urea cycle and its defects (1)

8/12/2019 Urea Cycle and Its Defects (1)

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Explain the fate of carbon skeleton and nitrogen group ofamino 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 inproduction of urea in the liver

Define and classify Hyperammonemias . List the enzymesdeficient in various hyperammonemias and its clinicalfeatures


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Amino group NH3Formation of urea

Carbon skeletons Formation of Glucose and

Ketone bodies.


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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


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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 )

UPTAKEDEFECTS :-

1)Hartnups diseaseLong neutral amino acid transporter

defect( Trp is not taken upPellagra like symptoms as Trp

Niacin is not formed )

2)CystinuriaBasic amino acid transporter defect that also

transports cysteineUrinary stones .Cystine forms Cystine by

disulfide linkage (less solubleStones )


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OVERVIEW OF AMINO ACID METABOLISM

ENVIRONMENT ORGANISM

Ingested

protein

Bio-

synthesisProtein

AMINOACIDS

Nitrogen

NH3

Carbon

skeletons

Urea

Degradation

(required)

12 3

a

b

PurinesPyrimidinesPorphyrins

c c

Used for

energy pyruvate-ketoglutaratesuccinyl-CoAfumarateoxaloacetate

acetoacetateacetyl CoA

(glucogenic)(ketogenic)

Recycling


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Affects central nervous system

1. Alkalization of intracellular compartment

2. Disrupts oxidative phosphorylationATP depletion

3. Increased glutamate in Brain

4. Decreased Neurotransmitters GABA convulsions

5. Cerebral edema


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Symptoms of AMMONIA toxicity

Flapping Tremor (Asterixis)

( Correlate flapping tremor later on with Liver

failure in Clinical medicine )

Slurred Speech

Blurred Vision

COMADeath


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Ammonotelic Fishes

Lots of water available

Uricotelic Reptiles and birds

Birds have to keep minimum body weight for flight

Ureotelic Mammals


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Body Proteins

Amino acids

Catabolism

UREA

25%

80-85%


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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.


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1) Reutilization: Glutamate and Glutamine are involved in

recycling of amino acids.

Glutamate + Ammonia GlutamineGlutamineSynthase

ATP ADP

They are secreted by the peripheral tissues in form of

glutamine which is taken up by hepatocytes where the NH3 isre-used for amino acid and nucleotide synthesis

Glutamine Glutamate + Ammonia

Glutaminase


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Two important reactions are involved in fixingammonia back to amino acids:

1. Reductive Amination:

2. Amino Transferases:

All non-essential amino acids except fortyrosine and cysteine are derived and aredependent on transamination from glutamate.


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1. Reductive Amination :

Alpha keto glutarate +

Ammonia

Glutamate

NAD(P)H NAD(P)

2. Transamination reaction:

Amino acid-1 Alpha keto acid-1

Amino acid-2Alpha keto acid-2

Transaminase

Glutamate

dehydrogenase

PLP


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Well balanced polarity

(Quite uncharged

because of amide

nitrogen yet sufficientlysoluble in plasmaNo

transporter required )

Non-Toxic

AMMONIA

ASPARTATE


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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)

ALL TRANSAMINASES

REQUIRE PLP (VIT B6)


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KA

AA Corresponding KA

New AA

TRANSAMINATION


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Aminoacids:

1. Transamination

2. Deamination

3. Transulfuration4. Glutaminase

5. Gastrointestinal tract bacteria

Degradation of Amino sugars Monoamine Oxidase

Pyrimidine catabolism


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Nitrogen part is toxic. Excreted in the form ofeither :

1. Ammonia charged and alkaline. Excreted asammonium ion in urine (3%)

2. Urea Neutral molecule Non toxic ( 80-85%)

3. Creatinine (3-4%) constant in urine ( 1% of Creatineevery day)

4. Uric acid from Purines only !


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Inter organ exchange of amino acids


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The Glucose alanine cycle

Kaplan lecture notes USMLE step 1


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lecture notes USMLE step 1

Very

important

NH3 removal

mechanism

( esp BRAIN)


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WHY ALANINE ? NOT GLUTAMATE DIRECTLY

2NDNITROGEN1STNITROGEN

(AST)

(ALT)


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Aminoacids:

1. Transamination

2. Deamination

3. Transulfuration4. Glutaminase

5. Gastrointestinal tract bacteria

Degradation of Amino sugars Monoamine Oxidase

Pyrimidine catabolism


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Nitrogen is Excreted in the form of either :

1. Ammonia charged and alkaline. Excreted asammonium 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 !


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Inter organ exchange of amino acids in

post absorptive state (FASTING)


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Inter organ exchange of amino acids in

absorptive state (after feeding)


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The Glucose alanine cycle

ALT

(Transamination)ALT

(Transamination)


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Well balanced polarity

(Quite non polar

because of amide

nitrogen yet sufficientlysoluble in plasmaNo

transporter required )

Non-Toxic

AMMONIA

ASPARTATE


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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


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Acetyl Co-A + Glutamate N-acetyl Glutamate

N-acetyl glutamate synthase(NAGS)

(NAG)

N-acetyl glutamate is the allosteric activator of Carbomylphosphate synthase-1.

Arginine


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Urea cycle disorders

Hyperammonemia

Encephalopathy

Respiratory alkalosis

VOMITING

AVOIDANCE OF HIGH PROTEIN FOODS

INTERMITTENT ATAXIA

LETHARGY

SEVERE MENTAL RETARDATION


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Symptoms of AMMONIA toxicity

Tremor

( Correlate flapping tremor later on with Liver

failure in Clinical medicine )

Slurred Speech

Blurred Vision

COMADeath


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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 anddeath.

CAUSE OF OROTIC ACIDURIAIncreased

Carbamoyl phosphatespills out from

mitochondia to cytosol

Pyrimidine synthesis

Orotic acid


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3. Citrullinemia :

Defect in arginosuccinate synthase

Citrullinuria

Autosomal recessive

4. Arginosuccinic aciduria: Defect in arginosuccinate lyase

Arginosuccinic acidblood, CSF, Urine

5. Hyperargininemia :

Diet without arginine

Defect in arginase enzyme


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:

Limit protein intake

Decrease bacterial source of ammonia Antibiotics

(Like Neomycin, Azithromycin)and Lactulose(purgative )

Replace intermediates of urea cycleArginine

Citrulline, Aspartate

Remove excess ammonia Hemodialysis, sodiumbenzoate, phenyl acetate

Very Important

Very Important


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Lactulose

Acidification

conversion to NH4+ and induction ofPurgation

Mainstay

Gut sterilization :-Neomycin/Azithromycin other antibiotics

Very Important

Combination of Sodium benzoate andPhenylacetate/Phenylbutyrate

Sodium benzoate + Glycine Hippuric acidexcreted

Phenylacetatephenylacetyl glutamineexcreted. (Phenylacetate conjugateswith glutamine to form phenylacetylglutamine, which is excreted by the kidneys)

Rarely used


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Sourcehttp://biocadmin.otago.ac.nz


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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


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MCQ 2

After thorough investigations a man is diagnosedwith orotic aciduria . To find out the cause oforotic aciduria which of the followinginvestigations will you prefer?

A. ALP levels

B. vitamin b12 assay

C. FIGLU excretion assay

D. Peripheral smear

E. serum bilirubin


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urea cycle and its defects (1)

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