Biochem Lecture 34 (C1 Metabolism)

Question 1

Which molecules are able to donate a carbon to this C1 synthesis pathway?

Answer 1

serine (major player)

histidine

formate

Question 2

What is likely the most common vitamin deficiency in the U.S.? Why?

Answer 2

folic acid

due to overcooking, EtOH-ism, incr need during preg

Question 3

How is folic acid metabolized?

Answer 3

folic acid is an essential vitamin (i.e. we can’t make it)

IN THE GUT: folic acid—DHFR—>THF

DHFR = dihydrofolate reductase

THF = tetrahydrofolate

IN PERIPH CELL: polyglutamation at PABA end (prevents it from leaving the cell)

Question 4

How is serine used as a 1-carbon source?

Answer 4

Ser—serine hydroxymethyltransferase—>Gly

this meanwhile converts THF to N5, N10-methenyl-THF

**Again this is the major source of C1 carbons**

Question 5

How does Histidine donate a carbon to C1 synthesis? Which metabolite in this pathway used to be used to measure plasma [folate] indirectly? Why?

Answer 5

His—bunch—’o—steps—>N-Formimino-glutamate—formiminotransferase—>glutatamte

This last step is coupled with THF—>5-formiminoTHF—>N5,N10—Methenyl-THF

N-formimino glutamate used to be used as indirect sign of folate deficiency because the ref range for plasma [folate] is so low that it is tricky to measure.

Question 6

What oxidation state does THF carry these single carbons?

Answer 6

It varies. Different pathways require different oxidation levels (e.g. methionine synthesis require methyl, = most reduced)

Question 7

How do you synthesize methionine once you have N5,N10-Methylene-THF?

Answer 7

FIRST STEP

N5,N10-Methylene-THF

—N5,N10-Methylene-THF reducatase—> **IRREVERSIBLE

N5-Methylene-THF

SECOND STEP

homocysteine + N5-Methylene-THF

—homocysteine methyltransferase—> **Vit B12 req’d

methionine + THF (regenerated)

Question 8

What is the fate of L-methionine once synth’d?

Answer 8

adenosylated into S-adenosylMethionine (SAM):

ATP + L-Met—S-Adenosyl methionine synthase—>SAM + Pi + PPi

SAM has an “activated” CH3 which it can now donate to various molecules

Question 9

What are some examples of molecules synthesize from CH3 donation from SAM?

Answer 9

phosphatidyl choline (see image)

creatine

carnitine

epinephrine

Question 10

What happens in B12 deficiency?

What other deficinency does this imitate?

Answer 10

Without B12 (cyanocolbamin), N5-Methylene-THF cannot by converted back to THF by the enzyme homocysteine methyltransferase

However, N10,N5-Methylene-THF is still being converted to N5-Methylene-THF b/c the action of N10,N5-Methylene-THF reductase is irreversible

Therefore, N5-Methylene-THF builds up at the expense of other forms of THF which are need for purine synthesis, e.g.

This leads to problems with cell division—>megaloblastic anemia (RBCs grow w/o dividing so get really big)

Folate deficiency causes similar effects.