Week 3 - Tetrahydrofolate, Vitamin B12, and S-Adenosylmethionine Flashcards
Describe how dietary folate and cobalamin are taken up from the diet and converted to active cofactors. Describe their different forms, and the types of reactions in which they participate, and the molecular basis for pathologies associated with their dietary or functional deficiency.
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Describe the molecular pathophysiology of: spina bifida, hyperhomocysteinemia, pernicious anemia, megaloblastic anemia, hereditary folate malabsorption, targeting folate metabolism for cancer treatment.
*key pathologies.. spinabifida - dont worry about mechanism..just pathology.
Describe the sources and recipients of one carbon transfer reactions. Describe how deficiency in cobalamin can affect other one carbon transfer reactions (the methyl trap hypothesis).
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*What are the oxidation states of carbon?
Reduced if has lots of H bound to it
What is outline of single carbon pool?
Refers to all different cofactors and substrates that bind cofactors to make single carbon transfers…FH4 is regenerated after carbon transfer..
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What is first place carbons bind?
FH4
What is the vitamin precursor for FH4?
Folate
Where does folate come from in diet?
Green leafy vegetables, liver, legumes, yeast, and fortified flour
Folic acid deficiency causes?
Malnutrition or malabsorption… Need more folate during pregnancy
Spina bifida
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Why are women recommended to take folate during pregnancy?
Because folate deficiency before or during pregnancy is associated with neural tube defects such as spina bifida Take 400 micrograms daily a month before and three months after getting pregnant
What happens to poly-glutamate tail on folate? What is folate reduced to in intestinal epithelial cells? In liver?
It is digested in the gut down to mono-glutamate N5-methyl tetrahydrofolate Polyglutamated in liver
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Hereditary folate malabsorption
Inherited mutation in the proton coupled folate transporter (PCFT) Causes functional folate deficiency despite adequate folate in diet
How is FH4 produced from folate?
It is reduced to FH2 and again to FH4 by enzyme DHFR
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What enzyme is used in Folate to FH4? What reducing agent?
DHFR - dihydrofolate reductase NADPH is reducing agent
What is active cofactor that can bind methyl groups?
FH4
After some reactions FH4 is turned back into FH2 and it needs to be reduced again back to FH4. What enzyme?
Dihydrofolate reductase
What is an important drug target in cancer? What drugs?
DHFR Methotrexate Trimethoprim Pyrimethamine
Methotrexate
Used in cancer (chemotherapy), rheumatoid arthritis
Trimethoprim
Antibacterial
Pyrimethamine
Antimalarial
FH4 to 5 methyl Fh4 reaction and intermediates
know the intermediate oxidation states.. 10 forymy., 5 10 methylene, 5 10 methyn, 5 methyl…
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What are we trying to make from FH4
5-methyl THF
What substrates can be combined with FH4 to make 5-methyl THF?
Formate Histitdine Serine (glycine)
If amino acid can degrade into acetyl coa and acetoacetate it is ketogenic..
so tryptophan is.
Formate + FH4 makes… What can it be reduced to?
10 formyl THF and water (-NH4 in two steps) 5-methyl THF (3 reductions)
Histidine + FH4 makes… What is it reduced to?
5,10 Methenyl THF (-NH4 in two steps) 5-methylTHF (2 reductions)
Serine + FH4 makes.. What is it reduced to? Enzyme?
Serine Hydroxymethyl transferase and PLP Makes Glycine and 5,10 methylene THF then it is reduced to 5-methyl THF
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