FCH 532 Lecture 24
Chapter 26: Amino acid metabolism
Wed. Urea cycle quiz
Friday: Ketogenic vs. glucogenic (or
both) amino acids-what common
metabolites do this amino acids go
towards?
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Figure 26-11 Degradation of amino
acids to one of seven common
metabolic intermediates.
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.
1.
Methionine adenosyltransferase
2.
Methyltransferase
3.
Adenosylhomocysteinase
4.
Methionine synthase (B12)
5.
Cystathionine -synthase (PLP)
6.
Cystathionine -synthase (PLP)
7.
-ketoacid dehydrogenase
NADH, H+
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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8.
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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!
Leu and Lys are 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.
Figure 26-23 The pathway
of lysine degradation in
mammalian liver.
Saccharopine dehydrogenase
(NADP+, Lys forming)
2.
Saccharopine dehydrogenase
(NAD+, Glu forming)
3.
Aminoadipate semialdehyde
dehydrogenase
4.
Aminoadipate
aminotransferase (PLP)
5.
-keto acid dehydrogenase
6.
Glutaryl-CoA dehydrogenase
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1.
7.
Decarboxylase
8.
Enoyl-CoA hydratase
9.
-hydroxyacyl-CoA
dehydrogenase
10. HMG-CoA synthase
11. HMG-CoA lyase
Trp is both glucogenic and
ketogenic
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Trp is broken down into Ala (pyruvate) and
acetoacetate.
First 4 reactions lead to Ala and 3hydroxyanthranilate.
Reactions 5-9 convert 3-hydroxyanthranilate to aketoadipate.
Reactions 10-16 are catalyzed by enzymes of
reactions 5 - 11 in Lys degradation to yield
acetoacetate.
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1. Tryptophan-2,3-dioxygenase, 2. Formamidase, 3.
Kynurenine-3-monooxygense, 4. kynureninase (PLP
dependent)
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Kynureinase, another PLP
mechanism
Reaction 4: cleavage of 3-hydroxykynurenine to alanine
and 3-hydroxyanthranilate is catalyzed by the PLP
dependent enzyme kynureinase.
This facilitates a C-C bond cleavage. (previous reactions
catalyzed the C-H and C-C bond cleavage)
Follows the same steps as transamination but does not
hydrolyze the tautomerized Schiff base.
Enzyme amino acid acts as a nucleophile tto attack the
carbonyl carbon (Cof the tautomerized 3hydroxykynurenine-PLP Schiff base.
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1008
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6. Amino carboxymuiconate semialdehyde decarboxylase
7. Aminomuconate semialdehyde dehydrogenase
8. Hydratase, 9. Dehydrogense 10-16. Reactions 5-11 in
lysine degradation.
-keto acid
dehydrogenase
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Glutaryl-CoA
dehydrogenase
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Decarboxylase
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Enoyl-CoA
hydratase
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-hydroxyacyl-CoA
dehydrogenase
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HMG-CoA
synthase
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HMG-CoA lyase
Phe and Tyr are degraded to
fumarate and acetoacetate
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The first step in Phe degradation is conversion to Tyr so both amino acids
are degraded by the same pathway.
6 reactions
1.
2.
3.
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4.
5.
6.
Phenylanalnine hydroxylase
Aminotransferase
p-hydroxyphenylpyruvate
dioxygenase
Homogentisate dioxygenase
Maleylacetoacetate isomerase
Fumarylacetoacetase
Phenylalanine hydroxylase has
biopterin cofactor
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1st reaction is a hydroxylation reaction by phenylalanine
hydroxylase (PAH), a non-heme-iron containing
homotetrameric enzyme.
Requires O2, FeII, and biopterin a pterin derivative.
Pterins have a pteridine ring (similar to flavins)
Folate derivatives (THF) also contain pterin rings.
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Figure 26-27 The
pteridine ring, the
nucleus of
biopterin and
folate.
Active BH4 must be regenerated
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Active form in PAH is 5,6,7,8-tetrahydrobiopterin (BH4)
Produced from 7,8-dihydrobiopterin via dihydrofolate
reductase (NADPH dependent).
5,6,7,8-tetrahydrobiopterin is hydroxylated to pterin-4acabinolamine by phenylalanine hydroxylase.
pterin-4a-cabinolamine is converted to 7,8dihydrobiopterin (quinoid form) by pterin-4a-carbinoline
dehydratase
7,8-dihydrobiopterin (quinoid form) is reduced by
dihydropteridine reductase to regenerate the active
cofactor.
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NIH shift
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A 3H that starts on C4 of Phe’s ring ends up on C3 of Tyr’s
ring rather than being lost to solvent.
Mechanism is called the NIH shift
1st characterized by scientists at NIH
1 and 2: activation of the
enzyme’s BH4 and Fe(II)
cofactors to yield pterin-4acarbinolamine and a reactive
oxyferryl [Fe(IV)=O2-]
3: Fe(IV)=O2- reacts with Phe
to form an epoxide across the
3,4 bond.
4: epoxide opening to form
carbocation at C3
5: migration of hydride from C4 to C3 to form
more stable carbocation.
6: ring aromatization to form Tyr
Phe and Tyr are degraded to
fumarate and acetoacetate
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The first step in Phe degradation is conversion to Tyr so both amino acids
are degraded by the same pathway.
6 reactions
Reaction 1 = 1st NIH shift
Reaction 3 is also an example of NIH shift (26-31)
1.
2.
3.
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4.
5.
6.
Phenylanalnine hydroxylase
Aminotransferase
p-hydroxyphenylpyruvate
dioxygenase
Homogentisate dioxygenase
Maleylacetoacetate isomerase
Fumarylacetoacetase
Amino acids as precursors
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Amino acids are essential precursors to biomolecules:
Nucleotides
Nucleotide coenzymes
Heme
Hormones
Neurotransmitters
Glutathione