1. Basic Pathways of Amino Acid Degredation

2. 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.

3. 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)

4. Disease states associated with defective amino acid degradation

5. Amino acids as a source of energy
6 entry points to TCA cycle:
Fumarate
Pyruvate
Oxaloacetate
Succinyl-CoA
α-Ketoglutarate
Acetyl-CoA
Acetoacetyl-CoA

6. Six amino acids can be degraded to pyruvate (C3)
PLP enzymes can catalyze:
Transamination

7. Serine metabolism by PLP-enzymes
Instead 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.
PLP enzymes can catalyze:
Transamination
Elimination (Serine dehydratase)
Retro-Aldol (SHMT)

8. SHMT is the main source of C1 pool

9. Glycine (C2) Cleavage Reaction
Similar to pyruvate dehydrogenase complex:
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+
PLP enzymes can catalyze:
Transamination (aminotransferase)
Elimination (serine dehydratase)
Retro-aldol (SHMT)
Decarboxylation (glycine cleavage system)

10. Specificity of PLP-dependent reactions
Arg357
Bacterial SHMT
Dunathan hypothesis

11. Two amino acids can be degraded to oxaloacetate (C4)

12. Five amino acids can be degraded to α-ketoglutarate (C5)

13. Histidine ammonia lyase
First step in histidine degradation Enzyme generates its own methylidene imidazolone cofactor (MIO)
Retey, J. BBA 2003

14. Proline and arginine are degraded to glutamate semialdehyde

15. Seven amino acids can be degraded to acetyl-CoA

16. PLP-dependent kynureninase
Removal of the α-proton
Attack by activated water molecule
Cleavage of Cα-Cβ bond 1.
β-keto 2.
PLP enzymes can catalyze:
Transamination (aminotransferase)
Elimination (serine dehydratase)
Retro-aldol (SHMT)
Decarboxylation (glycine cleavage system)
Retro-Claisen (kynureninase) 3.

17. Phenylalanine Hydroxylase (PheH)
Catalyzes first step in phenylalanine degradation
Deficiency in this step causes the genetic disease phenylketonuria (PKU)

18. Phenylketonuria
Aspartame (Equal, Nutrasweet)

19. PheH is an aromatic amino acid hydroxylase

20. Control of activated oxygen species
Ordered mechanism-no chemistry until both substrates bind

21. Multiple genetic diseases are due to further deficiencies in Phe catabolism

22. Discovery of Genetic Diseases
The Incidence of Alkaptonuria:
A Study in Chemical Individuality
Archibald E. Garrod, 1902
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 carried
out on exactly the same lines.

23. Four amino acids can be converted to succinyl-CoA

24. Methionine degredation involves formation of a potent methylating agent

25. Branched chain amino acid degradation