Tissue Uptake and Metabolism of Folate

Methyl-tetrahydrofolate from the intestinal mucosa circulates bound to albumin and is the main vitamer for uptake by extrahepatic tissues. Small amounts of other one-carbon substituted folates also circulate (about 10% to 15% of plasma folate is 10-formyl-tetrahydrofolate) and are also available for tissue uptake. There are two mechanisms for tissue uptake of folate  

The reduced folate transporter is a transmembrane protein with a high affinity for methyl-tetrahydrofolate and a low affinity for other vitamers. It is especially active in enterocytes and renal tubule epithelium, but is also found in other cells (Sirotnak and Tolner, 1999). 

The folate receptor is a glycophosphatidyl inositol anchored cell surface protein with a broader specificity that permits uptake of folate hy receptor-mediated endocytosis. At times of low folate requirement, the receptor is in intracellular vesicles, which migrate to the cell surface when the requirement for folate increases (Doucette and Stevens, 2001). 

Demethylated tetrahydrofolate monoglutamate is released hy extrahepatic tissues and is transported hound to a plasma folate binding protein similar to that in milk. It has a very low affinity for methyl-tetrahydrofolate and other one-carbon substituted derivatives. It functions mainly to return folate to the liver, where it is either conjugated for storage or methylated to 5-methyl-tetrahydrofolate that is secreted in the bile. 

Folate polyglutamate synthetase binds ATP, tetrahydrofolate-(oligo)-glutamate, then glutamate sequentially forming an intermediate folate 

---