15530542 ammonia metabolism urea cycle

8/8/2019 15530542 Ammonia Metabolism Urea Cycle

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AMMONIA METABOLISM

UREA CYCLE

Compiled by:-

PRATEEK CHOPRA

BT/BIO/05/310022

AMITY INSTITUTE OF BIOTECHNOLOGY

NOIDA


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OBJECTIVES

1. Define protein balance, nitrogen balance and essential amino acid.

2. Describe the transaminase, and glutamate dehydrogenase reactions

and discuss their roles in the removal of nitrogen waste in the body.

3. Identify the direct sources of nitrogen for the urea cycle.

4. Define hyperammonemia and discuss why a defect in either carbamoyl

phosphate synthetase I or ornithine transcarbamoylase leads to

hyperammonemia

5. Distinguish between ketogenic and gluconeogenic (glycogenic)

amino acids.

6. Describe the phenylalanine hydroxylase reaction and explain its

relationship to phenylketonuria;


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PHYSIOLOGICAL PREMISE

Have you ever carefully read a packet of EqualTM? If so,

you may have noticed a warning to phenylketonurics.

The chemical sweetener in equal is a dipeptide

containing phenylalanine and aspartate. Some

individuals are born with one of the more commonamino acid disorders, phenylketonuria. They are unable

to metabolize phenylalanine to tyrosine. Consequently

vast amounts of phenylalanine will accumulate in the

blood if too much of this amino acid is consumed in the

diet. Constant excess of phenylalanine in the blood can

cause severe mental retardation. Hence this is one ofseveral diseases tested for in newborns in all states.


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CatabolismUrea + CO

2AminoAcid Pool

Carbon compounds

+ nitrogen

De novo

synthesis

Dietary aminoacids

Porphyrins, creatine, carnitine,

hormones, nucleotides

Biosynthesis ofnitrogen compounds

Fates of amino acidsAmino acid sources

Figure 1. Sources and fates of amino acids

BODY PROTEIN

Proteolysis Protein synthesis


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PROTEIN BALANCE

positive: synthesis > degradation (e.g., growth, body building)

negative: synthesis < degradation (e.g., starvation, trauma, cancer cachexia)

BODY PROTEIN

Proteolysis Protein synthesis

Amino Acid Pool


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E-Amino acid

E-Keto acid

NH2

HOOC-CH-CH2CH

2COOH

O

HOOC-C-R

NH2

HOOC-CH-R

O

HOOC-C-CH2CH2COOH

E-Ketoglutarate

Glutamate

Cofactor = pyridoxal phosphate

Figure 2. Depiction of a general transamination

(aminotransferase) reaction. The E-amino acid otherthan glutamate can be a wide variety


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+ E-ketoglutarate+

glutamate

Aspartate aminotransferase

(glutamate-oxaloacetate transaminase)

NH2 Aspartate

HOOC-CH-CH2COOH

O Oxaloacetate

HOOC-C-CH2COOH

Alanine aminotransferase

(glutamate-pyruvate transaminase)

+ E-ketoglutarate+

glutamate

NH2 Alanine

HOOC-CH-CH3

O Pyruvate

HOOC-C-CH3

Figure 3. The reactions catalyzed by aspartate aminotransferase

and alanine aminotransferase.


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NADH NAD+

E-Ketoglutarate+ NH4

+

Glutamate

Glutamate

dehydrogenase

Glutamine

Glutamine

synthetase

NH3 + ATP

ADP + Pi

Figure 3. In non-hepatic tissues the linked reactions of glutamate

dehydrogenase and glutamine synthetase remove two ammonia

molecules from the tissues as a way of ridding the tissues of nitrogen

waste. The glutamine deposits the ammonia in the kidney for

excretion.


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Glutaminase

Glutamate

Glutamine

NH4+

Glutamate dehydrogenase

E-Ketoglutarate+ NH4

+

NAD+ NADH

Figure 5. Kidney production of ammonia for excretion following

successive removal of amino groups from glutamine via glutaminase

and glutamate dehydrogenase


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Figure 6. In liver, nitrogen waste from amino acids ends up in urea.Amino acids are derived either from the breakdown of protein in

various tissues or from what is synthesized in those tissues

E-Amino acid

E-Keto acid

E-Ketoglutarate

Glutamate

Aminotransferase

NAD+ + H2O

Glu

dehydrogenase

E-Ketoglutarate

Glutamate

NADH + NH4+NH4+

UREA

Ureacycle


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CYTOPLASM MITOCHONDRIA

Figure 7. Carbamoyl phosphate synthetase reaction and the urea cycle.

Overall: 3ATP+HCO3-

+NH4+

+asp 2ADP+AMP+2Pi+PPi+fumarate+urea

Ornithine

Citrulline

argininosuccinate synthetase argininosuccinase arginase

AMP+PPi

-Aspartate

Argininosuccinate

ATP

Arginine

Fumarate

(returns

to TCA

cycle)

Pi

Ornithine

Citrulline

Ornithine

transcarbamoylase

Carbamoyl phosphate

2ATP + HCO3- +NH4

+

2ADP + Pi

Carbamoylphosphate

synthetase

UREAO

H2N-C- NH2

Ornithine

-OOC-CH-NH3+

CH

2COO-


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UREA CYCLE FACTS

Found primarily in liver and lesser extent in kidney

Nitrogen added to the urea cycle via carbamoyl phosphate

and aspartate

Carbamoyl phosphate synthetase is allosterically

activated by N-acetylglutamate

(acetyl CoA + glutamatep N-acetylglutamate)

Arginine stimulates the formation of N-acetylglutamate


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Fatty liver can lead to cirrhosis

HYPERAMMONEMIASAcquired = Liver disease leads to portal-systemic shunting

Inherited = Urea cycle enzyme defects of CPS I or ornithine

transcarbamoylase lead to severe hyperammonemia


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O2

Tyrosine

H2O

Dihydrobiopterin

Phenylalanine

hydroxylase

Phenylalanine

NADP+ NADPH

Tetrahydrobiopterin

Figure 8. Unusual compounds produced from phenylalanine in

phenylketonuria. The phenylalanine hydroxylase reaction (or

regeneration of the tetrahydrobiopterin cofactor) are defective in

phenylketonuria.

primary defect in

phenylketonuria

Phenylpyruvate

Phenylacetate

Phenyllactate

X

15530542 ammonia metabolism urea cycle

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