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Basic Pathways of Amino Acid
Degredation
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)
Disease states associated with
defective amino acid degradation
Amino acids as a source of energy
6 entry points to TCA cycle:
Fumarate
Pyruvate
Oxaloacetate
Succinyl-CoA
α-Ketoglutarate
Acetyl-CoA
Acetoacetyl-CoA
Six amino acids can be degraded to
pyruvate (C3)
PLP enzymes can catalyze:
Transamination
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)
SHMT is the main source of C1 pool
Glycine (C2) Cleavage Reaction
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+
PLP enzymes can catalyze:
Transamination (aminotransferase)
Elimination (serine dehydratase)
Retro-aldol (SHMT)
Decarboxylation (glycine cleavage system)
Specificity of PLP-dependent reactions
Arg357
Bacterial SHMT
Dunathan hypothesis
Two amino acids can be degraded to
oxaloacetate (C4)
Five amino acids can be degraded to
α-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
1. Removal of the α-proton
1.
2. Attack by activated water molecule
3. Cleavage of Cα-Cβ bond
β-keto
2.
PLP enzymes can catalyze:
Transamination (aminotransferase)
Elimination (serine dehydratase)
Retro-aldol (SHMT)
Decarboxylation (glycine cleavage system)
Retro-Claisen (kynureninase)
3.
Phenylalanine Hydroxylase (PheH)
• Catalyzes first step in
phenylalanine
degradation
• Deficiency in this step
causes the genetic
disease
phenylketonuria (PKU)
Phenylketonuria
Aspartame (Equal, Nutrasweet)
PheH is an aromatic amino acid
hydroxylase
Control of activated oxygen species
Ordered mechanism-no chemistry until both substrates bind
Multiple genetic diseases are due to
further deficiencies in Phe catabolism
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.
Four amino acids can be converted to
succinyl-CoA
Methionine degredation involves
formation of a potent methylating agent
Branched chain amino acid
degradation