Metabolic Disorders Of Branchedchain Amino Acid Catabolism

As the name implies, the odor of urine in maple syrup urine disease (branched-chain ketonuria) suggests maple syrup or burnt sugar. The biochemical defect involves the a-keto acid decarboxylase complex (reaction 2, Figure 30-19). Plasma and urinary levels of leucine, isoleucine, valine, a-keto acids, and a-hydroxy acids (reduced a-keto acids) are elevated. The mechanism of toxicity is unknown. Early diagnosis, especially prior to 1 week of age, employs enzymatic analysis. Prompt replacement of dietary protein by an amino acid mixture that lacks leucine, isoleucine, and valine averts brain damage and early mortality.

Mutation of the dihydrolipoate reductase component impairs decarboxylation of branched-chain a-keto acids, of pyruvate, and of a-ketoglutarate. In intermittent branched-chain ketonuria, the a-keto acid decarboxylase retains some activity, and symptoms occur later in life. The impaired enzyme in iso-valeric acidemia is isovaleryl-CoA dehydrogenase (reaction 3, Figure 30-19). Vomiting, acidosis, and coma follow ingestion of excess protein. Accumulated

CH2 CH

NH3+

NH3+

NH3+

NH3+

L-Leucine

a-Keto acid a-Amino acid

H,C CHo

H,C CHo a-Ketoisocaproate f CoASH

Isovaleryl-CoA

S~CoA

CH, O I II CC H3C CH S ~ CoA p-Methylcrotonyl-CoA

CH C

I II

CH3 O

L-Valine a-Keto acid

a-Amino acid

CH3 O a-Ketoisovalerate

CoASH

H3C^

CH S~CoA

Isobutyryl-CoA

H2C C

Methacrylyl-CoA

H3C CH C

I II

CH3 O

L-Isoleucine a-Keto acid

a-Amino acid

a-Keto-p-methylvalerate f CoASH

a-Methylbutyryl-CoA

CC H3C C S~CoA

Tiglyl-CoA

Figure 30-19. The analogous first three reactions in the catabolism of leucine, valine, and isoleucine. Note also the analogy of reactions © and © to reactions of the catabolism of fatty acids (see Figure 22-3). The analogy to fatty acid catabolism continues, as shown in subsequent figures.

CH3

11

C

CH

H3C" nCK S~CoA ß-Methylcrotonyl-CoA

^Biotinyl-*CO2

- Biotin

II C

ß-Methylglutaconyl-CoA

C* H3C.. OH c -o' ^CH^CH^ ^~S~CoA ß-Hydroxy-ß-methylglutaryl-CoA

CH2 CH3

O CH2

Acetoacetate

CH2 CH3

Figure 30-20. Catabolism of the p-methylcrotonyl-CoA formed from L-leucine. Asterisks indicate carbon atoms derived from CO2.

3C S~CoA Acetyl-CoA

Figure 30-20. Catabolism of the p-methylcrotonyl-CoA formed from L-leucine. Asterisks indicate carbon atoms derived from CO2.

CH3 Tiglyl-CoA

a-Methyl-ß-hydroxybutyryl-CoA

a-Methylacetoacetyl-CoA

f CoASH

a-Methylacetoacetyl-CoA

II II

Acetyl-CoA

Propionyl-CoA

Figure 30-21. Subsequent catabolism of the tiglyl-CoA formed from L-isoleucine.

Methacrylyl-CoA

"S~CoA

p-Hydroxyisobutyryl-CoA

2O CoASH

p-Hydroxyisobutyrate

CH OI

Methylmalonate semialdehyde a-AA '(TV)

a-KA

Methylmalonyl-CoA

p-Aminoisobutyrate

isovaleryl-CoA is hydrolyzed to isovalerate and excreted.

My Life My Diet

My Life My Diet

I lost over 60 pounds and 4+ inches off my waist without pills, strenuous exercise, or any of the things that the diet experts tell you to do...and I did it in less than 4 months! If you have the desire, and can read through my e-book , then this is for you! I could have easily made it a lot more difficult, with stacks of information that people will never read, but why?

Get My Free Ebook


Post a comment