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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.


Fch 532 lecture 24

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



Fch 532 lecture 24

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


Fch 532 lecture 24

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


Fch 532 lecture 24

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.


Fch 532 lecture 24

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


Fch 532 lecture 24

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.


Fch 532 lecture 24

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


Fch 532 lecture 24

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


Fch 532 lecture 24

  • 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


Fch 532 lecture 24

  • 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.


Fch 532 lecture 24

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


Fch 532 lecture 24

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)


Fch 532 lecture 24

  • 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