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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?. Figure 26-11 Degradation of amino acids to one of seven common metabolic intermediates. Page 995.

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Fch 532 lecture 24
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?


Figure 26 11 degradation of amino acids to one of seven common metabolic intermediates
Figure 26-11 Degradation of amino acids to one of seven common metabolic intermediates.

Page 995


Met degradation
Met degradation

  • 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

Methyltransferase

Adenosylhomocysteinase

Methionine synthase (B12)

Cystathionine -synthase (PLP)

Cystathionine -synthase (PLP)

-ketoacid dehydrogenase

Propionyl-CoA carboxylase (biotin)

Methylmalonyl-CoA racemase

Methylmalonyl-CoA mutase

Glycine cleavage system or serine hydroxymethyltransferase

N5,N10-methylene-tetrahydrofolate reductase (coenzyme B12 and FAD)

NADH, H+

Page 1002


Branched chain amino acid degradation
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

  • Branched-chain amino acid aminotransferase

  • Branched-chain keto acid dehydrogenase (BCKDH)

  • Acyl-CoA dehydrogeanse


Figure 26 21 the degradation of the branched chain amino acids a isoleucine b valine and c leucine
Figure 26-21 The degradation of the branched-chain amino acids (A) isoleucine, (B) valine, and (C) leucine.

Page 1004



After the three steps, for Ile, the pathway continues similar to fatty acid oxidation (propionyl-CoA carboxylase, methylmalonyl-CoA racemase, methylmalonyl-CoA mutase).

  • Enoyl-CoA hydratase - double bond hydration

  • -hydroxyacyl-CoA dehydrogenase- dehydrognation by NAD+

  • Acetyl-CoA acetyltransferase - thiolytic cleavage

Page 1004


For Valine: similar to fatty acid oxidation (propionyl-CoA carboxylase, methylmalonyl-CoA racemase, methylmalonyl-CoA mutase).

  • Enoyl-CoA hydratase - double bond hydration

  • -hydroxy-isobutyryl-CoA hydrolase -hydrolysis of CoA

  • hydroxyisobutyrate dehydrogenase - second dehydration

  • Methylmalonate semialdehyde dehydrogenase - oxidative carboxylation

    Last 3 steps similar to fatty acid oxidation

Page 1004


For Leucine: similar to fatty acid oxidation (propionyl-CoA carboxylase, methylmalonyl-CoA racemase, methylmalonyl-CoA mutase).

  • -methylcronyl-CoA carboxylase-carboxylation reaction (biotin)

  • -methylglutaconyl-CoA hydratase-hydration reaction

  • HMG-CoA lyase

    Acetoacetate can be converted to 2 acetyl-CoA

    Leucine is a ketogenic amino acid!

Page 1004


Leu and lys are ketogenic
Leu and Lys are ketogenic similar to fatty acid oxidation (propionyl-CoA carboxylase, methylmalonyl-CoA racemase, methylmalonyl-CoA mutase).

  • 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
Figure 26-23 similar to fatty acid oxidation (propionyl-CoA carboxylase, methylmalonyl-CoA racemase, methylmalonyl-CoA mutase). The pathway of lysine degradation in mammalian liver.

Saccharopine dehydrogenase (NADP+, Lys forming)

Saccharopine dehydrogenase (NAD+, Glu forming)

Aminoadipate semialdehyde dehydrogenase

Aminoadipate aminotransferase (PLP)

-keto acid dehydrogenase

Glutaryl-CoA dehydrogenase

Decarboxylase

Enoyl-CoA hydratase

-hydroxyacyl-CoA dehydrogenase

HMG-CoA synthase

HMG-CoA lyase

Page 1006


Trp is both glucogenic and ketogenic
Trp is both glucogenic and ketogenic similar to fatty acid oxidation (propionyl-CoA carboxylase, methylmalonyl-CoA racemase, methylmalonyl-CoA mutase).

  • Trp is broken down into Ala (pyruvate) and acetoacetate.

  • First 4 reactions lead to Ala and 3-hydroxyanthranilate.

  • Reactions 5-9 convert 3-hydroxyanthranilate to a-ketoadipate.

  • Reactions 10-16 are catalyzed by enzymes of reactions 5 - 11 in Lys degradation to yield acetoacetate.


Page 1007 similar to fatty acid oxidation (propionyl-CoA carboxylase, methylmalonyl-CoA racemase, methylmalonyl-CoA mutase).


1. Tryptophan-2,3-dioxygenase, 2. Formamidase, 3. Kynurenine-3-monooxygense, 4. kynureninase (PLP dependent)

Page 1007


Kynureinase another plp mechanism
Kynureinase, another PLP mechanism Kynurenine-3-monooxygense, 4. kynureninase (PLP dependent)

  • 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 3-hydroxykynurenine-PLP Schiff base.


Page 1008 Kynurenine-3-monooxygense, 4. kynureninase (PLP dependent)


6. Amino carboxymuiconate semialdehyde decarboxylase Kynurenine-3-monooxygense, 4. kynureninase (PLP dependent)

7. Aminomuconate semialdehyde dehydrogenase

8. Hydratase, 9. Dehydrogense 10-16. Reactions 5-11 in lysine degradation.

Page 1007


  • Kynurenine-3-monooxygense, 4. kynureninase (PLP dependent)-keto acid dehydrogenase

  • Glutaryl-CoA dehydrogenase

  • Decarboxylase

  • Enoyl-CoA hydratase

  • -hydroxyacyl-CoA dehydrogenase

  • HMG-CoA synthase

  • HMG-CoA lyase

Page 1006


Phe and tyr are degraded to fumarate and acetoacetate
Phe and Tyr are degraded to fumarate and acetoacetate Kynurenine-3-monooxygense, 4. kynureninase (PLP dependent)

  • The first step in Phe degradation is conversion to Tyr so both amino acids are degraded by the same pathway.

  • 6 reactions


  • Phenylanalnine hydroxylase Kynurenine-3-monooxygense, 4. kynureninase (PLP dependent)

  • Aminotransferase

  • p-hydroxyphenylpyruvate dioxygenase

  • Homogentisate dioxygenase

  • Maleylacetoacetate isomerase

  • Fumarylacetoacetase

Page 1009


Phenylalanine hydroxylase has biopterin cofactor
Phenylalanine hydroxylase has biopterin cofactor Kynurenine-3-monooxygense, 4. kynureninase (PLP dependent)

  • 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.


Figure 26 27 the pteridine ring the nucleus of biopterin and folate
Figure 26-27 Kynurenine-3-monooxygense, 4. kynureninase (PLP dependent) The pteridine ring, the nucleus of biopterin and folate.

Page 1009


Active bh 4 must be regenerated
Active BH Kynurenine-3-monooxygense, 4. kynureninase (PLP dependent)4 must be regenerated

  • 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-4a-cabinolamine by phenylalanine hydroxylase.

  • pterin-4a-cabinolamine is converted to 7,8-dihydrobiopterin (quinoid form) by pterin-4a-carbinoline dehydratase

  • 7,8-dihydrobiopterin (quinoid form) is reduced by dihydropteridine reductase to regenerate the active cofactor.


Page 1010 Kynurenine-3-monooxygense, 4. kynureninase (PLP dependent)


Nih shift
NIH shift Kynurenine-3-monooxygense, 4. kynureninase (PLP dependent)

  • 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 Kynurenine-3-monooxygense, 4. kynureninase (PLP dependent): activation of the enzyme’s BH4 and Fe(II) cofactors to yield pterin-4a-carbinolamine 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 acetoacetate1
Phe and Tyr are degraded to fumarate and acetoacetate Kynurenine-3-monooxygense, 4. kynureninase (PLP dependent)

  • 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)


  • Phenylanalnine hydroxylase Kynurenine-3-monooxygense, 4. kynureninase (PLP dependent)

  • Aminotransferase

  • p-hydroxyphenylpyruvate dioxygenase

  • Homogentisate dioxygenase

  • Maleylacetoacetate isomerase

  • Fumarylacetoacetase

Page 1009


Amino acids as precursors
Amino acids as precursors Kynurenine-3-monooxygense, 4. kynureninase (PLP dependent)

  • Amino acids are essential precursors to biomolecules:

  • Nucleotides

  • Nucleotide coenzymes

  • Heme

  • Hormones

  • Neurotransmitters

  • Glutathione


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