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A READYMADE PRESENTATION ON METABOLISM OF UREA CYCLE
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AMMONIA METABOLISMUREA CYCLE
Compiled by:-PRATEEK CHOPRA
BT/BIO/05/310022AMITY INSTITUTE OF BIOTECHNOLOGY
NOIDA
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;
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 common amino 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 of several diseases tested for in newborns in all states.
Table 1- The essential and non-essential amino acids
Essential Nonessential
Argininea Methionineb Alanine Glutamine
Histidine Phenylalaninec Aspartate Glycine
Isoleucine Threonine Asparagine Proline
Leucine Tryptophan Cysteine Serine
Lysine Valine Glutamate Tyrosine
a Arg is synthesized in the urea cycle, but the rate is too slow to meet the needs of growth in children
b Met is required to produce cysteine if the latter is not supplied adequately by the diet.
c Phe is needed in larger amounts to form tyr if the latter is not supplied by the diet.
CatabolismUrea + CO2Amino Acid Pool
Carbon compounds + nitrogen
De novo synthesis
Dietary amino acids
Porphyrins, creatine, carnitine, hormones, nucleotides
Biosynthesis of nitrogen compounds
Fates of amino acidsAmino acid sources
Figure 1. Sources and fates of amino acids
BODY PROTEIN
Proteolysis Protein synthesis
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
-Amino acid
-Keto acid
NH2
HOOC-CH-CH2CH2COOH
O
HOOC-C-R
NH2
HOOC-CH-R
O
HOOC-C-CH2CH2COOH
-Ketoglutarate
Glutamate
Cofactor = pyridoxal phosphate
Figure 2. Depiction of a general transamination (aminotransferase) reaction. The -amino acid other than glutamate can be a wide variety
+ -ketoglutarate+ glutamate
Aspartate aminotransferase (glutamate-oxaloacetate transaminase)
NH2 Aspartate
HOOC-CH-CH2COOH
O Oxaloacetate
HOOC-C-CH2COOH
Alanine aminotransferase (glutamate-pyruvate transaminase)
+ -ketoglutarate+ glutamate
NH2 Alanine
HOOC-CH-CH3
O Pyruvate
HOOC-C-CH3
Figure 3. The reactions catalyzed by aspartate aminotransferase and alanine aminotransferase.
NADH NAD+
-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.
Glutaminase
Glutamate
Glutamine
NH4+
Glutamate dehydrogenase
-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
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
-Amino acid
-Keto acid
-Ketoglutarate
Glutamate
Aminotransferase
NAD+ + H2O
Glu dehydrogenase
-Ketoglutarate
Glutamate
NADH + NH4+NH4
+
UREA
Urea cycle
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
Carbamoyl phosphate synthetase
UREAO
H2N-C- NH2
Ornithine
-OOC-CH-NH3+
CH2COO-
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 + glutamate N-acetylglutamate)
Arginine stimulates the formation of N-acetylglutamate
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
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