2: One-Carbon Metabolism

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What are the one-carbon carriers?

FH4 - carries 1 C groups of various oxidation states
SAM - methylates
Vitamin B12 (cobalamin) - methylates homocysteine to methionine
Biotin - carries CO2 in carboxylation reactions

where does FH4 get its carbons?

serine
glycine
histidine
formaldehyde
formate

How do you make tetrahydrofolate (FH4)?

take in folate through diet then slap on some glutamate residues

use dihydrofolate reductase and NADPH to reduce folate to FH2 and then again to FH4

What are the the 4 one carbon forms of FH4? what amino acids do they come from?

5,10-methylene-FH4 from serine and some glycine
5,10-methenyl-FH4 from histidine
10-formyl-FH4 from Trp
5-methyl-FH4 from conversion from 5,10-methylene-FH4

What is the 1C pool trap?

the various methylated forms of FH4 can be interconverted back and forth except 5-methyl-FH4 which can't be reoxidized 5,10-methylene-NH4

which form of FH4 is involved in dUMP to dTMP? describe rxn

5,10-methylene FH4 oxidizes dUMP to dTMP via thymidylate synthase
the resulting FH2 gets reduced back to FH4 via NADPH and dihydrofolate reductase
Serine does its thing to FH4 reforming 5,10-methylene FH4

What are inhibitors of the enzymes in the dUMP to dTMP process? what's the ultimate result?

methotrexate inhibits dihydrofolate reductase

5-FdUMP (5-flourouracil) inhibits thymidylate synthase

thus, these drugs decrease rate of cell division (cancer)

how do some antibiotics kill bacteria? what are they?

bacteria make folate bc they dont have the transporter to bring them in. certain antibiotics target bacterial folate metabolism

sulfa drugs act as analogs to PABA (an intermediate in synthesis) to block folate production
trimethoprim inhibits bacterial dihydrofolate reductase
bactrim (for UTIs) contains trimethoprim and sulfamethoxazole

How is B12 absorbed?

B12 binds to intrinsic factor (IF) in stomach (from parietal cells).
B12-IF then gets absorbed in the ileum and carried in the blood to the liver via transcobalamins (TC)
B12 is stored in liver

What is pernicious anemia?

a lack of intrinsic factor --> B12 deficiency --> megaloblastic anemia and neurological deterioration

How is cobalamin absorbed and activated? (what state is Co ion in)

in liver absorbed with Co in 3+ oxidation state (1+ is active)
a reductase in the cytoplasm reduces it to 2+ which can enter the mitochondria or stay in the cytoplasm.

mitochondria: reductase reduces it again to 1+ which allows it to do methylmalonyl CoA --> Succinyl CoA

cytosol: methionine synthase reductase reduces it to 1+, it then picks up a methyl from 5-methyl-FH4 and helps methylate homocysteine to methionine (via methionine synthase)

what form of B12 is used in methylmalonyl CoA --> succinyl CoA? where do you see this rxn?

deoxyadenosyl - B12 along with the enzyme methylmalonyl CoA mutase

rxn important in catabolism of some branched-chain amino acids and odd-chain fatty acids

how is SAM made? (reactant, enzyme)

L-methionine gets added to the adenosyl in ATP resulting in the kicking off of 3 Ps

enzyme used = methionine adenosyl transferase

What are some rxns that use SAM?

norepinephrine --> epinephrine (from tyrosine)
guanidinoacetate --> creatine
PE --> PC
acetylserotonin --> melatonin (from tryptophan)

what's the sequence of the activated methyl cycle?

SAM is made from methionine and ATP, when SAM --> SAH which can be converted to homocysteine (kick off adenosine)
methyl-FH4 gives methyl to B12 forming methyl-B12
methyl-B12 gives methyl to homocysteine reforming methionine

High levels of homocysteine or homocystine could indicate what?

B12 deficiency
methionine synthase deficiency
folate deficiency
errors in cysteine biosynthesis

what molecule is found in most carboxylases?

biotin biatch (prosthetic group)

attached to lysine residue in carboxylase enzyme
activates and transfers CO2 (uses ATP) (ex-pyruvate to OAA)

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