Folate Absorption and Biochemistry

Harvard-MIT Division of Health Sciences and Technology HST.151: Principles of Pharmocology Instructor: Dr. Carl Rosow, Dr. David Standaert and Prof. Gary Strichartz Folate Absorption and Biochemistry Folate Uptake Spinach PABA Polyglutamated Folate (Fn) Glutamate Pteridine moiety Brush border folate hydrolase Intestinal Mucosa Blood Folate Enterohepatic circulation Me H4 Glutamate Jejunal/Ileal Lumen Me Liver H4 Other tissues Me H4 N5-methyl-tetrahydrofolate (Me-THF1) Me H4 H4 Me-THF (Me-FH4) Cbl THF (FH4) Me-Cbl Methionine Serine H4 THFn Homocysteine Folate Uptake TMP Synthesis Other folate reactions - Dietary folate is polylutamated - Hydrolyzed to monoglutamate form in jejunum/ileum by brush border folate hydrolase - Taken up by specific folate transporter in jejunum/ileum - Polyglutamation drives uptake in intestinal mucosa - Reduced and methylated to Me-THF for release into portal vein - 2/3 protein-bound in plasma - Taken up by liver and other tissues; demethylated to THF and polyglutamated again - Strong enterohepatic circulation - Malabsorption or dietary deficiency can cause symptoms within weeks or months - Vit. B12 (cobalamin) deficiency takes years to develop Biochemical Activities of Folate - One-carbon donor/acceptor - Nucleotide synthesis: purines (AMP, GMP) can also be synthesized by “salvage pathway”, but thymidine (methylation of dUTP to TMP) strictly requires folate - Amino acid metabolism: methionine synthesis from homocysteine; serine and glycine metabolism - Histidine, betaine, choline catabolism THF (FH4) Dihydrofolate reductase (DHFR) Glycine N5,10-CH2-THF (CH2-FH4) dUMP DHF (FH2) TMP Leucovorin Causes of Folate Deficiency - Decreased intake: poverty, famine, unusual diets - Increased requirements: pregnancy/lactation, hyperemesis gravidarum, prematurity/infancy - Malabsorption: congenital, drug-related?, tropical and non-tropical sprue - Defective cellular uptake (congenital) - Drugs: ethanol, sulfasalazine, oral contraceptives, anticonvulsants, antifolates (methotrexate, even trimethoprim and pyrimethamine in deficient patients) - Acute idiopathic