Nitrogen IV

Question 1

What amino acids formed succinyl CoA?

Answer 1

• methionine
• valine
• isoleucine
• threonine

Question 2

How is methionine used to make SAM?

Answer 2

1. Methionine

Methionine + ATP—> SAM (S-adenosylmethionine)

SAM is the major methyl-group donor in 1-C metabolism

Question 3

Explain in detail how methionine is made into SAM

Answer 3

ATP + methionine

Methionine adenosyl transferase. All three phosphates of ATP cleaved

Because the 🔼G of the reaction is very positive, and it must be overcome

All three phosphates of the ATP have been cleaved to force sulfur to hold a positive sulfur

Question 4

How does sulfur usually occur in organic compounds?

Answer 4

Have 2 bonds, 2 lone pairs and no charge

Question 5

Why does the sulfur in SAM have a positive charge?

Answer 5

The sulfur in SAM has a positive charge so it is activated, meaning it is chemically activated

Question 6

What is SAM used for?

Answer 6

Required for methylation reactions that require movement of -CH3

Note that the reactions using SAM are different than moving 1 carbon groups with THF

Question 7

What is the most reduced of the 1 carbon groups?

Answer 7

Methyl groups

Question 8

What is the function of THF?

Answer 8

Moves carbons in various. ‘Other’ oxidation states: (N- formyl, formyl, methenyl etc…)

Question 9

What 2 pathways detoxify homocysteine?

Answer 9

1. Methylate homocysteine to form methionine
2. Transfer the sulfur of homocysteine (which was originally methionine) to serine to form cysteine (trans-sulfuration pathway)

Question 10

Give a general description of detoxification of homocysteine

Answer 10

There are two major disposal pathways for homocystein. Conversion to methionine requires folate and vitamin B12 -derived coenzymes and is a remethylation process. The formation of cysteine requires vitamin B6 (pyroxidine) and is a trans sulfuration process- the sulfur of methionine becomes the sulfur of cysteine

Question 11

How can vitamin B6 be used to detoxify homocysteine?

Answer 11

• Cystathionine synthetase and cystathionase both require pyridoxal phosphate. (Vitamin B6)
• cystathionine beta-synthetase converts L-homocysteine to cystathionine (this part of reaction uses L-serine to make water
• cystathionine converted to L-cysteine

Enzyme: y-cystathionase

This second part of the reaction uses water and releases a-ketobutyrate + NH4+

Question 12

Why do Cystathionine synthetase and cystathionase both require pyridoxal phosphate. (Vitamin B6)?

Answer 12

Vitamin B6 (pyridixal phosphate ) helps to move around the function group (in this case the sulfur)

Question 13

What is the role of methyl THF?

Answer 13

The major role of methyl-THF is to support conversion of homocysteine into methionine

Resynthesis of methionine (methionine synthase)

-requires vitamin B12 and methyl-folic acid (THF-methyl)

Question 14

What does deficiency of vitamin B12 lead to?

Answer 14

Deficiency of vitamin B12 results in homocysteine accumulation and also the trapping of THF in the methyl-THF form (which is not useful for most reactions)

Question 15

Why does nature use vitamin B12?

Answer 15

Cobalamin

Cobalt is toxic, so nature uses B12 to (in a sense) put the cobalt “in a cage”

Enzymes hold B12 so that methyl groups can be moved around from a donor, to an acceptor substrate

Used to convert toxic homocysteine back to methionine

Methyl-THF + B12+ homocysteine—> methionine + empty THF

Question 16

What causes homocystinuria ?

Answer 16

Homocystinuria occurs due to a deficiency of cystathionine beta-synthase or homocysteine N-methyl transferase

Question 17

What are the features of homocystinuria?

Answer 17

Features: lens dislocation after age 3 and other ocular problems

• Childhood onset osteoporosis
• intellectual disability
• Atheroma formation due to oxidized lipid deposits (cardiovascular)
• Homocysteine can have other effect: lipid oxidation and platelet aggregation—> leads to fibrosis and calcification of atherosclerotic plaques

Question 18

Summarize how valine and isoleucine be converted to propionate-CoA

Answer 18

First: must get the N off of the amino acid so that it can enter a catabolic pathways (transamination). Now there is a branched-chain alpha keto acid

Then: oxidative decarboxylation: (branched chain a-keto acid dehydrogenase coenzymes: NAD, CoA, TPP, lipoic acid, FAD)- must activate the BC-alpha keto acid by forming the CoA derivative (same as we saw with Pyruvate DH complex)

In the end, we must discuss the fate of propinoyl CoA

Importaht: propinoyl CoA has 3 carbons

Question 19

What leads to maple syrup disease?

Answer 19

Oxidative decarboxylation of branched chain acids is deficient in maple syrup urine diseases

Question 20

Explain the final step of Succinate CoA(from propinoyl CoA )

Answer 20

1. Propinoyl CoA is converted to D-methylmalonyl-CoA via Propinoyl CoA carboxylase + Biotin /CO2
   - methylmalonyl CoA has 4 carbons but it is toxic and a dead end metabolite

D-methylmalonyl converted to L-methylmalonyl

Methylmalonyl -CoA mutase (enzyme ) +vitamin B12cam remove a methyl group from methylmalonyl CoA, and put it back on the same molecule, but in a different position, thus forming succinyl CoA

Question 21

Deficiency of the alpha keto acid dehydrogenase complex causes…

Answer 21

Maple syrup disease (MSUD)

Question 22

How is maple syrup disease caused?

Answer 22

Caused due to deficiency of alpha keto acid dehydrogenase (neurological problems, keto sis, hypotonia, seizure)

• propionyl carboxylase requires biotin
• methylmalonyl CoA metacentric requires B12

Question 23

What amino acids form Acetyl CoA or acetoacetate?

Answer 23

Leucine —> acetate (strictly ketogenic)

Lusine —> Acetyl CoA (strictly ketogenic)

Several other amino acids can be both keto and glucogenic