Pathways of Amino Acid Degredation

Lehninger 18.3

1/16/09

Overview• We cannot store amino acids so they are

converted into intermediates in metabolic or biosynthetic pathways. Malfunctions in these degradation pathways lead to a number of disease states.

• The carbon chains of the amino acids are converted to various intermediates based on chemical logic.

• Several enzyme cofactors are utilized in order to accomplish degradation.

Why do we need protein in our diet?

• Essential amino acid uptake for protein synthesis• Amino acids can be converted to biologically active

nitrogenous products

• Carbon chains of amino acids are very reduced (e.g. good source of energy)

CO2-N

CH3

NH

HN-2O3PO

HO

OH

NH3+

NN

NH3+

NO

creatine phosphate dopamine histamine nitric oxide

Disease states associated with defective amino acid degradation

Amino acids as a source of energy6 entry points to TCA

cycle:FumaratePyruvateOxaloacetateSuccinyl-CoAα-KetoglutarateAcetyl-CoAAcetoacetyl-CoA

Six amino acids can be degraded to pyruvate (C3)

PLP enzymes can catalyze:Transamination

Serine metabolism by PLP-enzymesInstead of electrons feeding into PLP, the β-hydroxy group can be eliminated from serine to ultimately form pyruvate.

Serine can also be converted to glycine by serine hydroxymethyltransferase.

N C HCO2

-

HO

:B

N C HCO2

- + CH2O

H:B

N C HCO2

-

H

+H3N C HCO2

-

H

Enz-PLP

glycine

H2N C HCO2

-

HO

serine

Enz-PLP

PLP enzymes can catalyze:TransaminationElimination (Serine dehydratase)Retro-Aldol (SHMT)

SHMT is the main source of C1 pool

Glycine (C2) Cleavage Reaction

PLP enzymes can catalyze:Transamination (aminotransferase)Elimination (serine dehydratase)Retro-aldol (SHMT)Decarboxylation (glycine cleavage system)

Similar to pyruvate dehydrogenase complex:

1.PLP-dependent decarboxylation

2,3. Lipoamide reaction, PLP cleavage

4. Loss of ammonia and one-carbon transfer to tetrahydrofolate

5. Oxidation of lipoamide by NAD+

Specificity of PLP-dependent reactions

N

CCO2

-

R

H

N

CR

H

CO2-

N

CH

CO2-

R

Dunathan hypothesis

Arg357

Bacterial SHMT

Two amino acids can be degraded to oxaloacetate (C4)

Five amino acids can be degraded toα-ketoglutarate (C5)

Histidine ammonia lyase

First step in histidine degradation

Enzyme generates its own methylidene imidazolone cofactor (MIO)

Retey, J. BBA 2003

Proline and arginine are degraded to glutamate semialdehyde

Seven amino acids can be degraded to acetyl-CoA

PLP-dependent kynureninase

HC

N C

CO2-

HO

R

B:

H2C

N C

CO2-

O

R

:OH

H2C

NH

C

CO2-

O

RHO

CH2

β-keto

PLP enzymes can catalyze:Transamination (aminotransferase)Elimination (serine dehydratase)Retro-aldol (SHMT)Decarboxylation (glycine cleavage system)Retro-Claisen (kynureninase)

1. Removal of the α-proton

2. Attack by activated water molecule

3. Cleavage of Cα-Cβ bond

1.

2.

3.

Phenylalanine Hydroxylase (PheH)

• Catalyzes first step in phenylalanine degradation

• Deficiency in this step causes the genetic disease phenylketonuria (PKU)

Phenylketonuria

ONH

+H3N

O

-O

O

O

Aspartame (Equal, Nutrasweet)

PheH is an aromatic amino acid hydroxylase

Control of activated oxygen species

NH

HN

NH

N NH2

O

R

H

H

H

O2

NH

HN

NH

N NH2

O

R

H

H

H

O2

NH

HN

N

N NH2

O

R

H

H

H

O

O

Ordered mechanism-no chemistry until both substrates bind

Multiple genetic diseases are due to further deficiencies in Phe catabolism

Discovery of Genetic Diseases

If it be, indeed, the case that in alkaptonuria and the other conditions mentioned we are dealing with individualities of metabolism and not with the results of morbid processes the thought naturally presents itself that these are merely extreme examples of variations of chemical behaviour which are probably everywhere present in minor degree, and just as no two individuals of a species are absolutely identical in bodily structure neither are their chemical processes carriedout on exactly the same lines.

The Incidence of Alkaptonuria: A Study in Chemical IndividualityArchibald E. Garrod, 1902

Four amino acids can be converted to succinyl-CoA

Methionine degredation involves formation of a potent methylating agent

Branched chain amino acid degradation