Week 3 - Tetrahydrofolate, Vit. B12, and S-Adenosylmethionine - Skildum

Question 1

What is the most common source of methyl donation?

Answer 1

Serine! You got this!

Question 2

Why is folate important for pregnancy?

Answer 2

Folate deficiency is associated with Spina Bifida. (a neural tube defect that has very sad effects)

Question 3

What is the cause of Hereditary folate malabsorption?

Answer 3

It is inhertied mutation of the Proton Coupled Folate Transporter gene. (SLC46A1)

SO even if you eat enough folate, you’ve got deficiency. (This is the deficiency that we saw in our case study!)

Question 4

The enzyme responsible for reducing both folate to dihydrofolate and dihydrofolate to teatrahydrofolate?

Answer 4

Dihydrofolate reductase

Question 5

What drugs use Dihydrofolate reductase (DHFR) as a drug target?

Answer 5

Methotrexate (cancer/ rheumatoid arthriris)
Trimethoprim (antibacterial)
Primethamine (antimalarial)

Question 6

Tryptophan, Threonine, Isoleucine, Lysins, Leucine, Phenylalanine, and Tyrosine can all be degraded to which ketone body?

Answer 6

Acetoacetate

not sure if this is important

Question 7

What are the BASIC oxidation states of THF?

Answer 7

1: THF
2: 10-Formyl-THF
3: 5,10-Methenyl THF
4: 5,10-Methylene THF
5: 5-Methyl THF

The numbers are referring to what is either bound to the 5’ or 10’ nitrogen

Question 8

THF can be directly converted to 10-Formyl THF by using what source of carbon?

Answer 8

Formate

Question 9

IF histidine is used by THF as the methyl donor, what step of the THF cycle does it enter?

Answer 9

It skips right to the 5,10-Methenyl THF

This is after a 5-formimino THF intermediate

Question 10

What step of the THF reaction is IRREVERSIBLE? Why is this significant?

Answer 10

The reduction of 5,10-Methylene THF to 5-Methyl THF.

It is referred to as the “methyl trap.” This is because 5-Methyl THF’s ONLY metabolic fate is to combine with cobalamin to produce methylcobalamine. When there is no B12 (cobalmine), the 5-methyl THF is jsut stuck and can’t do any other methyl trasnfer reactions.

Question 11

Why do you get neurological problems with Vit B12 dietary or functional deficiency?

Answer 11

Vitamin B12 is necessary to the process of creating SAM (s-adenosylmethionine). Sam is then used to donate methyl groups to many substrates.

LIKE neurotransmitter precursors.

Question 12

When using serine as a source of carbon donation, which step of the THF process does it enter?

Answer 12

Serine and THF create:

5,10-Methylene THF

Question 13

Thymidine (nucleotide), purine bases, methionine, and s-adenosyl methionine (SAM) are ALL products of what kinds of reactions?

Answer 13

Carbon donation reactions!

Question 14

IN the case of folate deficiency, why would magaloblastic anemia be a problem?

Answer 14

Blood cells divide rapidly becuase there is such a high tunrover rate. This kind of division requires a lot of deoxynucleotides to synthesize DNA. When these nucleotides are unavailable the cell continues to grow until they are, which results in gigantic RBC’s. Not cool.

Question 15

Why is methotrexate an effective cancer drug?

Answer 15

It inhibits DHFR (dihydroxyfolate reductase). This is the enzyme that converts FH2 to FH4 and making it part of the process of converting dUMP to dTMP (Thymine). So stopping the creation of DNA, stops all of the fast replicating cells (prominent in cancer). Also gives unfortunate side effects of chemo.

Question 16

Why is 5-Fluooracil an effective cancer drug?

Answer 16

It inhibits thymidylate synthase. This is the reaction converting dUMP to dTMP (Thymine). BY inhibitng DNA production, you inhibit the fast-replicating cells. (This is how cancer cells usually are, so it targets them in particular)

Question 17

Why can Vit B12 deficiency have such similar effects as folate deficiency??

Answer 17

For biosynthetic pathways, carbon is not donated DIRECTLY from N5-methyl FH4. First it is donated to homocysteine (a rxn requiring B12) to make methionine. Then an adenosine base is added to make SAM. SAM is then used to add methyls for biosynthetic rxns.
(So without B12, its the same is if you didn’t have folate)

Question 18

What is the usefulness of adenosylcobalamin?

Answer 18

Catalyzes the rxn converting methylmalonyl-CoA to Succinyl-CoA.

CONNECTION from past material:
Catabolism of branched or odd-chain fatty acids creates: methylmalonyl CoA

Back to the TCA cycle!

Question 19

Let’s talk about Vitamin B12 absorption:

Try to give the main bulletpoints of the process :)

Answer 19

• B12 first attaches to R-binders in the stomach
• R-binders are digested off by proteases
• B12 is then bound to intrinsic factors secreted from parietal cells
• B12/intrinsic factor complex taken up in intestines
• Tranported through the blood complexed to transcobalamin II protein
• Stored in the liver with cubillin

Question 20

What is pernicious anemia?

Answer 20

megaloblastic anemia and neuropathy (pain and numbness in the extremities)

Question 21

Why could autoimmune destruction of parietal cells cause pernicious anemia?

Answer 21

• Parietal Cells are what secrete intrinsic factors
• Intrinsic factors usually complex with Vit B12 to allow it to be taken up in the blood by transcobalamine II protein
• An absorption problem of B12 is going to produce pernicious anemia
• BECAUSE b12 usually helps catalyze the conversion of FH2 to FH4, which goes on to make thymine

Question 22

Hyperhomocysteinemia can cause cardiovascular and neurological problems. Describe how this problem can occur.

Answer 22

1) mutation in methionine synthase. This catalyzes the trasnfer of methyl from methylcobalamin to turn homocystein into methionine
2) Cobalamine deficiency
3) Vit. B6 (PLP) deficiency. Important for converting homocysteine to Cystanthionine, and then Cystathionine to Cysteine.