lecture 12: folate

Question 1

folate

Answer 1

water-soluble B vitamin (B9)
ability to donate and accept one-carbon moieties > nucleotide synthesis, re-methylation of homocysteine to methionine

Question 2

folate metabolism

Answer 2

reduction of pyrazine ring to THF, elongation of glutamate chain, acquisition and oxidation or reduction of 1C units

Question 3

predominate form of folate in blood circulation

Answer 3

5-methyl-THF

Question 4

polyglutamates

Answer 4

form for tissue folates, increased affinities for folate-dependent enzymes

binding of folate polyglutamates allows tissues to retain and concentrate polyglutamate form of vitamin

Question 5

FPG synthetase

Answer 5

conversion of folate to polyglutamate form

Question 6

folate coenzymes

Answer 6

act as acceptors or donors of 1C units
utilized in methionine, thymidylate, purine synthesis

Question 7

C1 THF synthase

Answer 7

interconversion of folate coenzymes
bidirectional

Question 8

purine cycle

Answer 8

THF enters purine cycle when it is formylated as 10-Formyl-THF
can be used to produce purines in a two-step process
can also be used to produce 5,10-methylene-THF through the actions of C1-THF synthase

Question 9

If folate is involved in purine synthesis, which active vitamin(s) cofactor/substrate is/are dependent upon folate?

Answer 9

riboflavin and thiamin??

Question 10

thymidylate cycle

Answer 10

5,10-methylene-THF is a carbon carrier
carbon donated to uridine to form thymidine
THF oxidized to DHF in the process
THF can then be charged with a new carbon from serine or 5,10-methylene-THF can be provided by purine cycle

Question 11

DHF reductase

Answer 11

DHF (inactive) reduced back to THF

Question 12

cSHMT

Answer 12

serine acts as a carbon donor, converted to glycine in process, converted directly to 5,10-methylene form

serine > 5,10-methylene + glycine

Question 13

megaloblastic anemia

Answer 13

enlarged RBCs due to defective thymidylate synthesis coupled with enlarged dUTP pool - uracil misincorporation into DNA

Question 14

methionine/methyl cycle

Answer 14

reduction of 5,10-methylene THF to 5-methyl-THF via MTHFR
5-methyl THF + homocysteine > methionine + THF via MS
methionine > AdoMet > methylation rxns
AdoMet back to homocysteine

Question 15

homocysteine

Answer 15

not in diet, generated from metabolism of AdoMet

2 fates:
to regenerate: folate-dependent methionine synthase rxn
or metabolized to cysteine

Question 16

folate insufficiency

Answer 16

usually dietary insufficiency
defects in DNA synthesis - particularly in fast growing tissues
uracil misincorporation from thymidylate synthesis

increase risk for vascular disease - high circulating homocysteine levels

increased risk for certain cancers - once established, increasing folate can increase cancer risk - folate antagonists

Question 17

THF is the cofactor form of folate. However, if I say that this cofactor comes in several active forms, what exactly am I referring to? What roles do these active forms serve?

Answer 17

THF comes in several active forms via various one-carbon substituents. The interconversion of these forms are mediated by C1-THF synthetase

10-formyl form used for purine cycle
5-10-methylene feeds into thymidylate synthesis
5-methyl group for methyl/methionine cycle

Question 18

regulation of re-methylation of homocysteine

Answer 18

AdoMet inhibits MTHFR (reduces re-methylation)
AdoMet activates CBS, stimulating conversion to cysteine
remethylation favored when AdoMet is low

Question 19

generation of 1C units

Answer 19

in mitochondria, folate-mediated 1C metabolism generates 1C units in form of formate, can form 10-formyl THF