 KG + 3NADPH + NH 3 + 2ATP ---> proline + 3NADP + + 2ADP + 2P i  KG + NADPH + NH 3 + ATP ---> glutamate + NADP + + ADP + P i

Proline degradation Proline Pyrroline-5-carboxylate

Non-enzymatic

Glutamate semialdehyde dehydrogenase Glutamate semialdehyde Glutamate

So….Proline = glutamate If: Glu =  -ketoglutarate + NADPH + NH 3 Then: Pro =  -ketoglutarate + NADPH + NH 3 If:  -ketoglutarate = 4 NADH + 2 GTP + 2 FADH 2 + NADPH Then: Pro = 4 NADH +2 GTP + 2 FADH NADPH + NH 3 If: NADH = 3 ATP GTP = ATP FADH 2 = 2 ATP NH 3 = -2 ATP Then: Pro = 16 ATP + 2 NADPH

Arginine Degradation Arginase

Ornithine-  -aminotransferase

Glutamate semialdehyde dehydrogenase Glutamate semialdehyde Glutamate

 KG + Acetyl-CoA + 4NADPH + 3NH 3 + 7ATP + CO 2 ---> arginine + 4NADP + + 6ADP + 1AMP+ 6P i + 1PP i  KG + NADPH + NH 3 + ATP ---> glutamate + NADP + + ADP + P i

So…Arg = Glutamate + NADPH + NH 3 If: Glu =  -ketoglutarate + NADPH + NH 3 Then: Arg =  -ketoglutarate + 2 NADPH + 2 NH 3 If:  -ketoglutarate = 4 NADH + 2 GTP + 2 FADH 2 + NADPH Then: Arg = 4 NADH +2 GTP +2 FADH NADPH + 2NH 3 If: NADH = 3 ATP GTP = ATP FADH 2 = 2 ATP NH 3 = -2 ATP Then: Arg = 14 ATP + 3 NADPH What is the problem with arginine degradation?

alpha-ketoglutarate glutamate glutamate semialdehyde prolineN-acetylglutamate semialdehyde arginine Control point

oxaloacetate + NADPH + NH 3 + ATP ---> aspartate + NADP + + ADP + P i Remember the cost of aspartate

Epimerase

oxaloacetate + 4NADPH + 2NH 3 + 3ATP + pyruvate + succinyl-CoA ---> lysine + 4NADP + + 3ADP + 3P i + CO 2

This is this is not the only way to make lysine Homocitrate synthase Homoaconitase Homoisocitrate DH  -ketoadipate

 -KG + acetyl-CoA + + 2NH 3 + 2NAD + + 4ATP + 4NADPH ---> Lysine + CO 2 + 2NADH + 4NADP + + 4ADP + 4P i

Lysine Degradation NADPH

 -ketoadipate NAD+

FADH2 NADH

So…Lysine = NADH +  -ketoadipate + 2 NH 3 If:  -ketoadipate = 2 NADH + FADH Acetyl-CoA Then: Lys = 3 NADH + FADH Acetyl-CoA + 2 NH 3 If: Acetyl-CoA = 3 NADH + FADH 2 + GTP Then: Lys = 9 NADH + 3 FADH GTP + 2 NH 3 If GTP = ATP, NADH = 3 ATP FADH 2 = 2 ATP and NH 3 = -2 ATP Then: Lys = 35 ATP

oxaloacetate + 3NADPH + NH 3 + 3ATP ---> threonine + 3NADP + + 3ADP + 3P i

gamma lyase/beta synthase

Threonine can be degraded in three ways (1) Threonine dehydrogenase pathway Threonine Dehydrogenase

Must break C  -C  bond on an amino acid and stabilize a carbanion

2-amino-  -ketobutyrate lyase

What happens to the glycine? Glycine Cleavage System: trifunctional enzyme STEP1: decarboxylation of glycine

THF N 5,N 10 -methylene-THF STEP 2: formation of N 5,N 10 -methylene-THF

NAD + NADH STEP 3: regeneration of catalytic site

There is another pathway of glycine degradation From glycine cleavage system Combine the glycine cleavage system with a reverse of the serine hydroxymethyltransferase rxn

So…2 glycine = 1 serine + NADH + NH 3

If: Ser = pyruvate + NH 3 If: 2 Gly = serine + NADH + NH 3 Then: 2 Gly = 14 ATP, 1 Gly = 7 ATP Then: 2 Gly = pyruvate + NADH + 2 NH 3 If: Pyruvate = 4 NADH + GTP + FADH 2 Then: 2 Gly = 5 NADH + GTP + FADH NH 3 If: NADH = 3 ATP GTP = ATP FADH 2 = 2 ATP NH 3 = -2 ATP

If: glycine is degraded by glycine cleavage system you get 1 N 5,N 10 - methylene tetrahydrofolate, NH 3 and NADH If Acetyl-CoA = 3 NADH + GTP + FADH 2 So… Thr = Gly + Acetyl-CoA + NADH Then: Thr = N 5,N 10 -THF + NH NADH + Acetyl-CoA Then: Thr = N 5,N 10 -THF + NH NADH + GTP + FADH 2 If NADH = 3 ATP GTP = ATP FADH 2 = 2 ATP NH 3 = -2 ATP Then: Thr = N 5,N 10 -THF + 16 ATP

If: 2 Thr are degraded to 2 Gly If: 1 Gly = N 5,N 10 - THF + 1 NH NADH by glycine cleavage system Then: 2 Thr = 2 Gly + 2 NADH + 2 Acetyl-CoA And 1 Gly + N 5,N 10 -methylene tetrahydrofolate = serine by serine hydroxymethyltransferase If: Ser = pyruvate + NH 3 Then: 2 Thr = 1 NH NADH + 2 Acetyl-CoA + serine Then: 2 Thr = 2 NH NADH + 2 Acetyl-CoA + pyruvate If: Acetyl-CoA = 3 NADH + GTP + FADH 2 Pyruvate = 4 NADH +GTP + FADH 2 Then: 2 Thr = 2 NH NADH + 3GTP + 3 FADH 2 If: GTP = ATP, NADH = 3 ATP FADH 2 = 2 ATP and NH 3 = -2 ATP Then: 2 Thr = 44 ATP, Thr = 22 ATP

(2) Threonine can be degraded by serine hydroxymethyltransferase

What happens to acetaldehyde: can’t be put onto THF NAD + NADH Thr = glycine + Acetyl-CoA + NADH Acetaldehyde dehydrogenase

If: glycine is degraded by glycine cleavage system you get 1 N 5,N 10 - methylene tetrahydrofolate, NH 3 and NADH If Acetyl-CoA = 3 NADH + GTP + FADH 2 Thus: Thr = Gly + Acetyl-CoA + NADH Then: Thr = N 5,N 10 -THF + NH 3 + 2NADH + Acetyl-CoA Then: Thr = N 5,N 10 -THF + NH NADH + GTP + FADH 2 If NADH = 3 ATP GTP = ATP FADH 2 = 2 ATP NH 3 = -2 ATP Then: Thr = N 5,N 10 -THF + 16 ATP

(3) Threonine can be converted to  -ketobutyrate by threonine (serine) dehydratase

What happens to  -ketobutyrate?  -ketobutyrate dehydrogenase Same mechanism as pyruvate dehydrogenase and  -ketoglutarate dehydrogenase.

Thr = propionyl-CoA + NADH NAD + NADH

What happens to propionyl-CoA?: Propionyl-CoA carboxylase Loss of ATP!

Methylmalonyl-CoA epimerase: Why?

Stability order of radicals allylic > R 3 C > R 2 CH > RCH 2 > CH 3 > vinylic

So… Thr = succinyl-CoA - ATP + NADH If: Succinyl-CoA = malate + GTP + FADH 2 Then: Thr = malate + GTP - ATP + NADH + FADH 2 If: Malate = pyruvate + NADPH - NADH If: Pyruvate ---> 4 NADH + GTP + FADH 2 Then: Thr = FADH 2 + pyruvate + NADPH Then: Thr = 4NADH + GTP + 2 FADH 2 + NADPH If GTP = ATP, NADH = 3 ATP FADH 2 = 2 ATP and NH 3 = -2 ATP Then: Thr = 17 ATP + NADPH If: GTP = ATP Then: Thr = malate + NADH + FADH 2

Degradation of glycine by this pathway makes 1 N 5,N 10 - methylene tetrahydrofolate, NH 3 and NADH If: NADH is 3 ATP but NH 3 is -2 ATP Then: Gly = 1 ATP + 1 N 5,N 10 -THF

Asp semialdehyde lysinethreonine/methionine

homoserine O-succinylhomoserine O-phosphohomoserine methionine threonine

oxaloacetate + 3NADPH + 2ATP + succinyl-CoA + cysteine + N 5 -methyl-THF ---> methionine + succinate + pyruvate + 3NADP + + 2ADP + 2P i N 5 -methyl-THF comes from serine ---> glycine + N 5,N 10 -methylene THF N 5,N 10 -methylene THF + NADH ---> N 5 -methyl THF + NAD +

2 ways to degrade serine. (1) Serine dehydratase breaks the C  -C  bond

Serine is converted to pyruvate + NH 3 at no cost

If: Pyruvate = 4 NADH + 1 FADH 2 + GTP Then: Ser = 13 ATP So: Ser = pyruvate + NH 3 Then: Ser = 4 NADH + FADH 2 + GTP + NH 3 If: NADH = 3 ATP GTP = ATP FADH 2 = 2 ATP NH 3 = -2 ATP

(2) Serine hydroxymethyltransferase: bifunctional enzyme STEP 1: formation of glycine

What happens to formaldehyde? STEP 2: formation of N 5,N 10 -methylene-THF Serine hydroxymethyl transferase can be run in reverse to make serine from glycine and N 5,N 10 -methylene THF

3-phosphoglycerate + NAD + + NADPH + NH ATP ---> Serine + NADH + NADP + + ADP + 2P i 3-phosphoglycerate + NAD + + NADPH + NH ATP + THF ---> glycine + NADH + NADP + + ADP + 2P i + N 5,N 10 -methylene THF CO 2 + NH N 5,N 10 -methylene THF + NADH ---> Glycine + THF + NAD + Reverse the glycine cleavage system

What happens to glycine? Glycine Cleavage System: trifunctional enzyme STEP1: decarboxylation of glycine

THF N 5,N 10 -methylene-THF STEP 2: formation of N 5,N 10 -methylene-THF

So…degradation of serine with serine hydroxymethyltransferase followed by the glycine cleavage system makes 2 N 5,N 10 - methylene-THF, NH 3 and NADH NAD + NADH If: NADH is 3 ATP but NH 3 is -2 ATP Then: Ser = 1 ATP + 2 N 5,N 10 -THF STEP 3: regeneration of catalytic site

Degradation of glycine by this pathway makes 1 N 5,N 10 - methylene tetrahydrofolate, NH 3 and NADH If: NADH is 3 ATP but NH 3 is -2 ATP Then: Gly = 1 ATP + 1 N 5,N 10 -THF

There is another pathway of glycine degradation From glycine cleavage system Combine the glycine cleavage system with a reverse of the serine hydroxymethyltransferase rxn

So…2 glycine = 1 serine + NADH + NH 3

If: Ser = pyruvate + NH 3 If: 2 Gly = serine + NADH + NH 3 Then: 2 Gly = 14 ATP, 1 Gly = 7 ATP Then: 2 Gly = pyruvate + NADH + 2 NH 3 If: Pyruvate = 4 NADH + GTP + FADH 2 Then: 2 Gly = 5 NADH + GTP + FADH NH 3 If: NADH = 3 ATP GTP = ATP FADH 2 = 2 ATP NH 3 = -2 ATP

Pyruvate + NH 3 + ATP + NADPH ---> alanine + ADP + P i + NADP +