Metabolism of Amino Acids Disposal of Nitrogen

Faisal Khatib MD; PhD Faculty of Medicine, University of Jordan

Amino Acids: Disposal of Nitrogen

Amino Acids are NOT Stored in the Body
Must be Supplied in the Diet The body can synthesize nonessential A. Acids

Excess A. Acids are Rapidly Degraded

Removal of Amino group: Ammonia The Carbon Skeleton of the Amino Acid ( keto Acid) The Carbon Skeleton can be a Source of Energy or Stored as Fat or Glycogen

Nitrogen Metabolism
Entrance of Nitrogen to the body Amino Acids Other Compounds Nitrogen Leaves the Body as Urea Ammonia Uric Acid and other Compounds

Protein Turnover
Replacement of lost proteins

Protein Turnover
Synthesis

Protein Concentration

Degradation

Rate of Turnover: Variable

-Short Half Lives: Regulatory or Misfolded Proteins (Minutes- Hours) -Long Half Lives: Most Proteins (Days Weeks) - Very Long Half Lives: Structural Proteins (Months Years)

Chemical Signals that Affect Protein Degradation

Modified or Altered Proteins N Terminal Residue
Ser Long Half Life Asp: Short Half Life

Sequences Rich in Pro, Glu, Ser and Thr (PEST)

Protein Degradation
Ubiquitin-Proteasome Lysosomes Energy- Dependent Non-energydependent Endogenous Proteins Extracellular and Cell surface Proteins

The Ubiquitin-Proteasome Degradation Pathway

Ubiquitin: Small Globular Protein ------Gly CO NH Lys

Proteasome: Large BarrelShaped

Nitrogen Balance
Amino Acids are NOT Stored in the Body Protein turnover
Daily synthesis = Daily degradation

Excess A. Acids are Rapidly Degraded

Removal of amino group The Carbon Skeleton can be used as Source of Energy or Stored as Fat or Glycogen

Nitrogen Intake = Nitrogen excretion

Removal of Amino group by Transamination

(Transaminase)

Substrate Specificity of Aminotransferases Name according to

Aminogroup Donor Glutamate Produced Reversible reactions

In the Synthesis of

Nonessential Amino acids

Mechanism of Action of Aminotransferases

Pyridoxal Phosphate (Vit B6) Is required

Amine

Aldehyde

S1

P1

S2

P2

ENZYME

Plasma Level of Aminotransferases is used for Diagnosis of Cellular Damage

Oxidative Deamination of Glutamate

Transport of Ammonia to Liver

Ammonia is TOXIC Compound Produced by Most Tissues Converted to the nontoxic Urea in the Liver Glu + NH3
ATP

Glutamine
ADP + Pi

Glu + Pyruvate

Ketoglutarate + Alanine

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Urea
The Major Disposal Form of Amino Groups Derived from A.Acids
Ammonia Aspartate

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O=

H2O
Fumarate
4
5

Arginine Urea

Agininosuccinate

Ornithine
2

Aspartate

Citrulline
1

NH3 +CO2

Carbamoyl Phosphate C=O NH2

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Formation of Carbamoyl Phosphsphate

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Urea Synthesis: Net Reaction

NH3 + CO2 + ASP + 3ATP

Urea + Fumarate + 2ADP +AMP +2Pi + PPi

NH3 + CO2 +2ATP

+ 2ADP + Pi

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Urea Cycle is Regulated by N-Acetylglutamate

Activator of Carbamoyl Phosphate Synthetase I

Its Concentration Increases after A Protein-rich Meal

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Hyperammonimia
Plasma Level of Ammonia is Normally Low High Levels >> Ammonia Intoxication:
Inherited Defects in the Urea Cycle Enzymes

Liver Diseases Hepatitis, Toxins, Liver Cirrhosis

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Inherited Defects in the Urea Cycle Enzymes

Overall prevalence 1 in 30,000 birth Most are Autosomal Recessive. Can Lead to Serious Consequences: Cerebral Edema, Mental Retardation Coma, Death Symptoms may Appear as Early as 2nd Day after Birth.

H2O
Fumarate

Arginine Urea

Agininosuccinate

Ornithine

Aspartate

Citrulline

NH3 +CO2

Carbamoyl Phosphate C=O NH2

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H2O
Fumarate

Arginine Urea

Agininosuccinate
Excretion

Ornithine

Aspartate

Citrulline

NH3 +CO2

Carbamoyl Phosphate C=O NH2

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