FCH 532 Lecture 23
Chapter 26: Amino acid metabolism
Alanine
aminotransferase
2. Serine dehydratase
3. Glycine cleavage
system
4, 5.Serine hydroxymethyltransferase
6. Threonine
dehydrogenase
7. -amino-ketobutyrate lyase.
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1.
Serine dehydratase
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PLP-enzyme forms a PLP-amino acid Schiff base (like
transamination) catalyzes removal of the amino-acid’s
hydrogen.
Substrate loses the -OH group undergoing an 
elimination of H2O rather than deamination.
Aminoacrylate, the product of this dehydration reaction,
tautomerizes to the imine which hydrolyzes to pyruvate and
ammonia.
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Figure 26-13 The serine dehydratase reaction.
1. Formation of Ser-PLP Schiff base, 2. Removal of the -H atom of serine, 3.  elimination
of OH-, 4. Hydrolysis of Schiff base, 5. Nonenzymatic tautomerization to the imine, 6.
Nonenzymatic hydrolysis to form pyruvate and ammonia.
Alanine
aminotransferase
2. Serine dehydratase
3. Glycine cleavage
system
4, 5.Serine
hydroxymethyltransferase
6. Threonine
dehydrogenase
7. -amino-ketobutyrate lyase.
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1.
Glycine conversion to pyruvate
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Gly is converted to Ser before it is transformed to pyruvate.
Gly to serine is catalyzed by serine
hydroxymethyltransferase (another PLP) enzyme that also
uses N5, N10-methylene-tetrahydrofolate (N5, N10-methyleneTHF) cofactor to proved the C1 unit necessary for this
conversion.
The methylene group is derived from another Gly and the
remaining parts are released as CO2 and ammonia catalyzed
by the glycine cleavage system
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Figure 26-14 The
reactions catalyzed by
the glycine cleavage
system, a multienzyme
complex.
1. PLP-dependent
glycine
decarboxylase (Pprotein)
2. Lipoamidecontaining protein
(H-protein)
3. THF requiring
enzyme (Tprotein)
4. NAD+-dependent,
FAD-requiring
dihydrolipoyl
dehydrogense (Lprotein)
Serine hydroxymethyltransferase
catalyzes PLP-dependent C-C
cleavage
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•
Catalyzes the conversion
of Thr to Gly and
acetaldehyde
Cleaves C-C bond by
delocalizing electrons of
the resulting carbanion into
the conjugated PLP ring:
H
B:
O H
H3C-HC--C-COON
H
C
2-O
H
O-
3PO
+
N
H
CH3
Asn and Asp are degraded to
OAA
•
Asp can be converted to Asp by L-asparaginase:
H O
O
C-CH2
H2N
-C-C-O-
Asparagine
NH3+
H2O
L-asparaginase
NH4+
O
H O
C-CH2-C-C-O-
-O
NH3+
Aspartate
Asn and Asp are degraded to
OAA
•
Transamination of aspartate to oxaloacetate:
H O
O
C-CH2
-O
-ketoglutarate
-C-C-O-
Aspartate
NH3+
aminotransferse
glutamate
O
O
C-CH2-C-C-O-O
O
Oxaloacetate
Arg, Glu, Gln, His, and Pro are degraded
to -KG
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Arg, Gln, His, and Pro are converted to Glu which is oxidized
to -ketoglutarate by glutamate dehydrogenase.
Gln to Glu is catalyzed by glutaminase
His requires several reactions to get to Glu.
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Figure 26-17
Degradati
on pathways of
arginine,
glutamate,
glutamine,
histidine, and
proline to ketoglutarate.
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Gln to Glu to -KG
2. Glutaminase
1. Glutamate dehydrogense
His to Glu
His is nonoxidatively
deaminated, hydrated,
and the imidazole ring is
cleaved to form Nformiminoglutamate
8. Histidine ammonia lyase
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9. Urocanate hydratase
10. Imidazolone proponase
11. Glutamate
formiminotransferase
Arg and Pro to Glu
3. Arginase
4. Ornithine-aminotransferase
5. Glutamate-5semialdehyde
dehydrogenase
6. Proline oxidase
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7. Spontaneous
Ile, Met and Val are degraded to succinylCoA
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Ile, Met, and Val are degraded to propionyl-CoA
Propioyl-CoA is a product of odd-chain fatty acid degradation
that is converted to succinyl-CoA via propionyl-CoA
carboxylase (biotin cofactor), methylmalonyl-CoA racemase,
and methylmalonyl-CoA mutase (B12 cofactor).
See Ch. 25-2E for review.
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Figure 25-18
Conversion
of propionyl-CoA to
succinyl-CoA.
Met degradation
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
•
Met reacts with ATP to form S-adenosylmethionine (SAM).
SAM’s sulfonium ion is a highly reactive methyl group so this compound is
involved in methylation reactions.
Methylation reactions catalyzed by SAM yield S-adenosylhomocysteine and a
methylated acceptor molecule.
S-adenosylhomocysteine is hydrolyzed to homocysteine.
Homocysteine may be methylated to regenerate Met, in a B12 requiring reaction
with N5-methyl-THF as the methyl donor.
Homocysteine can also combine with Ser to form cystathionine in a PLP
catalyzed reaction and -ketobutyrate.
-ketobutyrate is oxidized and CO2 is released to yield propionyl-CoA.
Propionyl-CoA proceeds thorugh to succinyl-CoA.
Methionine adenosyltransferase
2.
Methyltransferase
3.
Adenosylhomocysteinase
4.
Methionine synthase (B12)
5.
Cystathionine -synthase (PLP)
6.
Cystathionine -synthase (PLP)
7.
-ketoacid dehydrogenase
8.
Propionyl-CoA carboxylase (biotin)
9.
Methylmalonyl-CoA racemase
10.
Methylmalonyl-CoA mutase
11.
Glycine cleavage system or serine
hydroxymethyltransferase
12.
N5,N10-methylene-tetrahydrofolate
reductase (coenzyme B12 and
FAD)
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1.
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Page 922
Figure 25-18
Conversion
of propionyl-CoA to
succinyl-CoA.
Ile, Met and Val are degraded to succinylCoA
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•
•
Ile, Met, and Val are degraded to propionyl-CoA
Propioyl-CoA is a product of odd-chain fatty acid degradation
that is converted to succinyl-CoA via propionyl-CoA
carboxylase (biotin cofactor), methylmalonyl-CoA racemase,
and methylmalonyl-CoA mutase (B12 cofactor).
See Ch. 25-2E for review.
•
1.
2.
3.
Branched chain amino acid
degradation
Degradation of Ile, Leu, and Val use common enzymes for the
first three steps
Transamination to the corresponding -keto acid
Oxidative decarboxylation to the corresponding acyl-CoA
Dehydrogenation by FAD to form a double bond.
First three enzymes
1. Branched-chain amino acid aminotransferase
2. Branched-chain keto acid dehydrogenase (BCKDH)
3. Acyl-CoA dehydrogeanse
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Figure 26-21 The
degradation of the
branched-chain amino
acids (A) isoleucine,
(B) valine, and (C)
leucine.
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After the three steps, for Ile, the pathway
continues similar to fatty acid
oxidation (propionyl-CoA carboxylase,
methylmalonyl-CoA racemase,
methylmalonyl-CoA mutase).
4.
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5.
6.
Enoyl-CoA hydratase - double bond
hydration
-hydroxyacyl-CoA dehydrogenasedehydrognation by NAD+
Acetyl-CoA acetyltransferase thiolytic cleavage
For Valine:
Enoyl-CoA hydratase - double
bond hydration
8. -hydroxy-isobutyryl-CoA
hydrolase -hydrolysis of CoA
9. hydroxyisobutyrate
dehydrogenase - second
dehydration
10. Methylmalonate semialdehyde
dehydrogenase - oxidative
carboxylation
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7.
Last 3 steps similar to fatty acid
oxidation
For Leucine:
11. -methylcronyl-CoA carboxylasecarboxylation reaction (biotin)
12. -methylglutaconyl-CoA
hydratase-hydration reaction
13. HMG-CoA lyase
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Acetoacetate can be converted to 2
acetyl-CoA
Leucine is a ketogenic amino acid!
Lys is also ketogenic
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Leu proceeds through a typical branched amino acid breakdown but the
final products are acetyl-CoA and acetoacetate.
Most common Lys degradative pathway in liver goes through the
formation of the -ketoglutarate-lysine adduct saccharopine.
7 of 11 reactions are found in other pathways.
Reaction 4: PLP-dependent transamination
Reaction 5: oxidative decarboxylation of an a-keto acid by a multienzyme
complex similar to pyruvate dehydragense and a-ketoglutarate
dehydrogenase.
Reactions 6,8,9: fatty acyl-CoA oxidation.
Reactions 10 and 11 are standard ketone body formation reactions.
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