M1-C1-L66 --> One Carbon Metabolism
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- What are the three parts of THF?
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1. 6-methylpterin
2. PABA (p-aminobenzoate)
3. Glutamate - Folate is synthesized by what?
- Plants and bacteria
- What is the maximum number of glutamates that can be attached to THF?
- 8
- 1 carbon units in varying oxidation states are carried at which Nitrogens?
- N5 and/or N10
- What is the order of successive additions in folate?
- PABA to 6-methylpterin. Then glutamate residues.
- What does sulfonamide antibiotics do?
- Inhibit the addition of PABA to 6-methylpterin.
- Sulfonamides are specific to what organism and why?
- Bacteria. Not in humans or vertebrates b/c don't synthesize folate.
- What is the enzyme responsible for folate synthesis in microorganisms?
- Dihydropteroate Synthetase
- What is the enzyme responsible for THF synthesis in humans?
- Dihydrofolate Reductase (DHFR)
- In the synthesis of THF, where do the reducing electrons come from?
- NADPH of the pentose pathway
- Additions of 1 carbon units on THF allows for what type of synthesis. x 3
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1. Purine synthesis
2. Amino Acid synthesis
3. Thymidine synthesis - What inhibits the enzyme DHFR and how?
- Methotrexate and aminopterin act as folate analogs to competitively inhibit DHFR.
- What is the main source of methyl groups on THF?
- Serine
- Where on Folate is there reduction to become THF?
- Nitrogen 5, 6, 7, 8
- What enzyme allows serine to donate methyl group?
- Serine hydroxymethyl transferase
- Serine + THF --> ?
- N5, N10 Methylene THF
- What is the enzyme that allows for N5, N10 Methylene THF to become N5 Methyl THF?
- N5, N10 Methylene THF Reductase
- What is the most reduced form of THF?
- N5 Methyl THF
- What is unusual about the THF reaction in TMP synthesis?
- N5, N10 Methylene THF not only provides a 1C unit, but it ALSO reduces the donated unit to a methyl group. Thus producing DHF
- What prevents DHF to becoming THF?
- Methotrexate
- When should there be increased folate requirements?
- During lactation and pregnancy.
- What would be some causes for insufficiency of intestinal absorption of folate?
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1. Intestinal pathology
2. Alcoholism - Name a birth defect and anemia that is caused by folate deficiency?
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1. Neural Tube Deficiency
2. Megaloblastic (macrocytic) anemia - For a person with macrocytic anemia, what happens to hematopoietic cells?
- Cell division requires folate. Thus, a person with folate deficiency will have hematopoietic cells arrested in S phase of cell cycle.
- Even on marginal diets deficient in folate, not all mothers gave birth to babies with NTD's. Why?
- Folate deficient NTD's result usually result from a common gene polymorphism in the gene for 5, 10 Methylene THF Reductase. Even though it is common, not having this polymorphism can lead to a baby without NTD's.
- What is the only cobalt-containing compound that participates in human metabolism.
- Vitamin B12 or Cobalamin
- Describe the importance of methylcobalamin in the intersection of vitamin B12 and THF metabolism.
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Methylcobalamin is a B12 coenzyme required for synthesis of methionine.
Methylcobalamin gets its methyl group from N5 methyl THF. In the absence of B12, this folate becomes trapped in this compound since the reduction leading to 5 methyl THF is irreversible. - Describe the importance of 5'-deoxyadenosylcobalamin in the intersection of vitamin B12 and THF metabolism.
- This is the coenzyme required in propionate oxidation, which is important in catabolism of amino acids and fatty acids with odd number carbons.
- How do you make SAM (S-adenosyl Methionine)?
- ATP + Methionine
- How do you get from SAM to SAH (S-adenosyl Homocysteine)?
- SAM donates a methyl group.
- How do you go from SAH to Hcy (Homocysteine)
- SAH gives up an adenosine.
- How does Hcy become methionine?
- Hcy picks up a methyl group from the B12 sitting on methionine synthase. This methyl group is replenished from N5-methyl THF
- In small cases, what melecule might substitute for N5-methyl THF in methionine synthesis?
- Betaine
- Describe SAM's ability to donate methyl group compared to N5-methyl THF?
- SAM is 1000x's more active as a methyl donor.
- SAM participates as methyl donor in which reactions/pathways? x5
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1. Phospholipid synthesis
2. Amino acid derivative synthesis
3. Catecholamine metabolism
4. Post-translational protein methylation
5. DNA methylation - SAM acts as an allosteric inhibitor of what? x2
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1. Inhibitor of methylene THF reductase (MTHFR)
2. Inhibitor betaine Hcy methyl transferase - SAM acts as an allosteric activator of what?
- Activator of cystathionine synthase (enzyme that catalyzes condensation of Hcy to serine)
- What regulates SAM synthesis?
- SAM
- When SAM levels are high, methyl donors are ?
- Decreased
- When SAM levels are high, homocysteine is used in what?
- Cysteine synthesis
- When SAM levels are low, methyl donors are?
- Abundant
- When SAM levels are low, homocysteine is used in what?
- Methionine synthesis.
- Hyperhomocysteinemia (elevated plasma Hcy) has what type of consequence? x3
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1. Homocystinuria
2. Pregnancy disorders
3. Vascular damage.