1. Metabolism of Amino Acid
TUMS
Metabolism of Amino Acid
(Carbon Skeletons)
Part 2
Dr. Azin Nowrouzi
Tehran University of Medical Sciences

2. Fate of the C-Skeleton of Amino Acids2

4. Outline of catabolism of 20 amino acids
Products
# enzymatic steps
Cofactors
Glycogenic or Lipogenic
Alanine
Pyruvate 1
PLP G
Glycine 2
N5,N10 CH2 THF
Serine
Cysteine
PLP, NADH
Threonine 3
Aspartic acid
Oxaloacetate
Asparagine
Histidine
α-ketoglutarate 5
THFA, PLP
Glutamic acid
Glutamine
Arginine 4
PLP, NAD
Proline
O2, PLP 4

5. Amino acid
Products
enzymatic steps
Cofactors
Glycogenic or Lipogenic
Methionine
Succinyl CoA 9
ATP, CoA, NAD, biotin, Vit B12 G
Valine 10
PLP, NAD, CoA, Vit B12
Isoleucine
PLP, NAD, CoA, FAD, biotin, Vit B12
G, L
Leucine
Succinyl CoA, Acetoacetyl coA 6
Thiamin PP, lipoic acid, PLP, CoA, NAD, FAD L
Phenylalanine
Succinyl CoA, fumarate 7
O2, NADPH, tetrahydrobiopterin
Tyrosine
Succinyl CoA, Fumerate
Tryptophan
Succinyl CoA, Alanine
O2, NADPH, NAD
Lysine
Acetoacetyl CoA,
NADPH, NAD, NADP, PLP, CoA, FAD 5

6. Degradation of Carbon Skeletons
Seven products result from the catabolism of amino acid carbon skeletons:
oxaloacetate, α-ketoglutarate, pyruvate, fumarate, acetyl coA, acetoacetyl coA, succinyl coA
Glycogenic
Their catabolism produces pyruvate or one of the intermediates of the Crebs cycle.
These are substrates for gluconeogenesis
So they can produce glycogen in liver and muscle.
Lipogenic (or ketogenic)
Their catabolism produces acetoacetate or its precursors acetyl coA or acetoacetyl coA 6

7. Amino Acids that produce Oxaloacetate

8. Amino Acids that produce α-ketoglutarate

9. Amino Acids that produce Pyruvate

10. Amino Acids that produce Fumarate

11. Phenylketonuria (PKU) Disease
Deficiency of Phe hydroxylase
Occurs in 1:20,000 live births in U.S.
Seizures, mental retardation, brain damage
Treatment: limit phenylalanine intake
Screening of all newborns mandated in all states 11

12. Amino Acids that produce Acetyl CoA or Acetoacetyl CoA

13. Amino Acids that produce Succinyl CoA

14. Catabolism of Branched Chain Amino Acids

15. Transfer of nitrogen components from tissues to the liver for urea synthesis

16. Fed state 16

17. Fasting (starvation)
(i) For the first 7 days, maintain blood glucose (brain use 65% of glucose  Cal)
(ii) > 7 days: Protein proteolysis decreases (protect essential proteins) therefore use over a prolonged period compromises organism.
(iii) → Switch to Ketone bodies 17

18. 18

19. Where does this Ala & Gln come from?
AA are released from muscle during the post- absorptive state (O/N fast). Of the AA released by muscle Ala= 30% & Gln= 25% (total> 50%)
But output (Ala+Gln) > abundance in muscle proteins which contain 7-10% Ala & 6% Gln
Where does this Ala & Gln come from? 19

20. Sources of Alanine (from Muscle)
(i)Muscle: Protein → Ala + aa
aa→ NH4+ + α keto acids
α keto acids → Ala (“simplest” aa).
Therefore total Ala released > Ala derived from proteins
(ii) Liver: Ala → NH4+ + α keto acids
NH4+ → urea
(iii) As well Glucose → Pyruvate (no N) → Ala (with N)
Therefore Ala serves as a vehicle for transport of NH4+ from muscle to liver (NH4+ is generated through breakdown of aa  → energy).
(iv) Because free NH4+ is very toxic even at low levels therefore Pyruvate + NH4+ → Ala (non-toxic)
(v) In liver: NH4+ → urea for excretion
Sources of Alanine (from Muscle) 20

21. Specialized Amino Acid Roles
1. Certain NEAA continue being synthesized even when adequate levels are supplied in diet because of a specialized role
2. ARG → urea synthesis
ASP → urea synthesis
GLU → conduit for disposal of N
3. ALA & GLN → key role in exchange between tissues (liver & skeletal muscle)
4. Liver: major site gluconeogenesis (AA → Glucose)
major site urea synthesis (kidneys to a lesser extent)
5. Skeletal Muscle: 60% total body protein, 50% total body AA pool and is the major source to provide AA carbons → hepatic gluconeogenesis 21

22. Amino Acid Degradation
Removal of alpha-amino groups
Nitrogen excretion
Fate of carbon skeletons 22

23. Removal of alpha-amino groups
Mechanisms of –NH2 removal
Transamination
Oxidative deamination
Amino acid oxidases
Threonine or Serine dehydratase 23

24. A. Transamination
Removal of Nitrogen by aminotransferase 24

25. B. Oxidative Deamination25

26. L- and D- Amino Acid Oxidases
They are present in liver and kidneys.
They have low activity
Their physiologic value is not clear.
Amino Acid + H2O
α-ketoacid + NH3

27. D. Amino acid Dehydratase
Threonine
Urea
Serine and Threonine can be Directly Deaminated 27

28. Fate of Nitrogen in Different Organisms
Other excretion products
creatinine
uric acid 28

29. Disposal of amino group
Urea cycle (Krebs-Henseleit cycle)
Provides g of urea daily for urine formation in the kidneys
Carbamoyl Phosphate Synthetase
Ornitine Carbamoyl Transferase
Argininosuccinate Synthetase
Argininosuccinate Lyase
Arginase
Excretion of free ammonia
Glutamine synthetase
Glutaminase 29

31. Ammonium Ion is Converted into Urea
Urea cycle 31

32. The Urea Cycle is Linked to the Citric Acid Cycle
NH4+ 32

33. Amino Acid Metabolism 33