amino acids are metabolized leading to formation of acetoacetate one of the 7 intermediates of amino acid catabolism.

1. CATABOLISM OF AMINO ACID LEADING
TO ACETOACETATE FORMATION
PRESENTED BY: PRANAY SENAPATI
MSc. BIOTECHNOLOGY
2 ND SEMESTER
GUIDED BY: DR. MONA KEJRIWAL

2. • Amino acids are the
monomeric unit of
protein.
• Amino acids are
responsible for the uptake
of nitrogen.
• Of all the amino acids
liberated 75% are reused
and the remaining serve as
important precursors for
important biological
compounds.
• Any amino acid consist of
3 parts :
1. Amino group
2. Carboxylic group
3. Carbon skeleton
INTRODUCTION

3. AMINO ACID CATABOLISM
• It is important for maintaining the nitrogen balance.
• Nitrogen leaves the body as UREA, AMMONIA and other products derived from
amino acid metabolism.
• Depending upon the R-group there are 20 amino acids whose catabolism involves
3 steps:
I. Removal of the amino group – amino acid deamination.
II. Incorporation of removed amino group into synthesis of ammonia.
III. Conversion of deaminated amino acid’s carbon skeleton to TCA
intermediates or precursors
• Though 20 amino acids but the catabolism of these leads to only 7 metabolic
intermediates:
1. PYRUVATE
2. α-KETOGLUTARATE
3. SUCCINYL-CoA
4. FUMARATE
5. OXALOACETATE
6. ACETYL- CoA
7. ACETOACETATE

5. • Depending upon these metabolic intermediates amino acids are divided into:
a) GLUCOGENIC- amino acids whose carbon skeleton are degraded to PYRUVATE/
SUCCINYL-CoA/ FUMARATE/ OXALOACETATE/ α-KETOGLUTARATE and further converted
to glucose/glycogen.
b) KETOGENIC-amino acids whose carbon skeleton are degraded to ACETYL-
CoA/ACETOACETATE and further converted to ketone bodies in the liver but cannot be
converted to glucose.
c) BOTH GLUCOGENIC & KETOGENIC
CONTINUED……
SOLELY KETOGENIC AMINO ACIDS BOTH KETOGENIC & GLUCOGENIC
AMINO ACIDS
 LEUCINE
 LYSINE
 PHENYLALANINE
 TRYPTOPHAN
 TYROSINE
 ISOLEUCINE
 THREONINE

6. ACETOACETATE FORMING ACETYL-CoA FORMING
 LEUCINE
 LYSINE
 PHENYLALANINE
 TRYPTOPHAN
 TYROSINE
 LEUCINE
 LYSINE
 ISOLEUCINE
 THREONINE
•Ketogenic amino acids on the basis of intermediate formed:
LEUCINE LYSINE PHENYLALANINE TYROSINE TRYPTOPHAN

7. CATABOLISM OF LYSINE
Saccharopine
dehydrogenase
Saccharopine
dehydrogenase
Aminoadipate
semialdehyde
dehydrogenase
Aminoadipate
aminotransferase
α-keto acid
dehydrogenase

8. ASFGH
Glutaryl-CoA
dehydrogenase
Decarboxylase
Enoyl-CoA
hydratase
β-hydroxyacyl-CoA
dehydrogenase
HMG-CoA
synthase
HMG-CoA
lyase

9. ANALYSIS OF LYSINE CATABOLISM
 Step 1: Saccharopine dehydrogenase fuses α-ketoglutarate to lysine
 Step 2: Saccharopine dehydrogenase thus releases glutamate.
 Step 3: Aminoadipate semialdehyde dehydrogenase facilitates uptake of 1 hydrogen by
NAD(P)+
 Step 4: Aminoadipate aminotransferase (a PLP enzyme) transfers amino group to α-
ketoglutarate thus resulting glutamate
 Step 5: α-keto acid dehydrogenase involves CoA and releases CO2
 Step 6: Glutaryl-CoA dehydrogenase removal of 2 hydrogen thus releasing FADH2
 Step 7: Decarboxylase releases CO2
 Step 8: Enoyl-CoA hydratase hydration of double bond
 Step 9: β-hydroxyacyl-CoA dehydrogenase uptake of 1 hydrogen by NAD+ to form
NADH
 Step 10: HMG-CoA synthase
 Step 11: HMG-CoA lyase yields 1 acetyl-CoA 1 acetoacetate.
 The saccharopine pathway is thought to predominate in mammals because a genetic defect
in the enzyme that catalyzes Reaction 1 in the sequence results in hyperlysinemia and
hyperlysinuria (elevated levels of lysine in the blood and urine, respectively) along with
mental and physical retardation.

10. CATABOLISM OF LEUCINE/ ISOLEUCINE

11. A C
Enoyl-CoA hydratase
β-hydroxyacyl-CoA
dehydrogenase
Acetyl-CoA
acetyltransferase
HMG-CoA
lyase
β-methylglutaconyl-
CoA hydratase
β-methylcrotonyl-
CoA carboxylase

12. ANALYSIS OF LEUCINE/ ISOLEUCINE CATABOLISM
 The first three step of both isoleucine and leucine are similar:
Branched-chain amino acid aminotransferase causes the deamination of the amino acid
to corresponding α-keto acid and the amino group is taken up by α-ketoglutarate to
become glutamate.
Branched-chain α-keto acid dehydrogenase (BCKDH) causes oxidative decarboxylation
to the corresponding acyl-CoA.
Acyl-CoA dehydrogenase causes dehydrogenation, FAD takes up 2 hydrogen.
 Step 4: Enoyl-CoA hydratase causes hydration of the double bond.
 Step 5: β-hydroxyacyl-CoA dehydrogenase causes dehydration, NAD+ takes up 1
hydrogen.
 Step 6: Acetyl-CoA acetyltransferase causes thiolytic cleavage yielding acetyl-CoA and
propionyl-CoA, which is subsequently converted to succinyl-CoA
 Step 7: β-methylcrotonyl-CoA carboxylase (a biotin-dependent enzyme) requires ATP
 Step 8: β-methylglutaconyl-CoA hydratase causes double bond hydration.
 Step 9: HMG-CoA lyase to yield 1 acetyl-CoA and 1 acetoacetate.
 A genetic deficiency in BCKDH causes maple syrup urine disease (MSUD), so named because the
consequent buildup of branched-chain α-keto acids imparts the urine with the characteristic odor of
maple syrup. Unless promptly treated by a diet low in branched-chain amino acids (but not too low
because they are essential amino acids), MSUD is rapidly fatal. MSUD is an autosomal recessive
disorder.

13. CATABOLISM OF TRYPTOPHAN
tryptophan-2,3-
dioxygenase
formamidase
kynurenine-3-
monooxygenase
kynureninase
3-hydroxyanthranilate-
3,4-dioxygenase
amino carboxymuconate
semialdehyde decarboxylase
aminomuconate
semialdehyde
dehydrogenase
hydratase
dehydrogenase

14. α-keto acid
dehydrogenase
Glutaryl-CoA
dehydrogenase
Decarboxylase
Enoyl-CoA
hydratase
β-hydroxyacyl-CoA
dehydrogenase
HMG-CoA
synthase
HMG-CoA lyase

15. ANALYSIS OF TRYPTOPHAN CATABOLISM
 Step 1: tryptophan-2,3-dioxygenase
 Step 2: formamidase
 Step 3: kynurenine-3-monooxygenase
 Step 4: kynureninase (PLP dependent) breaks down 3-hydroxykynurenine to alanine + 3-
hydroxyanthranilate
 Step 5: 3-hydroxyanthranilate-3,4-dioxygenase
 Step 6: amino carboxymuconate semialdehyde decarboxylase releases CO2
 Step 7: aminomuconate semialdehyde dehydrogenase uptake of 1 hydrogen by NAD+ to
form NADH
 Step 8: hydratase
 Step 9: dehydrogenase
 Step 10: α-keto acid dehydrogenase involves CoA and releases CO2
 Step 11: Glutaryl-CoA dehydrogenase removal of 2 hydrogen thus releasing FADH2
 Step 12: Decarboxylase releases CO2
 Step 13: Enoyl-CoA hydratase hydration of double bond
 Step 14: β-hydroxyacyl-CoA dehydrogenase uptake of 1 hydrogen by NAD+ to form
NADH
 Step 15: HMG-CoA synthase
• Step 16: HMG-CoA lyase yields 1 acetyl-CoA 1 acetoacetate

16. CATABOLISM OF PHENYLALANINE/ TYROSINE
: phenylalanine hydroxylase
aminotransferase

17. p-hydroxyphenylpyruvate
dioxygenase
homogentisate dioxygenase
maleylacetoacetate isomerase
fumarylacetoacetase

18. ANALYSIS OF PHENYLALANINE/ TYROSINE CATABOLISM
The catabolism of phenylalanine and tyrosine proceed through the same pathway
 Step1: phenylalanine hydroxylase converts phenylalanine to tyrosine by addition of –OH
group
 Step 2: aminotransferase aids removal of amino group
 Step 3: p-hydroxyphenylpyruvate dioxygenase releases CO2 repositioning of the benzene
ring to α-carbon.
 Step 4: homogentisate dioxygenase disruption of benzene ring
 Step 5: maleylacetoacetate isomerase
 Step 6: fumarylacetoacetase yields 1 fumarate and 1 acetoacetate.
 Alkaptonuria and Phenylketonuria result from defects in Phenylalanine Degradation.
 PKU is caused by the inability to hydroxylatephenylalanine (Reaction 1) and therefore
results in increased blood levels of phenylalanine (hyperphenylalaninemia). The excess
phenylalanine is transaminated to phenylpyruvate, severe mental retardation occurs
within a few months of birth if the disease is not detected and treated immediately.
 Alkaptonuria result in the excretion of large quantities of homogentisic acid. This
condition results from deficiency of homogentisate dioxygenase (Reaction 4).
Alkaptonurics suffer no ill effects other than arthritis later in life (although their urine
darkens alarmingly because of the rapid air oxidation of the homogentisate they excrete).

19. CONCLUSION
 The study of amino acid catabolism has helped in the understanding of rare inherited
disorders.
 Proper degradation of amino acid is very essential for the prevention of fatal diseases-PKU,
MSUD, etc.
 The amino acids leucine and lysine are ketogenic in that they are converted only to the
ketone body precursors acetyl-CoA and acetoacetate. The remaining amino acids are, at
least in part glucogenic.