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Ammonia production and toxicity ط      Transport of ammonia , toxicity ط      Amino acid oxidase reaction ط      Ammonia transport to liver and kidney ط      Intracellular glutamine cycle                                            D4   452 -56 . Ammonia Production.

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Ammonia production and toxicity

ط     Transport of ammonia , toxicity

ط     Amino acid oxidase reaction

ط     Ammonia transport to liver and kidney

ط     Intracellular glutamine cycle

                                           D4   452 -56 

Ammonia Production
  • a) fig11.11, α-Keto/Amino Acid Cycle
    • α-KG GltDH (–NH4+/NADPH)  Glt
    • fig11.13, ammonia incorporation is stimulated by ATP/GTP
    • Glt GltDH (+NH4+/NADH)  α-KG
    • fig11.13, ammonia release is stimulated by ADP/GDP
  • b) fig11.14 – 11.15, Glutamine Cycle
    • Glt  Glt Synthetase (–NH4+/ATP)  Gln (carrier of ammonia)
    • Gln  Glt-ase (+NH4+)  Glt (ammonia released)
Ammonia Production

Release of Amonia by Other Reactions

  • c) fig11.19, Oxidative Deamination (L-AA)
    • α-Amino Acid AA Oxidase (–FMN/ +H2O2) α-Imino Acid Deamination (+NH3)  α-Keto Acid
    • D-AA oxidase by intestinal bacteria
  • d) fig, Non Oxidative Deamination
    • Serine Ser DH è a-Imino Acid Deamination (+NH3)  Pyruvic Acid
  • e) fig, Amino Desulfhydration
    • Cystein Cys DS a-Imino Acid Deamination (+NH3)  Pyruvic Acid
  • f) fig, Amino Decarboxylation
    • · Histidine His Decarboxylase (–CO2)  Histamine
    • · Serine Ser Decarboxylase (–CO2)  Ethanolamine
  • * Ammonia released in kidney is excreted
  • * Ammonia released in liver can be used to produce urea
Ammonia production and toxicity  Urea cycle

ط     Urea cycle : steps and regulation

ط     Transport and excretion of urea

ط     Clinical correlation:

                                    Metabolic disorders of urea synthesis

                                    Deficiency of urea cycle enzymes

                                           D4 452 -56 

Urea Cycle

Urea cycle is the mechanism of nitrogen excretion

fig11.21, 1 nitrogen form Ammonia and 1 nitrogen from Asp

Reactions of Urea Cycle
  • fig11.22 – 11.24, synth in liver:
        • In Mitoch:  HCO3– + ATP CPS-ase 1 (+ADP)  HCO3–P
  • HCO3–P + Ammonia CPS-ase 2 (–ATP)  Carbomyl Phosphate (1N)
  • Carbomyl Phspahte (1N) + Ornithine (2N) OTC-lase Citrulline (3N)
  • In Cyto:   Citruline (3N) + Aspartate ASS-tase (–ATP)  Argininosuccinate (4N)
  • Argininosuccinate AS lyase Arginin (4N) + Fumarate (to OA to PEP)
  • Arginine (4N) Arginase Ornothine (2N) + Urea (2N)
  • In Cyto:          Citruline (3N) + Aspartate ASS-tase (–ATP)  Argininosuccinate (4N)
Reactions of Urea Cycle

Ammonia (NH4+) is released from Gln

Glt can be transferred to Ornithine

fig11.23, CPS-ase 1 is activated by Acetyl Glutamate

ACoA + Glt è AG S-tase è AG

AG S-tase is activated by Arg

* Urea transported to kidneys are excreted

* but if transported to intestine it will under go bacterial urease releasing ammonia, which returns to liver

Clinical Correlation

* Ammonia is very toxic causing decrease in ATP that leads to coma

* High ammonia lead to α-KG to form Glt (leave TCA cycle, no energy)

* Deficiencies in each enzyme of urea cycle are found and treated by

1.        Limit prt intake:

decrease AA and increase α-KG in diet

acidify colon by Levuloase to decrease AA absorbance

use antibiotic to reduce bacterial transamination

2.        Remove excess ammonia

use compounds that bind to nitrogen and excreted in urine (need CoA/ATP)

3.        Replace urea cycle intermediates

Clinical Correlation

Metabolic Disorder of urea synthesiscc11.1

Hyperammonemia causes mental retardation due to:

1.        Deficiency in CPS

can be treated by limiting prt intake (as above)

or addition of arg (activates AG S-tase) to activate CPS-ase

2.        Deficiency in AG S-tase

treated by Carbomyl Glt (analogue of AG) to activate CPS-ase

Clinical Correlation

Deficiency of urea cycle enzymescc11.2

Hyperammonemia causes mental retardation due to:

1.        Deficiency in Orn T C-lase

Most common deficiency and in male more than female

Lead to mental retardation & death

Carbomyl Phosphate + Asp è orate (orotic acid)

2.        Deficiency in Arg S S-tase

Lead to citrullinemia, high citrulline in blood & urine

Treated with arg (arg => prt => creatine)

3.        Deficiency in Arg Lyase

Lead to increase of Argininosuccinate in urine

Treated with arg (complete the cycle)

4.        Deficiency in Arg-ase

Rare but cause abnormalities in CNS

High arg lead to excretion

Treated with EAA, but no arg

Catabolism of carbon skeleton of amino acids

ط      Ketogenic and Glucogenic amino acids

ط     Metabolic fate of some amino acids

ط     Site of entry into intermediates of CAC

L2 526 -36 

Amino Acids as Carbon Source

·         Table7.2, AAs are divided into ketogenic AAs & glucogenic AAs or both

·         Keto-AA cannot function as C source

·         fig11.2, Whereas Glc-AAs do, and enter the carbon skeleton in 7 points