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M1 Renal: Folate Metabolism Dr. Robert Lyons Assistant Professor, Biological hemistry Director, DA Sequencing ore Web: http://seqcore.brcf.med.umich.edu/mcb500 Fall 008
Amino Acid metabolism Amino acids Folate metabolism Glu, Gln, Asp, Methylene TF Met ycle Urea oxaloacetate P u rin e s DA RA P y rim id in e s TA ycle fumarate Uric Acid (energy) ucleic Acid metabolism
Folate ( nearbon ) Pathways lick on any blue box to see details (Start with the section with Diet and follow the paths with red arrows) MethylTF onnects to Amino Acids Donation of one carbon (from Ser, Gly) MethyleneTF TF ycle Methionine ycle TF TF Diet: DF DF FormylTF Folate Folate onnects to ucleic Acids lectures Purine biosynthesis Thymidylate synthetase
Folic Acid is Synthesized By Bacteria ( ) n Paraaminobenzoic acid (PABA) S sulfanilamide Dietary folate: folic acid (meats, green veggies) *requires* the intestinal enzyme onjugase for absorption.
F ol ic ac id ( ) n ADP Di hy d ro fo l at e ADP ( ) n ADP T et ra hy d ro fo la te ADP ( ) n
F ol ic ac id ( ) n ADP Di hy d ro fo l at e ADP ( ) n ADP T et ra hy d ro fo la te ADP ( Inhibitors of DFR are important therapeutics: Methotrexate chemotherapy Trimethoprim inhibits bacterial DFR Pyrimethamine inhibits malarial DFR ) n
Tetrahydrofolate (et c) seri ne glycine (etc) 5, 10 methylene Tetrahydrofolate (et c) glycine AD 4 AD (etc) 5, 10 methylene
5 methyl AD Biosynthesis of methionine Gly Ser AD 5, 10 methylene ADP Biosynthesis of thymidylate 5, 10 methenyl ADP 10 formyl Biosyntheses purines of (et c) 5 methyl (et c) 10 formyl
S () Methionine () ATP PPi Pi () S Adenine () () SAdenosyl Methionine Methionine ycle And Biological Methyl Groups 5 methyl S () () omocysteine Bios ynthetic Methylation reaction S () Adenine Methyl acceptor * see examples Methylated acceptor () () SAdenosyl omocysteine () () Serine S () () ysteine (remainder of homocysteine degraded for energy)
5 methyl TF TF S homocysteine vitamin B 1 S meth ionine
(etc) Tetrahydrofolate arbon donor (e.g. serine or glycine) (etc) 5, 10 methylene meth ionine AD homocyste ine (etc) 5 methyl AD
S ATP PP i Pi S adeni ne Methionine SAdenosyl methionine orepinephrine SAM SA Epinephrine ther methyl acceptors: DA ( pg Islands ) RA
AD AD carb on dono r 5 methyl TF TF S homocysteine Adenosine vitamin B 1 meth ionine S ATP PP i P i S S adeno syl h omocys teine adenin e meth yl group don ated to bio logical sub strate S Sad enosyl meth ionine a denine
5 methyl AD Biosynthesis of methionine Gly Ser 5, 10 methylene ADP AD Biosynthesis of thymidylate 5, 10 methenyl ADP 10 formyl Biosyntheses purines Folate Deficiencies: Symptom: megaloblastic anemia Dietary deficiency: ommon especially in developing countries, lower socioeconomic classes of
Folate deficiency secondary to bowel irritation: onjugase is essential for adequate absorption of dietary folates onjugase production may be compromised by bowel irritation: Tropical Sprue bowel irritation probably arising from bacterial origin, causes intestinal inflamation and malabsorption. eliac Sprue similar outcome, but the original irritation is due to an allergic response, for example to gliaden (a component in gluten)
Folate Deficiency Secondary to B1 deficiency: the methyl trap hypothesis other TF reactions 5 methyl Biosynthesis of Methionine AD AD 5 10, methylene TF carbon donor 5, 10 methylene 10 formyl Biosynthesis of Thymidylate Biosyntheses Purines of 5 methyl TF TF homocysteine B 1 methionine B1 is also critical in other reactions, ones for which the deficiency has serious neurological consequences.
Additional Source Information for more information see: http://open.umich.edu/wiki/itationpolicy Slide 4: Robert Lyons Slide 5: Robert Lyons Slide 6: Robert Lyons Slide 7: Robert Lyons Slide 8: Robert Lyons Slide 9: Robert Lyons Slide 10: Robert Lyons Slide 11: Robert Lyons Slide 1: Robert Lyons Slide 1: Robert Lyons Slide 15: Robert Lyons Slide 16: Robert Lyons Slide 18: Robert Lyons