Amino acid catabolism and the processes involved

Amino acid catabolism

1. Lehninger CHAPTER 18
Amino Acid Oxidation
Production of Urea
–How proteins are digested in animals
–How amino acids are degraded in animals
–How urea is made in made and excreted
Key topics:

2. Metabolic Circumstances of
Amino Acid Oxidation
Amino acids undergo oxidative catabolism
under three circumstances:
–Protein amino-acid residuesfrom normal turnover
are recycled to generate energy and molecular
components
–Dietary amino acidsthat exceed body’s protein
synthesis needs are degraded
–Proteins in the body are broken downto supply
amino acids for catabolism when carbohydrates
are in short supply (starvation, diabetes mellitus),

3. Dietary Proteins are
Enzymatically Hydrolyzed
•Pepsincuts protein into peptides in the stomach
•Trypsinand chymotrypsincut proteins and larger
peptides into smaller peptides in the small
intestine
•Aminopeptidaseand carboxypeptidases Aand B
degrade peptides into amino acids in the small
intestine

4. Overview
of Amino
Acid
Catabolism

5. The Amino
Group is
Removed
From All
Amino Acids
First

6. Fates of Nitrogen in Organisms
•Plants conserve almost all the nitrogen
•Many aquatic vertebrates release ammoniato their
environment
–Passive diffusion from epithelial cells
–Active transport via gills
•Many terrestrial vertebrates and sharks excrete nitrogen
in the form of urea
–Urea is far less toxic that ammonia
–Urea has very high solubility
•Some animals, such as birds and reptiles excrete
nitrogen as uric acid
–Uric acid is rather insoluble
–Excretion as paste allows to conserve water
•Humans and great apes excrete both urea (from amino
acids) and uric acid (from purines)

7. Excretory
Forms of
Nitrogen

8. Enzymatic Transamination
•Typically, -ketoglutarate
accepts amino groups
•L-Glutamineacts as a
temporary storage of nitrogen
•L-Glutamine can donate the
amino group when needed for
amino acid biosynthesis
•All aminotransferases rely on
the pyridoxal phosphate
cofactor

9. Structure of Pyridoxal Phosphate
and Pyridoxamine Phosphate
•Intermediate, enzyme-
bound carrier of
amino groups
•Aldehydeform can
react reversibly with
amino groups
•Aminatedform can
react reversibly with
carbonyl groups

10. Pyridoxal Phosphate is
Covalently Linked to the
Enzyme at Rest
•The linkage is made via an
nucleophilic attack of the
amino group an active-site
lysine side chain
•After dehydration, a Schiff
base linkageis formed
•The covalent complex is
called internal aldimine
because the Schiff base
connects PLP to the enzyme

11. Internal Aldimine in Aspartate
Aminotransferase (Lys
258
-purple)

12. Chemistry of the Amino Group
Removal by the Internal Aldimine
•The external aldimine of PLP is a good
electron sink, allowing removal of -hydrogen

13. PLP Also Catalyzes
Racemization of Amino Acids
•The external aldimine of PLP is
a good electron sink, allowing
removal of -hydrogen

14. PLP Also Catalyzes
Decarboxylation of
Amino Acids
•The external aldimine of
PLP is a good electron sink,
allowing removal of -
carboxylate

15. Ammonia is
Transported in the
Bloodstream
Safely as
Glutamine
•Un-needed glutamine
is processed in
intestines, kidneys
and liver

16. Glutamate can Donate
Ammonia to Pyruvate to
Make Alanine
•Vigorously working muscles
operate nearly anaerobically
and rely on glycolysis for
energy
•Glycolysis yields pyruvatethat
muscles cannot metabolize
aerobically; if not eliminated
lactic acid will build up
•This pyruvate can be
converted to alaninefor
transport into liver

17. Excess Glutamate is Metabolized in
the Mitochondria of Hepatocytes

18. The Glutamate
Dehydrogenase
Reaction
•Two-electron oxidation
of glutamate followed
by hydrolysis
•Net process is
oxidative deamination
of glutamate
•Occurs in mitochondrial
matrix in mammals
•Can use either NAD
+
or
NADP
+
as electron
acceptor

19. Ammonia is Re-captured via
Synthesis of Carbamoyl Phosphate
•This is the first nitrogen-acquiring reaction

20. Nitrogen
from
Carbamoyl
Phosphate
Enters the
Urea Cycle

21. The Reactions in the Urea Cycle
•1ornithine + carbamoyl phosphate => citrulline
–(entry of the first amino group).
–citrulline passes into the cytosol.
•2a citrulline + ATP => citrullyl-AMP + PPi
•2b citrullyl-AMP + Aspartate => argininosuccinate + AMP
–(entry of the second amino group).
•3argininosuccinate => arginine + fumarate
–fumarate enters the citric acid cycle.
•4arginine => urea + ornithine
–Ornithine passes to the mitochondria to continue the cycle

22. Urea
Cycle N-2
from
Aspartate

23. Entry of Aspartate into the Urea
Cycle
•This is the second nitrogen-acquiring reaction

24. Aspartate –Arginosuccinate Shunt Links
Urea Cycle and Citric Acid Cycle

25. Not All Amino Acids can be
Synthesized in Humans
•These amino acids
must be obtained
as dietary protein
•Consumption of a
variety of foods
(including
vegetarian only
diets) well supplies
all the essential
amino acids

26. Fate of Individual Amino Acids
•Seven to acetyl-CoA
–Leu, Ile, Thr, Lys, Phe, Tyr, Trp
•Six to pyruvate
–Ala, Cys, Gly, Ser, Thr, Trp
•Five to -ketoglutarate
–Arg, Glu, Gln, His, Pro
•Four to succinyl-CoA
–Ile, Met, Thr, Val
•Two to fumarate
–Phe, Tyr
•Two to oxaloacetate
–Asp, Asn

27. Summary of
Amino Acid
Catabolism

28. Biotin –single C transfers as CO
2
•Eg. Pyruvate
Carboxylase

29. Tetrahydrofolate
•Single Carbon Transfers –intermediate
oxidation state –methylene, formyl, …

32. S-Adenosyl Methionine
•Methyl Transfers

34. 6 Amino Acids -> Pyruvate
Ala, Gly, Ser, Cys,Trp,Thr.

35. A third Mechanism for Glycine Degradation
•D-Amino Acids prominent in bacterial peptidoglycan
•Calcium Oxalate –75% of Kidney Stones

36. 7 AAs -> Acetyl CoA [W,K,F,Y, L]

37. 7 AAs -> Acetyl CoA [ I , L];
T not shown

38. W, indole Ring
Recycling

39. Metabolic Diseases –Defects of
Aromatic AA degradation

40. R, H, P, E,Q -> α-
ketoglutarate

41. I, M, T, V->
Succinyl-CoA

42. Branched-chain amino acids: valine,
isoleucine, and leucine.

43. Asp and Asn
to
oxaloacetate.

44. Clinical conditions
1.Phenylketonuria (PKU)
-deficiency of the enzyme, phenylalanine hydroxylase.
-The hydroxylation of phenylalanine is a required step in both
the normal degradation of the carbon skeleton of this amino
acid and the synthesis of tyrosine
Symptoms:
-When untreated, this metabolic defect leads to excessive
urinary excretion of phenylpyruvateand phenyllactate, and
severe mental retardation.
-In addition, individuals with PKU tend to have very light skin
pigmentation, unusual gait, stance, and sitting posture, and a
high frequency of epilepsy.
Prevention
-low-phenylalanine diet (diet restrictions)

46. Clinical conditions
2. Alkaptonuria(black urine disease)
-involves a deficiency in the enzyme that catalyzes the oxidation of
homogentisicacid (homogentisateoxidase).
-This condition occurs in 1 in 1000,000 live births,
-homogentisicacid accumulates and is excreted in urine.
-This compound oxidizes on standing or on treatment with alkali,
and gives the urine a dark color.
-Individuals with alkaptonuriaultimately suffer from deposition of
dark (ochre-colored) pigment in cartilage tissue, with subsequent
tissue damage, including severe arthritis; the onset of these
symptoms is generally in the 3rd or 4th decade of life.
Treatment
-Although alkaptonuriais relatively benign compared with PKU, no
treatment, only symptomatic treatments.
-High doses of ascorbic acid have been used in some patients, to
retard the deposition of pigment on collagen, but the progress of the
disease is not significantly affected by this strategy.

47. Summary

48. Summary of
Amino Acid
Catabolism

49. Other disorders (inborn errors of
aa metabolism)
•Albinsm
•Maple syrup urine disease
•Homocystinuria
•Read and summarise !

50. Reading asignment
1.During starvation there are two amino acids whose concentration
increases significantly in the circulation. Identify those amino acids
and explain the underlying mechanism
2.Starting with ornithine, list all the enzymes involved in the
conversion of NH
4
+
to urea.
3.List two amino acids that are exclusively ketogenic
4.List two amino acids that are both ketogenic and glucogenic
5.What do we mean by inborn errors of amino acid metabolism? List
any three errors of a.a metabolism
6.Using glutamine as an example, differentiate between oxidative
deamination and transamination
7.What is alanine-glucose cycle? How does it occur and where
8.Mention an animal that excretes both urea and uric acid
9.What is the relationship between uric acid excretion and alcohol
consumption? (read from Harper’s book)
10.Outline how serine can be converted to glycine.
11.Mention at least three vitamins that are central to amino acids
catabolism and give examples of reactions that they catalyze

51. 12.What is alkaptonuria? Explain the deficient enzyme in this
defect and the underlying pathogenesis. How do we control
this disease?
13.Explain the symptoms of phenyl ketonuria
14. What are the metabolic causes of albinism?