamethoxazole - blocks dihydropoteroate synthetase
together they block sucessive steps in the folate synthesis pathway
What does trimethoprim inhibit?
competitive inhibitor of DHFR (like methotrexate)
