3. Table1-Theessentialand non-essentialaminoacids
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.
4. Catabolism
Urea + CO2
De novo
synthesis
Carbon compounds
+ nitrogen Amino Acid Pool
Dietary amino
acids
Porphyrins, creatine, carnitine,
hormones, nucleotides
Biosynthesis of
nitrogen compounds
Amino acid sources
Fates of amino acids
Figure 1. Sources and fates ofamino acids
BODY PROTEIN
Proteolysis Protein synthesis
5. DIGESTION AND ABSORPTION OF PROTEINS
Protein digestion
A- STOMACH
⚫ -Digestion ofproteinsbeginsin the stomach.
⚫ Gastric HCLcausesdenaturation ofproteins i.e. lossofthe
tertiary structure.
⚫ Thepolypeptidechain unfoldsandbecome exposed to the action
of proteases,which include pepsin andrennin.
Pepsin:
⚫ Pepsin is secreted bythe chief cells of the gastric mucosaasthe
inactive zymogen, pepsinogen.This is activated to pepsin byHCL
andbypepsin itself (autocatalysis).
6. ⚫ It is an endopeptidasei.e. hydrolysispeptidebondswithin the
main polypeptide chain.
⚫ It is specific for the peptide bondsformed by aromaticamino acids
e.g.tyrosineor acidic amino acidse.g. glutamic acid.
Rennin:
⚫ Renninisabsent from the stomachof adults but it isimportant in
the digestion of proteinsininfants.
⚫ It acts on the casein ofmilk, changingit to a paracasein,which is
then acted on bypepsin.
HCl
Pepsinogen Pepsin
7. B- Intestine
⚫ In the intestine, the alkaline content ofthe pancreaticand bile
secretionsneutralizesthe acid of stomach contents.
⚫ Thealkaline pH inhibits the action of pepsin but activates the
pancreaticand intestinal enzymes.
⚫ The pancreatic enzymes include:
1-Endopeptidases:
⚫ -These includes trypsin,chymotrypsin and elastase.
⚫Trypsin is specific for peptide bondsofbasic amino acids
⚫ Chymotrypsin for peptide bondscontainingaromaticamino acids
⚫Elastase for peptide bondsnext to smallamino acids as glycine, serine
andalanine.
8. ⚫ Trypsin,chymotrypsin andelastase are secreted asan inactive
zymogens:trypsinogen, chymotrypsinogenandproelastase
respectively.
⚫ Trypsinogenisactivated to trypsin byanother proteolytic enzyme
called enterokinase,which issecreted bythe intestinal mucosa.
⚫ Then trypsin activatesadditionalmolecules of trypsinogen,
chymotrypsinogenand proelastase.
2-Carboxypeptidase:
⚫ Carboxypeptidaseis an exopeptidase,hydrolyzingthe carboxy-
terminal peptide bond to liberate single aminoacids.
11. Catabolism Of Amino Acid Nitrogen
Protein turnover
⚫ -Proteinturnover isthe continuousdegradationand resynthesis
of all cellular proteins.
⚫ -Eachday,humansturn over1-2% oftheir total bodyproteins,
principallymuscle protein.
⚫ 75-80%of the liberated amino acidsis reutilized for new
proteinsynthesis.
⚫ The nitrogen of the remaining20-25%forms ureaand the
carbonskeletons are then degraded to amphibolic intermediates.
Body protein
⚫ Protein Degradation resynthesis
of new protein
Amino acid
12. Removal of Nitrogen fromAmino Acids
Removingthe α-amino groupis essentialfor producing energy
fromanyamino acid,andis an obligatorystep
in the catabolismofall amino acids.
1-Transamination.
3-Ammoniatransport
2- Oxidativedeamination
4- Reactionsof ureacycle.
1-Transamination
⚫ Transamination isthe removal ofthe alpha- amino groupfrom
amino acid.
⚫ Mostamino acidsundergo transamination except lysine,
threonine,proline andhydroxyproline.
⚫ Transaminationreactions are catalyzedby transaminases,which
requirepyridoxal phosphateasacoenzyme.
14. ⚫Fate of ammonia:
a-Formationof non-essentialamino acids.
b-Formationof purineand pyrimidine nucleotides.
c-Formation ofglutamine:is catalyzedbythe mitochondrial enzyme
glutamine synthetase, present in the kidneyand brain:
⚫ -In the kidney,glutamine ishydrolyzedbythe enzyme
glutaminase producingammonia which is excreted in urine.
-Themajor mechanism for detoxification of ammoniain braintissue
is formation ofglutamine,which passesto the kidney to be
hydrolyzedto ammonia,excreted in urine.
d-Formationof urea
16. Disorders of urea cycle (inherited ammonia
intoxication)
⚫ Inborn errors of metabolism are associatedwith each reaction of
the urea cycle.Thesemetabolic disorder include the following:
⚫ All defects in urea cycle result in symptoms of ammonia
intoxication and treatment involveslow protein diet to prevent
braindamage.Food intake shouldbe in frequent small meals to
avoid sudden increasesin bloodammonia levels.
Metabolic error Defective enzyme
1- Hyperammonemia type I -Carbamoylphosphate
synthetase
2- Hyperammonemia type II -Ornithine transcarbamoylase.
3- Citrulinemia -Argininosuccinatesynthetase
4- Argininosuccinic aciduria - Argininosuccinase
5- Hyperargininemia - Liver arginase
17. Hyperammonemia
⚫ The levels of serum ammoniaare normally low (5–35μmol/ L).
⚫ However,when liver functionis compromised,due either to
genetic defects ofthe urea cycle or liver disease,blood levels can
riseabove1,000 μmol/ L. Suchhyperammonemiaisa medical
emergency, becauseammoniahasadirect neurotoxic effecton
the CNS.
⚫ Causes of Hyperammonemia:
⚫ Acquired hyperammonemia:Liver diseaseis acommon
causeof hyperammonemiain adults, and maybe due, for
example, to viral hepatitisor to hepatotoxinssuchas alcohol.
⚫ Congenital hyperammonemia:Genetic deficiencies of each
of the five enzymesof the ureacycle have been described,
18. HYPERAMMONEMIAS
Acquired = Liver disease leads to portal-systemic shunting
Inherited = Urea cycle enzyme defects of CPS I (type I hyperammonemia) or
ornithine transcarbamoylase lead to severe hyperammonemia ( type 2
hyperammonemia)
Symptoms:
- Slurring speech
- Severe cases lead to coma and death
-Flapping tremor
-Blurring of vision
Why ammonia is toxic
1↑ NH3→↑ conversion of ketoglutarate to glutamate → depression of
kreb`s cycle affect cellular respiration.
2further ↑ NH3→↑ conversion of glutamate to glutamine → ↓ brain pool of
glutamine → ↓ the neurotransmittor GABA
3↑ glutamine →↑glutamine outflow from the brain in exchange with
trptophan inflow to the brain →↑ neurotransmitter serotonin
19. Fate of glycine
⚫ Glycine isnon-essentialamino acid , glucogenic
⚫ Glycine participatesin the synthesisof the following products:
1- Synthesis of heam:
⚫ The alpha –carbon and nitrogen atom of glycine are used for
synthesis of the porphyrin ring of hemoglobin.The source of
the methylene bridge atoms linking the pyrrole rings.
porphobilinogen
20. 2- Synthesisof creatine:
⚫ -Creatine formation occurs in three organs: kidney,liver and
muscles.It ispresent in the muscle, brain andblood,both as
phosphocreatine or free state. Creatinephosphateis the store of
energy in muscles andsuppliesthe muscles with energyduring
muscular exercise.
⚫ Synthesis : Creatineis synthesizedfrom3 amino acids:glycine
andthe guanidinogroup ofarginine, plusa methyl groupfrom
SAM.
⚫ -Exceretion :V
ery small amountsofcreatine isexcreted in
urine.The excretory product ofcreatine iscreatinine ( 1.0 gm/
dayin females and 1.5 gm/ dayin males).
⚫- Blood creatine : 0.2 – 0.6 mg/ dl.
- Blood creatinine: 0.6 – 1.2 mg/ dl
21. ⚫ Clinical significance:Creatineisreversiblyphosphorylatedto creatine
phosphateby creatine kinase,usingA
TP asthe phosphatedonor.
⚫ The presence of creatine kinase in the plasmais indicative of heart
damage,andis usedin the diagnosisof myocardialinfarction
3-Formation of glycine conjugates:
⚫ 4-Synthesis of purines
6-Formation of bile salts:
7–Synthesis of serine
22. 5 –Synthesisof glutathione
⚫ Glutathioneis present in two forms : reduced (2G-SH)and
oxidizedforms (G-S-S-G).It hasthe followingfunctions:
1-It protects Hb andcell membranesof the RBCsagainstoxidation
byH2O2, thus protecting RBCsagainst hemolysis.Thisrequires
two enzymes:glutathione reductase and glutathione peroxidase.
G-S-S-G+ NADPH+H+
Oxidized glutathione
2GSH + H2O2
2GSH + NADP+
reduced glutathione
G-S-S-G +2 H2O
Glutathione
reductase
Glutathione
peroxidase-selenium
⚫ 2-In the reduced form, glutathioneacts as ahydrogen carrier.
⚫ 3-The SH-groupof glutathioneprotects the β-cells of pancreasfrom
the degenerative action of some compoundsas dehydroascorbic acid.
⚫ 4-It maintainsthe SH-groupof someenzymes in the active form.
23. β -Alanine CH2-CH2-COOH
NH2
⚫ Little free beta-alanineis present in tissues.
⚫ Considerablymore is present asbeta- alanyldipeptides and as
coenzymeA.
24. HISTIDINE
⚫ Histidine issemi-essential amino acidbeing requiredonly for
growinghumans(children) . It is glucogenicamino acid.
⚫ It participatesin
(1)Synthesisof histamine bydecarboxylation. Histamine is a
vasodilatorthat is secreted bythe mast cells in allergicconditions.
(2)Synthesisof carnosineand anserinebycombinationwith β-
alanine.
25. THREONINE CH3- CH- CH- COOH
OH NH2
⚫ Threonineisan essential and glucogenic amino acid.
BIOSYNTHESISOFTHREONINE:-
⚫ It isnot synthesized in the body
CA
T
ABOLISMOFTHREONINE:-
1-Bydeamination, it forms alpha ketobutyrate which undergoes
oxidative decarboxylation, forming propionyl COA, the later is
glucogenicbeingconvertible to succinyl COA
OH NH2
Threonine
Threonine
dehydratase
CH -CH-CH-COOH NH3
CH -CH -C-COOH
3 3 2
NAD
NADH+H
COASH
CO2
CH3-CH2-COSCOA
Propionyl COA
O
α-ketobutyrate
31. Phenylketonurea (PKU)
⚫ Phenylalaninehydroxylasedeficiency
⚫ Excessphenylalanineandits metabolites
⚫ T
wo forms:
⚫ Common - defect in PhenylalanineHydroxylase
⚫ Rarer - defect in tetrahydrobiopterin synthesis
⚫ Normal at birth andmonths to diagnose
⚫ Vomitting sever/ misdiagnosed pyloricstenosis.
⚫ Fair skin and blue eyes
⚫ Eczema and skin rash
33. diagnosis
⚫ Guthrie test; bacterialinhibition , positivein 4 hr old
⚫ Clinical featureare rarely seen Neonatal screening
⚫ Preferable sampleat >24-48 hr oflife
⚫ Positivetest should be followed byPhenylalanineand
tyrosine
⚫ IncreasePA,andincrease P
Ametabolites in urine like
phenylpyruvic
34. Tyrosinemia type 1 (Tyrosinosis) :
Tyrosinosis is characterized by accumulation of metabolites that adversely affect the activities of
several enzymes and transport systems.The metabolic defect is in fumarylacetoacetate hydrolase
and possibly in malylacetoacetate hydrolase. Both acute and chronic forms are known: -
*In acute tyrosinosis, infants exhibit diarrhea, vomiting, and cabbage –like odor and failure to thrive.
Death from liver failure in untreated cases occurs within 6-8 months.
*In chronic tyrosinosis, there is similar but milder symptoms that lead to death by the age of 10 years.
Plasma tyrosine levels are elevated (6-12mg/dl), as are those of additional amino acids e.g. methionine.
Treatment involves diet low in tyrosine and phenylalanine and low in methionine.
Tyrosinemia type 11(Richner –hanhart syndrome)
The probable site of metabolic defect is hepatic tyrosine transaminase
Clinical findings include elevated plasma tyrosine levels (4-5mg/dl),
characteristic eye and skin lesions and moderate mental retardation.
Tyrosine is the only amino acid whose urinary concentration is elevated.
However, renal clearance and reabsorption of tyrosine are within normal limits.
Metabolites excreted in urine include, P-hydroxyphenylpyruvate,P-hydroxyphenyl lactate,
Phydroxyphenylacetate,N–acetyltyrosine and tyramine..
35. Alkaptonuria: a.k.a. Black Urine Disease
First recognized “Inborn Error of Metabolism”
due to deficiency of Homogentisate oxidase enzyme
Symptoms. Homogentisate in the urine oxidizes to a black color
Also, black deposits in the sclera
In adults, accumulation of deposits
in connective tissue leads to arthritis
No effective treatment
37. Maple Syrup Urine Disease
Recessive metabolic disorder
Rare in the general population 1 in 225,000 live births
but common in some smaller populations:
Caused by defect in -ketoisocaprate dehydrogenase
(branched chain keto acids decarboxylase) enzyme
--blocks first step in Leu, Ile and Val degradation
Leu & Ile directly, Val by competitive inhibiton
Symptoms: presents in infants lethargy, distinctive odor, coma
Diagnosis:. Accumulation of Keto Acids in the Urine
produce smell of Maple Syrup
Treatment: Low Ile/ Leu diets
