one-carbon metabolism Flashcards
one-carbon metabolism
term applied to reactions in which a single carbon atom is transferred from one compound to another
tetrahydrofolate (THF) central cofactor in many of these reactions
folic acid
essential vitamin in mammals
dihydrofolate reductase converts it to tetrahydrofolic acid (THF)- converts 2 NADPH, H+ to 2 NADP+ in the process
THF then used in AA synthesis, purine synthesis, thymidine synthesis
abundant in leafy vegetables, beans, whole grains, etc.
taken up by intestinal mucosal cells, reduced by DHFR, and reduced form is circulated
likely most common vitamin deficiency in US due to overcooking, alcoholism
in deficiency, levels of N-formimino glutamate (FIFIu) elevated, also elevated levels of homocysteine and N5-methyl-THF
serine hydroxymethyltransferase
transfers side chain beta-carbon of serine to THF
makes glycine and N5,N10-methylene-THF
this pathway provides the major source of active one-carbon units in most cells
serine
synthesized from 3-phosphoglycerate (intermediate in glycolysis)
used as major source of active one-carbon units when enzyme serine hydroxymethyltransferase transfers the beta-carbon of serine to THF
formiminotransferase
enzyme that degrades histidine by transfering one-carbon unit to THF
source of one-carbon units
makes 5-formimino-THF, which can then be converted to N5,N10-methenyl-THF
tetrahydrofolic acid (THF)
made from folic acid by dihydrofolate reductase
has 2 H attached to ring
used to carry activated one-carbon units
carried at the N5 or N10 positions or by bridging these positions
becomes N5,N10-methylene-THF when carries carbon unit
can carry carbons in methyl, methylene and formyl states
polyglutamylated when enters cells to retain it in the cell, since the polyglutamylated form is not exported efficiently
states of one-carbon groups
all carried by THF methyl state (methanol) is most reduced - CH3 - used to make methionine methylene state (formaldehyde) is intermediate - CH2 - used to make thymidylate formyl state (formic acid) is most oxidized - CHO or CHNH - used for de novo purine biosynthesis
N5,N10-methylene-THF reductase
reduces N5,N10-methylene-THF to N5-methyl-THF
NADPH dependent
not reversible
N5-methyl-THF
made from N5,N10-methylene-THF by N5,N10-methylene-THF reductase
used for the methylation of homocystein to make methionine by enzyme homocysteine methyltransferase
requires vit B12
homocysteine methyltransferase
enzyme that catalyzes methylation of homocysteine using N5-methyl-THF - creates L-methionine and THF
requires vitamin B12
in B12 deficiency, results in buildup of homocystein and N5-methyl THF
vitamin B12
aka cobalamin
consist of large polycyclic ring with cobalt bound in center
used as cofactor by homocysteine methyltransferase in making methionine
converted to tetrahydrofolic acid by dihydrofolate reductase - uses 2 NADPH and releases 2 NADP+
needed for AA synthesis, purine synthesis, thymidine synthesis
if deficiency, get accumulation of homocysteine and N5-methyl-THF
s-adenosylmethionine synthase
converst methionine to s-adenosylmethionine (SAM)
ATP dependent reaction
consumes energy of two phosphate bonds
makes activated methol group that can then be transferred to acceptor molecules
SAM dependent methylation used in synthesis of other molecules s.a. choline
s-adenosylmethionine (SAM)
made by s-adenosylmethionine synthase from methionine
results in activated methyl group that can then be transferred to acceptor molecules, resulting in their methylation, which is essentially irreversible
SAM converted to SAH when it methylates acceptors
needed to make PC - has 3 SAM dependent methylation reactions
after methylation, hydrolyzed to homocysteine and adenosine (homocysteine can then be used for resynthesis of methionine or synthesis or cysteine and creatine and carnitine)
activated methyl cycle
methyl groups enter cycle via THF dependent synthesis of methionine
FIRST CYCLE:
1: methionine activated to SAM in ATP dependent step
2: SAM methylates substrates and is converted to SAH
3: SAH is hydrolysed to adenosine and homocysteine
4: homocysteine is remethylated in B12 dependent process using N5-methyl-THF by homocysteine methyltransferase - makes methionine and THF
OTHER CYCLE:
1: THF converted to N5,N10-methylene-THF using carbon from serine (makes glycine)
2: N5,N10-methylene-THF converted to N5-methyl-THF (uses NADPH)
3: N5-methyl-THF combined with homocysteine and used to regenerate THF and methionine (step 4 of first loop)
folate trap hypothesis
proposes that B12 deficiency causes N5-methyl-THF to accumulate at the expense of other forms of THF
N5,N10-methylene-THF reductase not reversible so cellular THF is depleted
results in folate deficiency
