urea cycle.. lgis
TRANSCRIPT
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Urea Cycle
Dr. Zahid AzeemAssistant Professor of Biochemistry
AJ&K Medical College Muzaffarabad
For MBBS-batch 2017
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• Turnover mean both degradation and synthesis
• Proteins are constantly degraded and
resynthesized
• Why degradation?
To remove
a) Damaged Proteins
b) Un-needed Proteins
c) Defective Proteins
d) Old Proteins (Actually the half life of many proteins is
determined at the time of their synthesis)
Protein Turnover
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Half life of aminoacids
Highly stabilizing residues (t1/2>20 hours)
Ala Cys Gly Met
Pro Ser Thr Val
Intrinsically destabilizing residues
(t1/2= 2 to 30 minutes)
Arg His Ile Leu
Lys Phe Trp Tyr
Destabilizing residues after chemical
modification (t1/2= 3 to 30 minutes)
Asn Asp Gln Glu
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Amino acid oxidation and the production of urea
Waste or reuse
Oxidation
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Ammonia has to be eliminated
• Ammonia originates in the catabolism of amino acidsthat are primarily produced by the degradation of proteins – dietary as well as existing within the cell:
digestive enzymes
proteins released by digestion of cells sloughed-off the walls of the GIT
muscle proteins
hemoglobin
intracellular proteins (damaged, unnecessary)
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Ammonia has to be eliminated
• Ammonia is toxic, especially for the CNS, because it reacts with -ketoglutarate, thus making it limiting for the TCA cycle decrease in the ATP level
• Liver damage or metabolic disorders associated with elevated ammonia can lead to tremor, slurred speech, blurred vision, coma, and death
• Normal conc. of ammonia in blood: 30-60 µM
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Overview of amino acid catabolism in mammals
2 CHOICES1. Reuse
2. Urea cycle
Fumarate
Oxaloacetate
7Dr. Inayat Abbasi
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Nitrogen removal from amino acids
Transamination
Oxidativedeamination
Urea cycle
AminotransferasePLP
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Nitrogen removal from amino acids
Step 1: Remove amino group
Step 2: Take amino group to liver for nitrogen excretion
Step 3: Entry into mitochondria
Step 4: Prepare nitrogen to enter urea cycle
Step 5: Urea cycle
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Step 1. Remove amino group ; Transamination
• Transfer of the amino group of an amino acid to an -ketoacid the original AA is converted to the corresponding -keto acid and vice versa: Transamination is catalyzed by transaminases (aminotransferases) that require participation of pyridoxalphosphate
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Step 2: Take amino group to liver for nitrogen excretion; Oxidation
deaminationn
Glutamatedehydrogenase
The glutamate dehydrogenase of mammalian liverhas the unusual capacity to use either NAD+ orNADP+ as cofactor
Glutamate releases its amino group asammonia in the liver.
The amino groups from many of the-amino acids are collected in theliver in the form of the amino groupof L-glutamate molecules.
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Oxidationdeamination
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1. Glutamate
transferres one amino group WITHIN cells:
Aminotransferase → makes glutamate from -ketogluta-rate
Glutamate dehydrogenase → opposite
2. Glutamine
transferres two amino group BETWEEN cells → releases its amino group in the liver
3. Alanine
transferres amino group from tissue (muscle) into the liver
Nitrogen carriers
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Glucose-alanine cycle
Ala is the carrier of ammonia and of the carbonskeleton of pyruvate from muscle to liver.The ammonia is excreted and the pyruvate is usedto produce glucose, which is returned to themuscle.
Alanine plays a special role in transporting amino groups to liver.
According to D. L. Nelson, M. M. Cox :LEHNINGER. PRINCIPLES
OF BIOCHEMISTRY Fifth edition
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Step 3: entry of nitrogen to mitochondria
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Step 4: prepare nitrogen to enter urea cycle
Regulation
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Step 5: Urea cycleaspartate
Ornithine transcarbamoylase
Argininosuccinate synthase
Argininosuccinate lyase
Arginase 1
19Dr. Inayat Abbasi
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Dr. Inayat Abbasi 20
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OOA
Oxaloacetate → aspartate
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The overall chemical balance of the biosynthesis of urea
NH3 + CO2 + 2ATP → carbamoyl phosphate + 2ADP + Pi
Carbamoyl phosphate + ornithine → citrulline + Pi
Citrulline + ATP + aspartate → argininosuccinate + AMP + PPi
Argininosuccinate → arginine + fumarate
Arginine → urea + ornithine
Sum: 2NH3 + CO2 + 3ATP urea + 2ADP + AMP + PPi + 2Pi
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Deficiencies of urea cycle enzymes
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Ammonia toxicity
Ammonia encephalopathy
• Increased concentration of ammonia in the blood and other biological fluids → ammonia difuses into cells, across blood/brain barrier → increased synthesis of glutamate from -ketoglutarate, increased synthesis of glutamine
-ketoglutarate is depleted from CNS → inhibition of TCA cycle and production of ATP
• Neurotransmitters – glutamate (excitatory neurotr.) and GABA (inhibitory neurotr.), may contribute to the CNS effects – bizarre behaviour
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Deficiencies of urea cycle enzymes
• Infant born with total deficiency of one or more enzymessurvive at least several days.
• Many enzymes deficiencies are partial → enzymes havealtered Km values.
• Case are known of deficiencies of each enzymes.
• Interruption of the cycle at each point affected nitrogenmetabolism differently - some of the intermediates candiffuse from hepatocytes → accumulate in the blood → passinto the urine.
• If symptoms are not detected early enough → severe mentalretardation → brain damage is irreversible.
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• Urea Level in Blood:
• In clinical practice, blood urea level is taken asan indicator of renal function. The normalurea level in plasma is from 20 t0 40 mg/dl.Blood urea level is increased where renalfunction is inadequate.
• Urinary excretion of urea is 15 to 30g/day (6-15g nitrogen/day). Urea constitutes 80% ofurinary organic solids.
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• Clinical importance of urea:• An active man consuming 300grams
carbohydrates, 100grams of fats and 100 gramsof proteins excretes 16.5 grams of N daily. 95%Nis eliminated through kidneys and remaining 5%through feces.
• Normal Urea level:• Healthy adult in fasting condition has urea 20-
40mg/100ml of plasma. Pakistani individualtaking less protein may have normal level of urea15-40mg/100ml of plasma.
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Causes of Increased Urea Levels (Uremia):
• Pre-renal Causes:
• Here the plasma volume is mostly reduced such as salt and water depletion.
• Sever and prolonged diarrhea/dehydration.
• Hemorrhage and shock; shock due to sever burns.
• Ulcerative colitis with severe chloride loss
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Thank you for your attention