Explain the fate of carbon skeleton and nitrogen group of amino
acids. Explain the ways of transport of nitrogen from various parts
of the body to the liver Describe the urea cycle and the enzymes
involved in production of urea in the liver Define and classify
Hyperammonemias. List the enzymes deficient in various
hyperammonemias and its clinical features
Slide 3
Amino group NH 3 Formation of urea Carbon skeletons Formation
of Glucose and Ketone bodies.
Slide 4
FATE OF THE CARBON SKELETONS Carbon skeletons are used for
energy Glucogenic: TCA cycle intermediates or Pyruvate
(Gluconeogenesis) Ketogenic: Acetyl CoA, Acetoacetyl CoA, or
Acetoacetate
Slide 5
PROTEINS Gastric juice ( acidity denatures proteins )
Intestinal enzymes hydrolyze AMINO ACIDS Amino acid transporters
Na+Amino acid symporter (can take up di and tri peptides ) UPTAKE
DEFECTS :- 1)Hartnups disease Long neutral amino acid transporter
defect( Trp is not taken up Pellagra like symptoms as Trp Niacin is
not formed ) 2)Cystinuria Basic amino acid transporter defect that
also transports cysteine Urinary stones.Cystine forms Cystine by
disulfide linkage (less soluble Stones )
Slide 6
Difference btw total nitrogen intake and total nitrogen loss in
feces POSITIVE NITROGEN BALANCE MORE NITROGEN INGESTION THAN LOSS
Growing infants and pregnant women NORMAL BALANCE INTAKE MATCHES
OUTPUT Normal Individuals NEGATIVE BALANCE NITROGEN OUTPUT EXCEEDS
INTAKE Following surgery, cancer, malnutrition (decreased protein
intake )
Slide 7
OVERVIEW OF AMINO ACID METABOLISM ENVIRONMENT ORGANISM Ingested
protein Bio- synthesis Protein AMINO ACIDS Nitrogen NH 3 Carbon
skeletons Urea Degradation (required) 1 23 a b Purines Pyrimidines
Porphyrins cc Used for energy pyruvate -ketoglutarate succinyl-CoA
fumarate oxaloacetate acetoacetate acetyl CoA
(glucogenic)(ketogenic) Recycling
Slide 8
Slide 9
Affects central nervous system 1.Alkalization of intracellular
compartment 2.Disrupts oxidative phosphorylation ATP depletion
3.Increased glutamate in Brain 4.Decreased Neurotransmitters GABA
convulsions 5.Cerebral edema
Slide 10
Symptoms of AMMONIA toxicity Flapping Tremor (Asterixis) (
Correlate flapping tremor later on with Liver failure in Clinical
medicine ) Slurred Speech Blurred Vision COMA Death
Slide 11
Ammonotelic Fishes Lots of water available Uricotelic Reptiles
and birds Birds have to keep minimum body weight for flight
Ureotelic Mammals
Slide 12
Body Proteins Amino acids Catabolism UREA 25% 80-85%
Slide 13
Sources of Amino Acids : Exogenous Diet Endogenous 1.Breakdown
of muscle protein 2.Biosynthesis from intermediates of citric acid
cycle. Utilization of Amino acids: Synthesis of New proteins
Formation of Nucleotides Formations of Porphyrins and
Catecholamines Production of energy and Ammonia.
Slide 14
1) Reutilization: Glutamate and Glutamine are involved in
recycling of amino acids. Glutamate + AmmoniaGlutamine Glutamine
Synthase ATPADP They are secreted by the peripheral tissues in form
of glutamine which is taken up by hepatocytes where the NH3 is
re-used for amino acid and nucleotide synthesis Glutamine Glutamate
+ Ammonia Glutaminase
Slide 15
Two important reactions are involved in fixing ammonia back to
amino acids: 1.Reductive Amination: 2.Amino Transferases: All
non-essential amino acids except for tyrosine and cysteine are
derived and are dependent on transamination from glutamate.
Well balanced polarity (Quite uncharged because of amide
nitrogen yet sufficiently soluble in plasma No transporter required
) Non-Toxic AMMONIA ASPARTATE
Slide 18
UREA BIOSYNTHESIS IS DIVIDED INTO 4 STAGES:- 1. TRANSAMINATION
2. OXIDATIVE DEAMINATION 3. AMMONIA TRANSPORT 4. REACTIONS OF THE
UREA CYCLE
Slide 19
DEF :- THE TRANSFER OF THE ALPHA-AMINO GROUP FROM ONE AMINO
ACID TO A KETO ACID, RESULTING IN FORMATION OF A NEW AMINO ACID AND
CORRESPONDING KETO ACID. E.G :- REACTION CATALYZED BY ALANINE
AMINOTRANSFERASE ALANINE PYRUVATE (AMINO ACID ) (CORRESPONDING KETO
ACID ) -KETOGLUTARATE GLUTAMATE (KETO ACID )(NEW AMINO ACID)
Nitrogen part is toxic. Excreted in the form of either :
1.Ammonia charged and alkaline. Excreted as ammonium ion in urine
(3%) 2.Urea Neutral molecule Non toxic ( 80-85%) 3.Creatinine
(3-4%) constant in urine ( 1% of Creatine every day) 4.Uric acid
from Purines only !
Slide 25
Inter organ exchange of amino acids
Slide 26
The Glucose alanine cycle
Slide 27
Amino acid catabolism in various tissues: 1.Intestines:
predominantly use glutamine and asparagine for energy. 2. Liver :
based on the blood levels of Glutamine (starvation / anabolism)
produces Urea or proteins Cannot metabolize branched chain amino
acids 3.Muscle: breaks down branched chain amino acids Produces
Alanine transport form of ammonia to liver Produces glutamine to
the kidneys.
Slide 28
Kaplan lecture notes USMLE step 1
Slide 29
Very important NH 3 removal mechanism ( esp BRAIN)
Nitrogen is Excreted in the form of either : 1.Ammonia charged
and alkaline. Excreted as ammonium ion in urine (3%) 2.Urea Neutral
molecule Non toxic ( 80-85%) 3.Creatinine (3-4%) constant in urine
( 1% of Creatine every day) 4.Uric acid from Purines only !
Slide 33
Inter organ exchange of amino acids in post absorptive state
(FASTING)
Slide 34
Inter organ exchange of amino acids in absorptive state (after
feeding)
Slide 35
The Glucose alanine cycle ALT (Transamination)
Slide 36
Well balanced polarity (Quite non polar because of amide
nitrogen yet sufficiently soluble in plasma No transporter required
) Non-Toxic AMMONIA ASPARTATE
Slide 37
Ammonia + Bicarbonate + ATP Carbomyl Phosphate Citrulline
Arginosuccinate Arginine CPS -1 Ornithine Transcarbomylase
Arginosuccinate synthase Arginosuccinate Lyase Arginase Ornithine
Aspartate NAG N-acetyl Glutamate High protein Diet Cytoplasm
Mitochondria Fumarate Urea activator TCA cycle Oxaloacetate
Slide 38
Slide 39
Acetyl Co-A + GlutamateN-acetyl Glutamate N-acetyl glutamate
synthase (NAGS) (NAG) N-acetyl glutamate is the allosteric
activator of Carbomyl phosphate synthase-1. Arginine
Slide 40
Urea cycle disorders Hyperammonemia Encephalopathy Respiratory
alkalosis VOMITING AVOIDANCE OF HIGH PROTEIN FOODS INTERMITTENT
ATAXIA LETHARGY SEVERE MENTAL RETARDATION
Slide 41
Symptoms of AMMONIA toxicity Tremor ( Correlate flapping tremor
later on with Liver failure in Clinical medicine ) Slurred Speech
Blurred Vision COMA Death
Slide 42
Hyperammonemia type -1 Autosomal recessive Defect in CPS- 1 1
in 200,000 No orotic aciduria Cerebral Oedema, coma and death.
Hyperammonemia type -2 X-linked recessive Defect in OTC MC urea
cycle defect Orotic aciduria present Cerebral oedema, coma and
death. CAUSE OF OROTIC ACIDURIA Increased Carbamoyl phosphate
spills out from mitochondia to cytosol Pyrimidine synthesis Orotic
acid Usmle!
Slide 43
3. Citrullinemia : Defect in arginosuccinate synthase
Citrullinuria Autosomal recessive 4. Arginosuccinic aciduria:
Defect in arginosuccinate lyase Arginosuccinic acid blood, CSF,
Urine 5. Hyperargininemia : Diet without arginine Defect in
arginase enzyme
Slide 44
Limit protein intake Decrease bacterial source of ammonia
Antibiotics (Like Neomycin, Azithromycin) and Lactulose (purgative
) Replace intermediates of urea cycle Arginine Citrulline,
Aspartate Remove excess ammonia Hemodialysis, sodium benzoate,
phenyl acetate Very Important
Slide 45
Lactulose Acidification conversion to NH4+ and induction of
Purgation Mainstay Gut sterilization :-Neomycin/Azithromycin other
antibiotics Very Important Combination of Sodium benzoate and
Phenylacetate/Phenylbutyrate Sodium benzoate + Glycine Hippuric
acid excreted Phenylacetate phenylacetyl glutamine excreted.
(Phenylacetate conjugates with glutamine to form
phenylacetylglutamine, which is excreted by the kidneys) Rarely
used
Slide 46
Slide 47
Source http://biocadmin.otago.ac.nz
Slide 48
MCQ 1 Select the CORRECT answer. The first reaction in the
degradation of the majority of common amino acids involves
participation of : A.NAD + B.Pyridoxal Phosphate C.Thiamine
Pyrophosphate(TPP) D.FAD E.NAD and TPP
Slide 49
MCQ 2 After thorough investigations a man is diagnosed with
orotic aciduria. To find out the cause of orotic aciduria which of
the following investigations will you prefer? A. ALP levels B.
vitamin b12 assay C. FIGLU excretion assay D. Peripheral smear E.
serum bilirubin