Lecture 8 Remethylation and Transsulfuration Pathways

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11 Apr 2012
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Lecture 8 Remethylation and Transsulfuration Pathways
Folate Structure
THF (tetrahydrofolate) central molecule
N5methyl THF –CH3
N10formyl THF –(C=O)H
N5N10methylene THF
Each serve different purposes
Folate Sources
Don’t use folacin
Folate is the generic descriptor
Folic acid is the synthetic form of the vitamer – very stable and inexpensive
New synthetic form called “Metafolin” (5-methyl-THF)
Folic acid fortification US/CAN – 1998 (to prevent neural defects)
Added to white flour, select grain products
Increases folic acid intake ~ 100μg
Dietary Sources
Excellent 55μg+, enriched grains, legumes, leafy greens
Good 33 μg+, corn beans sprouts
Top contributors of folate: orange juice, pasta, green salad
Bioavailability from supplements/fortification > natural dietary, because:
oMore stable
oNot trapped in cellular matrices
1dietary folate equivalent (DFE) = 1 μg food folate = 0.6 μg folic acid = 0.5 μg
synthetic folate taken on empty stomach
Folate aborption
proximal 1/3 SI
ofacilitated by GCPH folate conjugase (Zn-dependent exopeptidase), not rate
limiting
oproton coupled folate transporter (PCFT), transmembrane carrier
oreduced folate carrier (RFC), transmembrane carrier
ospecies specific mechanism of absorption
ofolates produced by bacteria in large intestine (rate of absorption slow, but
transit time in colon long net impact high
Folate metabolism
ofolate circulates in aqueous fraction of blood (serum) in -CH3 form
ounmetabolized folic acid in circulation in countries with fortified supply of food
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ofolate circulates as monoglutamyl form
o~2/3 folate in plasma is bound to albumin, α-2-macroglobulin (low affinity non-
specific binder)
osignificant concentration of high affinity binder in pregnancy, leukemia patients
(most folate bound)
ocellular transport
odiverse range of influx and efflux transporters
oOnce inside cell, folate polyglutamylated (traps folate)
oNecessary form of coenzyme
Function, Mechanism of action of Folate (Transfer of 1-C units)
oPurine synthesis
oPyrimidine synthesis
oAmino acid metabolism
oSer, Gly, Met, His
oRegeneration of Met from homocysteine
oRemethylation of homocysteine to produce Met
oAdditional methylation reactions via SAM
Genetic variation
oSNPS affect different enzymes in folate metabolism
o5,10-methyleneTHF reductase affected
opolymorph alters Ala for a Val (MTHFRC667T)
oDecreased enzyme activity
oIncreased folate intake stabilizes enzyme
Folate excretion
oUrinary excretion
oFolate freely filtered in glomerulus, reabsorbed in proximal renal tubule.
Net effect: most folate reabsorbed
oBulk products: para-acetamidobenzoate, para-acetamidobenzoylglutamate
oEnterohepatic circulation involves release of hepatic 5-CH3-THF into
bile with reabsorption in SI
Nutrition Assessment Approaches
oDietary
oWeighed food record, FFQ, 24h recall
oBiochemical
oPlasma folate concentration
oRBC folate concentration
oPlasma homocysteine
oMegaloblastic anemia
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