protein metabolism and acids samya1
TRANSCRIPT
Protein MetabolismProtein Metabolism
PROF. DR.PROF. DR. MOHAMED NAGUIBMOHAMED NAGUIB
Amino acids
Dietary protein
PepsinStomach
Polypeptides and amino
acidsTrypsinChymotrypsin CarboxypeptidaseElastase
Pancreas
To liverOligopeptides and amino
acidsAminopeptidases
Small intestine
Digestion of dietary proteins by the proteolytic enzymes of the gastro-intestinal tract.
Digestion of dietary proteins by the proteolytic enzymes of the gastro-intestinal tract.
TripeptidaseDipeptidase
liver
H2N-CH-COHN-CH-CONH-CH-CO NH-CH-CONH-CH-CONH-CH-CONH-CH-COOH
R1 R2 R3 R4 R5 R6 R7
Pepsin
PhenyalanineTyrosine
Amino acids
Enzymes are secreted inactive to avoid autodigetionChronic pancreatitis :maldigetion
N.B. :
•The digestion destroys its antigenicity.
•If absorbed as polypeptide, produces allergy in the form of urticaria , bronchial asthma
and hay's fever.
AbsorptionAbsorption
From lumen to intestinal cellFrom lumen to intestinal cellBy By a.aa.a or or peptidepeptide transport system (carrier) transport system (carrier)
ATPATP Against concentration gradient Against concentration gradient Needs Na ion as cotransporterNeeds Na ion as cotransporter
ACTIVE PROCESSACTIVE PROCESS
Inside the cell complete dig by Inside the cell complete dig by Aminopeptidase ,Aminopeptidase , Di Di &Tripeptidase&Tripeptidase
Fate of absorbed amino acids: •Anabolic pathway
• Catabolic pathway
•Anabolic pathway:
• Amino acids enter in the formation of proteins for wear and tear, plasma proteins, hemoglobin, enzymes, some hormones
• Also enter in the formation of non protein nitrogenous compounds (NPN) as purines, pyrimidines, creatine and thyroxine.
Catabolic pathwayCatabolic pathway
a) a) Urea:Urea:
formed in the liver, is considered as the main formed in the liver, is considered as the main
metabolic end product of protein catabolism.metabolic end product of protein catabolism.
b) b) Supplying energySupplying energy: :
1 gram protein yields 1 gram protein yields 4.1 K cal4.1 K cal, only if there is, only if there is
shortage in carbohydrate and fats. shortage in carbohydrate and fats.
Nitrogen Balance
There is no storage (depot) for protein, but there is a certain percentage of protein that undergoes turnover.
It is a comparison between
1.the intake of nitrogen (mainly in the form of dietary protein) and
2.the excretion of nitrogen (mainly in the form of undigested protein in stool and urea and ammonia in urine). Also nitrogen output is through nails, hair and desquamated skin.
Nitrogen balance:
Nitrogen equilibrium:
The normal adult human will be in nitrogen equilibrium when N2 lost is just balanced by N2 intake
N2 LOST = N2 INTAKE
Positive nitrogen balance:Positive nitrogen balance:
A condition in which there is increase in the NA condition in which there is increase in the N22 intake intake over the output. over the output.
NN22 INTAKE INTAKE << N N22 LOST LOST
It may occur in It may occur in growth, pregnancy or convalescence from diseasesgrowth, pregnancy or convalescence from diseases..
Nitrogenintake
Nitrogenoutput
Negative nitrogen balance:Negative nitrogen balance:
A condition in which there is either A condition in which there is either decreased decreased
NN22 intake intake as in : as in :
starvationstarvation malnutrition,maldigestion, malabsorption,malnutrition,maldigestion, malabsorption, severe vomiting, severe diarrhea severe vomiting, severe diarrhea
Or Or increased Nincreased N22 lost lost as in as in
hemorrhage, burns, hemorrhage, burns, old age or debilitating disease.old age or debilitating disease.
NN22 LOST > N LOST > N22 INTAKE INTAKE
General Metabolism of ProteinsGeneral Metabolism of Proteins: :
Complete breakdown of proteins and Complete breakdown of proteins and amino acids give rise toamino acids give rise to
Urea Urea + Co + Co22 + H + H22O + EnergyO + Energy..
The major pathway for amino acids excess The major pathway for amino acids excess after protein synthesis is the after protein synthesis is the removal of the removal of the
amino groupamino group and its conversion to ammonia and its conversion to ammonia . .
The liverThe liver is the major site of removal of amino is the major site of removal of amino group from amino acidsgroup from amino acids....
The amino group is removed by different mechanismsThe amino group is removed by different mechanisms::
11 . .TransaminationTransamination
22 . .Oxidative deaminationOxidative deamination
33 . .Non-oxidative deaminationNon-oxidative deamination
44 . .TransdeaminationTransdeamination
I . TransaminationI . Transamination: : It transfers the amino group from an amino It transfers the amino group from an amino
acid to acid to αα -keto acid. -keto acid.
All the amino acids participate in the reaction All the amino acids participate in the reaction of transamination of transamination except threonine and lysine.except threonine and lysine.
Vitamin BVitamin B66 is required as a coenzyme. is required as a coenzyme.
Its enzymes are termed Its enzymes are termed transaminasestransaminases
a) Aspartate transaminase: (AST) or(GOT)a) Aspartate transaminase: (AST) or(GOT)
COOH
CHNH2
CH2
CH2
COOH
COOH
C
CH2
COOH
O
COOH
C
CH2
CH2
COOH
OCOOH
CHNH2
CH2
COOHB6
+ GOT+
Glutamic acid Oxaloacetic acid α-Ketoglutaric acid Aspartic acid
b) Alanine transaminase: (ALT)or(GPT)b) Alanine transaminase: (ALT)or(GPT)
COOH
CHNH2
CH2
CH2
COOH
COOH
C
CH3
O
COOH
C
CH2
CH2
COOH
OCOOH
CHNH2
CH3
+ GPT
B6+
Glutamic acid Pyruvic acid α-Ketoglutaric acid Alanine
Transaminases are cytosolic and mitochondrial Transaminases are cytosolic and mitochondrial enzymes. It is a freely reversible process.enzymes. It is a freely reversible process.
Biological importance of TransaminationBiological importance of Transamination
1- Synthesis of new non-essential amino acids.1- Synthesis of new non-essential amino acids.
2- Degradation of most amino acids except 2- Degradation of most amino acids except lysine lysine and threonine.and threonine.
3- Formation of components of citric acid cycle 3- Formation of components of citric acid cycle (filling up reaction of citric acid cycle).(filling up reaction of citric acid cycle).
4-Transaminase enzymes are used in diagnosis and 4-Transaminase enzymes are used in diagnosis and prognosis of the diseases.prognosis of the diseases.
N.B.N.B. Transaminase enzymes are present Transaminase enzymes are present inside the cells and small traces are present inside the cells and small traces are present
in the blood ( 5 - 40 IU/L)in the blood ( 5 - 40 IU/L) . .
The increase in their level denote cell The increase in their level denote cell damage with the release of enzymes from damage with the release of enzymes from
the destructed cellsthe destructed cells . .
E.gE.g . . in cardiac infarction in cardiac infarction SGOT SGOT is increasedis increased
in hepatic infection, in hepatic infection, SGPT SGPT is increasedis increased above above the normal levelsthe normal levels..
II. Oxidative deaminationII. Oxidative deamination::
It is catalyzed by :It is catalyzed by : Amino acid oxidasesAmino acid oxidases Occur in liver and kidneyOccur in liver and kidney . .
It includes removal of hydrogen (oxidation) and It includes removal of hydrogen (oxidation) and removal of NHremoval of NH33 (deamination) (deamination) . .
There are There are D- and L-amino acid oxidasesD- and L-amino acid oxidases that that oxidizes D- and L-amino acids respectively, to oxidizes D- and L-amino acids respectively, to the corresponding the corresponding αα-keto acids and the amino -keto acids and the amino group is released as ammonia (NHgroup is released as ammonia (NH33))..
R-CH-COOH R-C-COOHAmino acid oxidaseNH2
NH
Flavin Flavin-H2
H2O
H2O2 O2
1/2 O2
H2O
CatalaseR-C-COOH
-Ketoacid
Aminoacid Iminoacid
O
NH3
Oxidative deaminationOxidative deamination
1
2
D-amino acid oxidaseD-amino acid oxidase uses uses FADFAD as coenzyme as coenzyme which is of which is of limitedlimited occurance in mammals and occurance in mammals and of of high activityhigh activity, ,
L-amino acid oxidase L-amino acid oxidase uses uses FMNFMN as coenzyme as coenzyme which is ofwhich is of high high occurrance in mammals, but of occurrance in mammals, but of low activitylow activity. Imp for . Imp for LysineLysine
L-Glutamate dehydrogenase L-Glutamate dehydrogenase usesuses NAD OR NAD OR NADPNADP as coenzyme .For as coenzyme .For Glutamic acid Glutamic acid the only the only a.a undergo O.D in a.a undergo O.D in high rate.high rate.
III - Non-oxidative deaminationIII - Non-oxidative deamination
(direct deamination):(direct deamination):
The α- amino group of The α- amino group of serine and threonineserine and threonine
( amino acids containing ( amino acids containing hydroxyl grouphydroxyl group) can be ) can be directly converted to NHdirectly converted to NH33 without removal of without removal of
hydrogen. hydrogen. This reaction is catalyzed by serine and This reaction is catalyzed by serine and
threonine threonine dehydratasedehydratase which need which need pyriodoxal pyriodoxal phosphatephosphate as coenzyme. as coenzyme.
Non-oxidative deaminationNon-oxidative deamination (direct deamination) (direct deamination)
CH2-CH-COOH
L-serine
OH NH2
CH2=C-COOH
NH2
Serine
dehydratase
CH3-C-COOH
NH
CH3-CO-COOH
NH3
H2O
H2O
pyruvic acid
PLP
Non-oxidative deaminationNon-oxidative deamination
IV .Transdeamination (L-Glutamate dehydrogenase)IV .Transdeamination (L-Glutamate dehydrogenase)::
Vit B6NAD
NADP
12
1
COOH
CHNH2
CH2
CH2
COOHNADPH+H
COOH
C
CH2
CH2
COOH
NH
NH3
COOH
C
CH2
CH2
COOH
O
NADH+H+
Iminoacid
L-glutamic aciddehydrogenase
NADP(NAD)
H2O
• The reaction is both mitochondrial and cytoplasmic, occurs mainly in the liver and
kidney.
• ATP and GTP are allosteric inhibitors while ADP and GDP activate the enzyme.
• It is a reversible reaction.
Glutamic acid
Α-ketoglutaric acid
Oxidative Oxidative deaminationdeamination
Metabolism of ammoniaMetabolism of ammonia
Blood level: 100 ug per dl Blood level: 100 ug per dl
Sources of blood ammonia:Sources of blood ammonia:
1.From amino acids :1.From amino acids :
TransdeaminationTransdeamination Oxidative deaminationOxidative deamination Non-oxidative deamination .Non-oxidative deamination .
2.From glutamine2.From glutamine ::
Renal glutaminase Renal glutaminase Intestinal glutaminase Intestinal glutaminase
3.From amines3.From amines : whether dietary amine or : whether dietary amine or monoamine hormones by monoamine hormones by amine oxidase.amine oxidase.
4. From catabolism of purines and 4. From catabolism of purines and
pyrimidinespyrimidines . .
5.From bacterial action in the intestine5.From bacterial action in the intestine either either from dietary from dietary proteinprotein residue or from residue or from ureaurea diffuses into the intestinediffuses into the intestine
(This is of significance in cases of kidney (This is of significance in cases of kidney failure )failure )
Fates of ammonia (Removal of ammonia)Fates of ammonia (Removal of ammonia)::
form form non-essential aminonon-essential amino acids and other biosynthetic acids and other biosynthetic reactions.reactions.
GlutamineGlutamine synthesis in the brain, liver, muscle and synthesis in the brain, liver, muscle and renal tissues renal tissues (4%).(4%).
The majority of NHThe majority of NH33 ( (90%)90%) will produce will produce ureaurea in the liver in the liver
by urea cycle.by urea cycle.
Excretion in Excretion in urineurine upto upto 1 gm /24 hours urine.1 gm /24 hours urine.
Traces in Traces in bloodblood ( (up to 100 ug / dl).up to 100 ug / dl).
NH3
Oxidative Deamination Non Oxidative Deamination Transdeamination
Glutamine Purine and pyrimidine
UreaNew aminoacid
Traces in the blood
up to 100 ug / dl
Sources and Fates of ammonia
90 %
4 % 1 %
From bacterial action in the intestine on protein
Excretion in urine Excretion in urine upto 1 gm /24 hours upto 1 gm /24 hours urineurine
..From aminesFrom amines..From aminesFrom amines
ATP ADP+p
Glutamine synthetase
H2O
Glutamine synthesis and ammonia Glutamine synthesis and ammonia formationformation
Glutamic acidGlutamineGlutamine Glutamic acid
GlutaminaseGlutaminase+
In the liver,brain and muscleIn the liver,brain and muscle In the
kidneyIn the kidney
Mechanism of ammonia excretion by the kidneyMechanism of ammonia excretion by the kidney::
NH4CL
NaHCO3
Glutamine
N.B. Ammonia excretion increases in cases of Metabolic acidosis and decrease in cases of alkalosis.
Ammoniacal EncephalopathyAmmoniacal Encephalopathy Interfere with CACInterfere with CAC ManifistationManifistation Causes:CongenitalCauses:Congenital Aquired: liver failiureAquired: liver failiure portocaval shuntportocaval shunt gastrointestinal bleedinggastrointestinal bleeding Treatment:glu,alpha ketoglu,benzoic acid Treatment:glu,alpha ketoglu,benzoic acid
, phenyl acitic , phenyl acitic restriction of protiens,frequent small mealsrestriction of protiens,frequent small meals dialysisdialysis
Krebs urea cycleKrebs urea cycleor ornithine cycle for urea formationor ornithine cycle for urea formation
Urea is formed in the Urea is formed in the liver mainlyliver mainly ,,
some in the brain and renal tubulessome in the brain and renal tubules
one molecule of COone molecule of CO22 and two molecules and two molecules
of NHof NH33 using 3 ATP's. using 3 ATP's.
O
H2N- C - NH2
Urea
It is released into the blood with aIt is released into the blood with a
level of level of
20 - 40 mg/dL20 - 40 mg/dL
It is the major end product of nitrogen It is the major end product of nitrogen catabolism in humans catabolism in humans representing representing 80-90% of the nitrogen excreted.80-90% of the nitrogen excreted.
Urea formationUrea formation
NH2NH2
3ATP3ATP
COCO22 +2 NH +2 NH3 3 COCO + H+ H22OO
NH2NH2
ureaurea
Five reactionsFive reactions each of them utilises each of them utilises specific enzyme in urea cycle.specific enzyme in urea cycle.
The first 2 reactions of urea cycle The first 2 reactions of urea cycle are mitochondrialare mitochondrial and the rest 3 and the rest 3 reactions are cytoplasmic.reactions are cytoplasmic.
cytoplasmcytoplasm
mitochondriamitochondria
Five enzymes of urea cycleFive enzymes of urea cycle::
Carbamoyl phosphate synthetase 1Carbamoyl phosphate synthetase 1
Ornithine transcarbamoylase Ornithine transcarbamoylase (citrulline synthase)(citrulline synthase)
Argininosuccinate synthetase.Argininosuccinate synthetase.
Argininosuccinase.Argininosuccinase.
Arginase.Arginase.
Urea Cycle
Urea Cycle
mitochondriamitochondria
cytoplasmcytoplasm
Reactions (steps) of the urea cycleReactions (steps) of the urea cycle::
1.1. Carbamoylphosphate formation:Carbamoylphosphate formation:
Using active Using active COCO2 2 , NH, NH3 3 , 2 ATP, 2 ATP and and
carabmoylphosphate synthetase Icarabmoylphosphate synthetase I, which is , which is a mitochondrial enzyme active in presence of a mitochondrial enzyme active in presence of N-acetylglutamic acid.N-acetylglutamic acid.
carabmoylphosphate carabmoylphosphate
synthetase Isynthetase I
COCO22 + NH + NH3 3 + 2ATP H+ 2ATP H22N.CO. P + 2 ADP + PN.CO. P + 2 ADP + P
Carbamoyl phosphateCarbamoyl phosphate
2.2. Formation of citrulline:Formation of citrulline:
By transfer of carbamoyl group from its By transfer of carbamoyl group from its
phosphoric anhydride to the amino group of phosphoric anhydride to the amino group of
ornithine. ornithine. It is done by mitochondrial It is done by mitochondrial ornithine ornithine
transcarbamoylase.transcarbamoylase. Citrulline then diffuses from the Citrulline then diffuses from the
mitochondria to the cytosol where the rest mitochondria to the cytosol where the rest
of the urea cycle occurs.of the urea cycle occurs.
HH22N.CO. PN.CO. P
PP
Carbamoyl phosphateCarbamoyl phosphate
ornithineornithine CitrullineCitrulline
transcarbamoylasetranscarbamoylase
Formation of citrulline:Formation of citrulline:
ornithineornithine
2
CarbamoylCarbamoyl
3.3. Formation of argininosuccinate:Formation of argininosuccinate:
Citrulline plus aspartate forms arginino-Citrulline plus aspartate forms arginino-succinate by succinate by argininosuccinate synthetase. argininosuccinate synthetase.
This requires This requires ATPATP that changes to that changes to AMP+PPiAMP+PPi because the ureido group (-NH -CO-NHbecause the ureido group (-NH -CO-NH22) is ) is
very stable and requires energy for activtion.very stable and requires energy for activtion.
Formation of argininosuccinateFormation of argininosuccinate::
CitrullineCitrulline arginino-succinatearginino-succinate
aspartateaspartate
ATP AMP+ PPi
argininosuccinate synthetaseargininosuccinate synthetase
+
3
4.4. Cleavage of argininosuccinate:Cleavage of argininosuccinate:
To form arginine and fumarate by To form arginine and fumarate by
argininosuccinase. argininosuccinase.
This enzyme is present in liver and kidneyThis enzyme is present in liver and kidney
of humans.of humans.
arginino-succinatearginino-succinate
Cleavage of Cleavage of argininosuccinate:argininosuccinate:
argininearginine
argininosuccinaseargininosuccinase
fumaratefumarate
4
5.5. Formation of urea:Formation of urea:
Liver Liver arginasearginase enzyme cleaves enzyme cleaves argininearginine to form to form ureaurea and regenerates and regenerates ornithineornithine and thus completes the urea and thus completes the urea cycle. cycle.
argininearginineornithineornithine
arginasearginase
ureaurea
Formation of ureaFormation of urea
UREA CYCLEUREA CYCLE
LINK BETWEEN KREBS' UREA CYCLE AND LINK BETWEEN KREBS' UREA CYCLE AND KREBS' TRICARBOXYLIC ACID CYCLEKREBS' TRICARBOXYLIC ACID CYCLE::
COCO22 + NH + NH33
2ATP2ATP
2
1
3
1. The 1. The fumaratefumarate resulting from reaction resulting from reaction number 4 (in Krebs urea cycle), under the number 4 (in Krebs urea cycle), under the influence of argininosuccinase, undergoes influence of argininosuccinase, undergoes conversion to conversion to malatemalate by fumarase enzyme by fumarase enzyme in citric acid cycle.in citric acid cycle.
This This malatemalate forms forms oxaloacetateoxaloacetate by malate by malate dehydrogenase. dehydrogenase.
LINK BETWEEN KREBS' UREA CYCLE AND KREBS' TRICARBOXYLIC ACID CYCLE:
2.The 2.The COCO22 used in urea cycle comes used in urea cycle comes
mainly from Krebs' mainly from Krebs' tricarboxylic acidtricarboxylic acid cycle. cycle.
3.3. The The oxaloacetate from CACoxaloacetate from CAC undergoes Transamination by SGOT to undergoes Transamination by SGOT to form form aspartate aspartate in cytoplasmin cytoplasm. .
This aspartate is needed in urea cycle This aspartate is needed in urea cycle at argininosuccinic synthetase enzyme.at argininosuccinic synthetase enzyme.
The first NH2 group comes from L-glutamic acid by L-glutamate dehydrogenase.Free ammonia The second NH2 group comes from amino group of aspartic acid.
REGULATION OF UREA CYCLEREGULATION OF UREA CYCLE::
1.1. Excess Excess ammoniaammonia formation formation stimulates stimulates
urea formation.urea formation.
2.2. High High argininearginine level stimulates N- level stimulates N-acetylacetyl
glutamate synthase enzyme, thus glutamate synthase enzyme, thus
increases urea formation.increases urea formation.
3.3. High High ureaurea level inhibits level inhibits
carbamoylphosphate synthase carbamoylphosphate synthase (reaction 1),(reaction 1),
ornithine transcarbamoylase ornithine transcarbamoylase (reaction 2)(reaction 2)
and arginase enzymes and arginase enzymes (reaction 5).(reaction 5).
4.4. Carbamoylphosphate synthetase is Carbamoylphosphate synthetase is inactiveinactive
in the absence of activator, in the absence of activator, N-acetylglutamate.N-acetylglutamate.
Metabolic fate of the carbon Metabolic fate of the carbon skeleton of amino acidsskeleton of amino acids
According to the body need.According to the body need. The Carbon skeleton The Carbon skeleton after removal of the amino group is :after removal of the amino group is :
oxidized oxidized or converted to glucoseor converted to glucose ketone bodies and fatketone bodies and fat
Catabolism of Amino AcidsCatabolism of Amino Acids
Amino group Carbon skeleton
ORTransferred to a keto acid to form anewamino acid
Converted to Glucose,
Or ketone bodies
Released as
ammonia
Oxidized to CO2 +H2OEnergy
Amino Acid is composed of
AND
OR
According to the metabolic fateAccording to the metabolic fateAminoacids are classified intoAminoacids are classified into::
1.1. Ketogenic amino acidsKetogenic amino acids
2.2. Glucogenic amino acidsGlucogenic amino acids
3. Ketogenic-glucogenic
(mixed) amino acids
1- Glucogenic Amino Acids:1- Glucogenic Amino Acids:
They produce They produce PyruvatePyruvate Intermediates of citric acid cycleIntermediates of citric acid cycle Glucose.Glucose.
This group includes most amino acids This group includes most amino acids as glycine,alanine,cysteine,glutamic as glycine,alanine,cysteine,glutamic acid,aspartic acid,serineacid,aspartic acid,serine
2- Ketogenic Amino Acids:2- Ketogenic Amino Acids:
This group includes This group includes leucineleucine..
It produces It produces Acetyl CoA Acetyl CoA AcetoacetateAcetoacetate which give ketone bodies and fat.which give ketone bodies and fat.
3- Both Ketogenic and3- Both Ketogenic and
Glucogenic Amino Acids:Glucogenic Amino Acids: This group includes This group includes
phenylalanine, tyrosine, phenylalanine, tyrosine, tryptophan, isoleucine and lysinetryptophan, isoleucine and lysine. .
Their products can give both, Their products can give both, glucose and ketone bodies.glucose and ketone bodies.
Fate of carbon skeletonFate of carbon skeleton
Glucogenic Amino AcidsGlucogenic Amino Acids
Ketogenic Ketogenic Amino AcidsAmino Acids
Both Both Ketogenic Ketogenic and and Glucogenic Glucogenic Amino Amino AcidsAcids
Fate of carbon skeleton
The coenzyme for serine dehydratase is:The coenzyme for serine dehydratase is:
a. Thiamine pyrophosphate.a. Thiamine pyrophosphate.
b. Pyridoxal phosphate.b. Pyridoxal phosphate.
c. Adenosine triphosphate.c. Adenosine triphosphate. d. Nicotinamide mononucleotide.d. Nicotinamide mononucleotide.
MCQMCQ
MCQMCQ
Urea cycle consume:Urea cycle consume: a. 1 ATPa. 1 ATP b. 2 ATPb. 2 ATP c. 3 ATPc. 3 ATP d. 4 ATPd. 4 ATP
The urea cycleThe urea cycle
a. Supplies the body requirement for a. Supplies the body requirement for arginine in infants.arginine in infants.
b. Converts urea to uric acid.b. Converts urea to uric acid.
c. Converts ammonia into urea.c. Converts ammonia into urea.
d. Acts as an energy-supplying mechanism byd. Acts as an energy-supplying mechanism by oxidizing waste materials.oxidizing waste materials.
e. Converts urea to ammonia and carbon e. Converts urea to ammonia and carbon dioxide.dioxide.
Urea formation ocurs mainly in:Urea formation ocurs mainly in: a. Liver.a. Liver.
b. Blood.b. Blood.
c. Kidney.c. Kidney.
d. Spleend. Spleen..
An amino acid not involved in urea cycle is: An amino acid not involved in urea cycle is:
a. Arginine.a. Arginine.
b. Histidine.b. Histidine.
c. Ornithine.c. Ornithine.
d. Aspartic acid.d. Aspartic acid.
L-amino acid oxidase:L-amino acid oxidase:
a) Catalyses an oxidation coupled to the a) Catalyses an oxidation coupled to the
production of ATPproduction of ATP b) Is present in large amounts in normal cells b) Is present in large amounts in normal cells
with high activitywith high activity c) In vivo catalyses a reaction producing Hc) In vivo catalyses a reaction producing H22OO22
d) Uses pyridoxal phosphate as its coenzymed) Uses pyridoxal phosphate as its coenzyme e) Transferes the amino group of an amino e) Transferes the amino group of an amino
acid to an acceptor moleculeacid to an acceptor molecule
The following statements on ammonia are The following statements on ammonia are incorrect except:incorrect except:
a) Its blood level is about 1mg/dla) Its blood level is about 1mg/dl b) It is produced in the brain which is unableb) It is produced in the brain which is unable
to detoxify itto detoxify it c) It is mainly converted to glutaminec) It is mainly converted to glutamine d) Its blood level increase in case of hepatic d) Its blood level increase in case of hepatic
failurefailure e) Its excretion in urine in the form of NHe) Its excretion in urine in the form of NH44CLCL
is decreased in case of acidosisis decreased in case of acidosis
In the urea cycle :In the urea cycle :1. Carbamoyl phosphate is derived directly from1. Carbamoyl phosphate is derived directly from
glutamine and COglutamine and CO22
2. Ornithin reacts with aspartate to generate 2. Ornithin reacts with aspartate to generate arginosuccinate.arginosuccinate.3. The 3. The αα-amino group of arginine forms one of -amino group of arginine forms one of nitrogens of urea.nitrogens of urea.4. N-acetylglutamate is a positive allosteric 4. N-acetylglutamate is a positive allosteric effector of ornithine transcarbamoylase.effector of ornithine transcarbamoylase.5. Aspartate provides nitrogen for synthesis of 5. Aspartate provides nitrogen for synthesis of arginine.arginine.
The first step in the catabolism of most The first step in the catabolism of most amino acids is the transfer of the alpha-amino acids is the transfer of the alpha-amino group to:amino group to:
A.Alpha-ketoglutarate to form oxaloacetate.A.Alpha-ketoglutarate to form oxaloacetate. B.Alpha-ketoglutarate to form aspartate.B.Alpha-ketoglutarate to form aspartate. C.Alpha-ketoglutarate to from alanine.C.Alpha-ketoglutarate to from alanine. D.Alpha-ketoglutarate to from glutamateD.Alpha-ketoglutarate to from glutamate
Which of the following enzyme reaction take place Which of the following enzyme reaction take place during the synthesis of urea from ammonium ion during the synthesis of urea from ammonium ion and glutamate?and glutamate?
a.Carbamoyl phosphate + citrulline = ornithine.a.Carbamoyl phosphate + citrulline = ornithine.
b.Aspartate + citrulline + ATP = argininosuccinate + b.Aspartate + citrulline + ATP = argininosuccinate + AMP + PPi.AMP + PPi.
c.Argininosuccinate = aspartate + arginine.c.Argininosuccinate = aspartate + arginine.
d.CO2 + NHd.CO2 + NH33++ + 2ADP = carbamoyl phosphate + 2ATP. + 2ADP = carbamoyl phosphate + 2ATP.
Place (T) if it is TRUE of (F) if it is FLASEPlace (T) if it is TRUE of (F) if it is FLASE::
Carbamoyl-phosphate synthetase I is a rate-limiting step for Carbamoyl-phosphate synthetase I is a rate-limiting step for urea synthesisurea synthesis(………).(………).
Ammonia excretion decreases in cases of Metabolic Ammonia excretion decreases in cases of Metabolic acidosisacidosis(………).(………).
Ammonia is the major end product of nitrogen catabolism in Ammonia is the major end product of nitrogen catabolism in humanshumans(………)(………)
in cardiac infarction SGOT is increased andin cardiac infarction SGOT is increased and
in hepatic infection, SGPT is increased above the normal levelsin hepatic infection, SGPT is increased above the normal levels . .(………)(………)
11 mg protein yields 4.1 K calmg protein yields 4.1 K cal(………).(………).Excess ammonia formation stimulatesExcess ammonia formation stimulates
urea formationurea formation.. . . (………)(………)
COOH
CHNH2
CH2
CH2
COOH
COOH
C
CH3
O
COOH
C
CH2
CH2
COOH
OCOOH
CHNH2
CH3
+ GPT
B6+
SerineSerine
Non-essential amino acid derived from the amino acid glycine.Non-essential amino acid derived from the amino acid glycine.
SerSerineine
CH COOH
NH2
CH2
OHα –amino β –hydroxy propionic acid
αβ
• The main pathway to biosynthesis of serine starts with the glycolytic intermediate 3-phosphoglycerate.
• An NADH-linked dehydrogenase converts 3-phosphoglycerate into a keto acid, 3-phosphopyruvate
• Aminotransferase activity with glutamate as a donor produces 3-phosphoserine, which is converted to serine by phosphoserine phosphatase.
• As indicated below, serine can be derived from glycine (and visa versa) by a single step reaction that involves serine hydroxymethyltransferase and tetrahydrofolate (THF).
• The main pathway to biosynthesis of serine starts with the glycolytic intermediate 3-phosphoglycerate.
• An NADH-linked dehydrogenase converts 3-phosphoglycerate into a keto acid, 3-phosphopyruvate
• Aminotransferase activity with glutamate as a donor produces 3-phosphoserine, which is converted to serine by phosphoserine phosphatase.
• As indicated below, serine can be derived from glycine (and visa versa) by a single step reaction that involves serine hydroxymethyltransferase and tetrahydrofolate (THF).
Biosynthesis of serineBiosynthesis of serine
I.Biosynthesis of serineI.Biosynthesis of serine
1.From glycolytic intermediates (3-phosphoglycerate)1.From glycolytic intermediates (3-phosphoglycerate)
22..From glycine by serine hydroxymethyl transferaseFrom glycine by serine hydroxymethyl transferase
..H-CH- COOH I
NH2
CH2-CH-COOH I I
OH NH2
Serine
Glycine
THF ~ CH2OH
THFPLP
Serine hydroxymethyltransferase
Conversion of Serine to PyruvateConversion of Serine to Pyruvate
..CH2-CH-COOH I I
OH NH2
CH2=C-COOH
NH2
CH3C-COOH II NH
H2O
NH3Serine
Pyruvic acid
H2O
O
CH3C-COOH
)Glucogenic( )Glucogenic(
II- Catabolism of serineII- Catabolism of serine::
1- Conversion to glycine, then by glycine 1- Conversion to glycine, then by glycine
cleavage system, it is cleaved to COcleavage system, it is cleaved to CO22 & NH & NH33
2- Conversion to pyruvate by serine dehydratase2- Conversion to pyruvate by serine dehydratase
(serine is glucogenic amino acid).(serine is glucogenic amino acid).
Catabolism of serineCatabolism of serine
Serine
PyruvateGlycine
Serine hydroxymethyltransferase
THF
PLP PLP
H2O
NH3
Serine dehydratase
)Glucogenic( )Glucogenic(glycine cleavage systemglycine cleavage systemglycine cleavage systemglycine cleavage system
CO2 +NH3CO2 +NH3
THF ~ CH2OH
THF ~ CH2OH
CH COOH
NH2
CH2
OH
III- Functions and derivativesIII- Functions and derivatives:: Incorporated into proteins.Incorporated into proteins.
1.It provides the carbon skeleton of cysteine.1.It provides the carbon skeleton of cysteine.
2.It forms glycine by serine hydroxymethyltransferase.2.It forms glycine by serine hydroxymethyltransferase.
3.Synthesis of ceramide 3.Synthesis of ceramide
(conjugation with palmitoyl CoA).(conjugation with palmitoyl CoA).
4.Synthesis of ethanolamine by decarboxylation. 4.Synthesis of ethanolamine by decarboxylation.
Thus it is essential for the synthesis of phospholipids. Thus it is essential for the synthesis of phospholipids.
(It is a lipotropic factor).(It is a lipotropic factor).
5.It is a source for one carbon moiety.5.It is a source for one carbon moiety.
CysteineCysteine
It is non essential sulfur containing It is non essential sulfur containing and glucogenic amino acid.and glucogenic amino acid.
SH NH2
CH2-CH-COOH
SH NH2
CH2-CH-COOH
I- SynthesisI- Synthesis::
Cysteine is formed in the body from Cysteine is formed in the body from
1.1.homocysteinehomocysteine (provides the thiol group) (provides the thiol group)
2. 2. serineserine provides the carbon skeleton. provides the carbon skeleton.
Homocysteine is provided by Homocysteine is provided by methionine.methionine.
NH2NH2
II-Functions and DerivativesII-Functions and Derivatives::
1.It is one of the 1.It is one of the 20 primary amino acids20 primary amino acids of proteins. of proteins.
2.Cysteine is converted to pyruvate and thus it is a 2.Cysteine is converted to pyruvate and thus it is a glucogenic amino acidglucogenic amino acid. .
3- Formation of 3- Formation of thioethanolaminethioethanolamine..
4. Formation of 4. Formation of bile saltsbile salts::
Cysteine forms taurine which shares in formation of bile Cysteine forms taurine which shares in formation of bile acids and salts e.g. sodium taurocholate.acids and salts e.g. sodium taurocholate.
ThioethanolamineThioethanolamine
11..Provides the thiol group of Provides the thiol group of ACPACP
component of fatty acid Synthase multienzyme complexcomponent of fatty acid Synthase multienzyme complex..
2.Is a component of 2.Is a component of CoASH.CoASH.
5- Synthesis of cystine:5- Synthesis of cystine:
The disulfide bond of cystine stabilize tertiary structure of proteins.e.g. insulin, Keratin and immunoglobulins.
The disulfide bond of cystine stabilize tertiary structure of proteins.e.g. insulin, Keratin and immunoglobulins.
NAD NADH+HNAD NADH+H++
6- Synthesis of Glutathione 6- Synthesis of Glutathione
Tripeptide : Glu- Cys- GlyTripeptide : Glu- Cys- Gly
It is an important reducing agent, since it is present in It is an important reducing agent, since it is present in reduced (G-SH) and oxidized forms (G-S-S-G)reduced (G-SH) and oxidized forms (G-S-S-G) . .
GlyGlyCysCysGluGlu
7- 7- HH22S formed by the action of desulfhydraseS formed by the action of desulfhydrase is the is the
source of active sulfate (PAPS) which is used for source of active sulfate (PAPS) which is used for synthesis of sulfur containing compounds e.g. synthesis of sulfur containing compounds e.g. sulfolipids.PAPS is also used in detoxification sulfolipids.PAPS is also used in detoxification reactions as in case of indole and skatole.reactions as in case of indole and skatole.
Cysteine
Pyruvate
H2SNH3
Cysteine desulfhydrase
(PAPS)(PAPS)(PAPS)(PAPS)
active sulfateactive sulfateactive sulfateactive sulfate
SHSH
PyruvicPyruvic
8- The thiol group of cysteine forms the active8- The thiol group of cysteine forms the active
group of many enzymes e.g. group of many enzymes e.g.
1.glyceraldehyde-3-phosphate dehydrogenase, 1.glyceraldehyde-3-phosphate dehydrogenase, 2.fatty acid synthase multienzyme 2.fatty acid synthase multienzyme complex.complex.
SH NH2
CH2-CH-COOH
SH NH2
CH2-CH-COOH
MethionineMethionine
It is essential sulfur containing and It is essential sulfur containing and glucogenic amino acid glucogenic amino acid
I- Functions and DerivativesI- Functions and Derivatives::
1- Methionine condenses with ATP forming S-adenosyl 1- Methionine condenses with ATP forming S-adenosyl methionine (active methionine methionine (active methionine (SAM)(SAM) which is the which is the main main methyl donormethyl donor in the body. in the body.
The activated methyl group may transfer to various The activated methyl group may transfer to various acceptors in transmethylation reactions. acceptors in transmethylation reactions.
Active methionine (SAM)Active methionine (SAM)
ATPATP
Active methionineActive methionine
After transmethylation, the remaining part, After transmethylation, the remaining part, homocysteine, has 3 routes of metabolism, depending homocysteine, has 3 routes of metabolism, depending on the physiological needs of the bodyon the physiological needs of the body::
homocysteine desulfhydrasehomocysteine desulfhydrase
-Ketobutyrate, ammonia and H2S-Ketobutyrate, ammonia and H2S
II
IIIIII
IIII
22 - -SAM is used in many transmethylation reactionsSAM is used in many transmethylation reactions
(a) Phosphatidyl Ethanolamine Phosphatidyl Choline(a) Phosphatidyl Ethanolamine Phosphatidyl Choline
(b) Norepinephrine (b) Norepinephrine EpinephrineEpinephrine
(c) Guanidoacetic acid (c) Guanidoacetic acid creatinecreatine
(d) N-acetyl serotonin(d) N-acetyl serotonin melatoninmelatonin
(e)Nicotinamide(e)Nicotinamide methylnicotinamide methylnicotinamide
CH3CH3
CH3CH3
CH3CH3
CH3CH3
CH3CH3
II- Metabolism of HomocysteineII- Metabolism of Homocysteine::
After transmethylation, the remaining After transmethylation, the remaining part, homocysteine, has 3 routes of part, homocysteine, has 3 routes of metabolism, depending on the metabolism, depending on the physiological needs of the body:physiological needs of the body:
11....If methionine is needed, homocysteine is If methionine is needed, homocysteine is remethylated (salvage pathway)remethylated (salvage pathway)..
2.If cysteine is needed, it is synthesized via 2.If cysteine is needed, it is synthesized via
cystathionine , homoserine is further metabolized tocystathionine , homoserine is further metabolized to
form propionyl CoA. thus, methionine is glucogenic.form propionyl CoA. thus, methionine is glucogenic.
Homocysteine desulfhydrase which hydrolyzes homocysteine to -Ketobutyrate, ammonia and H2S
Homocysteine desulfhydrase which hydrolyzes homocysteine to -Ketobutyrate, ammonia and H2S
3. When methionine and cysteine are present in adequate amounts, cystathionase activates homocysteine desulfhydrase which hydrolyzes homocysteine to -Ketobutyrate, ammonia and H2S.
3. When methionine and cysteine are present in adequate amounts, cystathionase activates homocysteine desulfhydrase which hydrolyzes homocysteine to -Ketobutyrate, ammonia and H2S.
Phenylalanine
CH2 CH-COOH I
NH2
Tyrosine
CH2 CH-COOH I
NH2
IOH
Amino Acids with Aromatic Side Chain
1. They are aromatic amino acids. 2. Phenylalanine is essential amino acid, while tyrosine
is not essential in the presence of a good supply of
phenylalanine. 3. Hydroxylation of Phenylalanine gives rise to tyrosine.
1. They are aromatic amino acids. 2. Phenylalanine is essential amino acid, while tyrosine
is not essential in the presence of a good supply of
phenylalanine. 3. Hydroxylation of Phenylalanine gives rise to tyrosine.
1-Synthesis of tyrosine 1-Synthesis of tyrosine
II-II- Catabolic pathways of phenylalanineCatabolic pathways of phenylalanine::
There are 2 pathways for catabolism of There are 2 pathways for catabolism of phenylalanine:-phenylalanine:-
1- Direct pathway (1- Direct pathway (minor)minor) where phenylalanine by where phenylalanine by transamination reaction forms transamination reaction forms phenylpyruvic acidphenylpyruvic acid which is excreted in urine via its metabolites. which is excreted in urine via its metabolites.
2- Phenylalanine is transformed to 2- Phenylalanine is transformed to tyrosinetyrosine ( (majormajor pathway) in the liver then tyrosine is catabolized to pathway) in the liver then tyrosine is catabolized to fumaric acid and acetoacetic acidfumaric acid and acetoacetic acid i.e. phenylalanine i.e. phenylalanine and tyrosine are both glucogenic and ketogenic.and tyrosine are both glucogenic and ketogenic.
Catabolism of PhenylalanineCatabolism of Phenylalanine
..
Major Catabolic Pathway
Major Catabolic Pathway
Minor Catabolic Pathway
Minor Catabolic Pathway
Minor Catabolic Pathway of Phenylalanine
Minor Catabolic Pathway of Phenylalanine
Acetoacetate
L-Phenylalanine
Tetrahydrobiopterin + O2Phenylalanine
hydroxylaseDihydrobiopterrin
+ H2O
L-Tyrosine
Fumarate
NADP+
NADPH+H+
GlucogenicGlucogenic KetogenicKetogenic
ReductaseReductase
Major Catabolic Pathway of PhenylalanineMajor Catabolic Pathway of Phenylalanine
III- Functions and derivatives:III- Functions and derivatives:
11((MelaninMelanin: in the melanocytes (pigment cells) in the skin, : in the melanocytes (pigment cells) in the skin, hair and eyehair and eye..
TyrosinaseTyrosinase
Tyrosine Dopa dopaquinoneTyrosine Dopa dopaquinone
condensation and cyclization melanincondensation and cyclization melanin
22 . .Synthesis of Synthesis of thyroidthyroid hormones hormones T T44
HO CH2 CH COOH
NH2
I
I
HO CH2 CH COOH
NH2
I
I
CH COOH
NH2
CH3
Tetra-iodothyronine (T4, thyroxine).Tetra-iodothyronine (T4, thyroxine).
Alanine Alanine
++
3-5-Diiodotyrosine 3-5-Diiodotyrosine 3-5-Diiodotyrosine 3-5-Diiodotyrosine
Synthesis of thyroidSynthesis of thyroid hormones hormones T T33
HO CH2 CH COOH
NH2
I
3-Monoiodotyrosine 3-Monoiodotyrosine
HO CH2 CH COOH
NH2
I
I3-5-Diiodotyrosine 3-5-Diiodotyrosine
++
CH COOH
NH2
CH3
AlanineAlanine
Tri-iodothyronine (T3 )Tri-iodothyronine (T3 )
Both reactions occur in the thyroglobulin, Then T3 Both reactions occur in the thyroglobulin, Then T3
and T4 are releasedand T4 are released..
3) Tyrosine forms3) Tyrosine forms catecholamines catecholamines
This occurs in cells of neural origin and in This occurs in cells of neural origin and in the adrenal medulla. .the adrenal medulla. .
Catabolism of PhenylalanineCatabolism of Phenylalanine
II
IIII
IIIIII
Minor Catabolic PathwayMinor Catabolic Pathway
Major Catabolic PathwayMajor Catabolic Pathway
Functions of Phenylalanine and TyrosineFunctions of Phenylalanine and Tyrosine
1. Synthesis of catecholamines;1. Synthesis of catecholamines;
a. Adrenaline (epinephrine).a. Adrenaline (epinephrine).
b. Noradrenaline (norepinephrine).b. Noradrenaline (norepinephrine).
c. Dopamine.c. Dopamine.
2. Synthesis of thyroid hormones;2. Synthesis of thyroid hormones;
a. Tri-iodothyronine (T3).a. Tri-iodothyronine (T3).
b. Tetra-iodothyronine (T4, thyroxine).b. Tetra-iodothyronine (T4, thyroxine).
3. Synthesis of melanin pigments.3. Synthesis of melanin pigments.
4.4. Synthesis of tissue proteins.Synthesis of tissue proteins.
5.5. Source of energy.Source of energy.
L-Tyrosine
Tetrahydrobiopterin (BH4) + O2
Tyrosinehydroxylase
Dihydrobiopterrin(BH2) + H2O
DOPA
NADP+
NADPH
BH2 ReductaseBH2 Reductase
Synthesis of CatecholaminesSynthesis of Catecholamines(Dopamine, Adrenaline and Noradrenaline)(Dopamine, Adrenaline and Noradrenaline)
..
CatecholaminesCatecholamines
L-Phenylalanine
Phenylalaninehydroxylase
Phenylalaninehydroxylase
Tetrahydrobiopterin (BH4) + O2
Dihydrobiopterrin(BH2) + H2O
BH2 ReductaseBH2 Reductase
III- Metabolic Disorders of phenylalanine and Tyrosine III- Metabolic Disorders of phenylalanine and Tyrosine catabolism catabolism-:-:
1.Phenylketonuria (PKU):1.Phenylketonuria (PKU):
2. Tyrosinemia or tyrosinosis2. Tyrosinemia or tyrosinosis
3.Alkaptonuria 3.Alkaptonuria
4.Albinism4.Albinism
11..Phenylketonuria (PKU)Phenylketonuria (PKU)::
It is an inherited metabolic disorder of phenylalanine It is an inherited metabolic disorder of phenylalanine caused by defective liver phenylalanine hydroxylase caused by defective liver phenylalanine hydroxylase or dihydrobiopterin reductase. or dihydrobiopterin reductase.
The disease is characterized by The disease is characterized by
phenylpyruvic, phenylacetic phenylpyruvic, phenylacetic
and phenyllactic acid and phenyllactic acid
in blood and urine.in blood and urine.
**both parents must be carriersboth parents must be carriers of the gene of the gene
The signs and symptoms includeThe signs and symptoms include-:-:
1. Mental retardation.1. Mental retardation. 2. Eczema of the skin.2. Eczema of the skin. 3. Mousy odour of urine.3. Mousy odour of urine. 4. Hypopigmentation4. Hypopigmentation
Hypopigmentation as a result of decreased melanin pigment will lead to fair skin and hair and blue eyes.
Hypopigmentation as a result of decreased melanin pigment will lead to fair skin and hair and blue eyes.
The disease could be diagnosed byThe disease could be diagnosed by
1. increased plasma phenylalanine levels (>20 mg/dl) 1. increased plasma phenylalanine levels (>20 mg/dl)
(normal: 0.7 – 4 mg/dl); and by (normal: 0.7 – 4 mg/dl); and by
2. using ferric chloride test which gives a blue-green 2. using ferric chloride test which gives a blue-green
colour with urine.colour with urine.
Treatment is through a diet low in Treatment is through a diet low in phenylalanine and rich in tyrosine.phenylalanine and rich in tyrosine.
22..Tyrosinemia or tyrosinosisTyrosinemia or tyrosinosis::
Inherited metabolic disorders characterized by Inherited metabolic disorders characterized by high levels of plasma tyrosinehigh levels of plasma tyrosine. .
Death usually occurs early from liver failure. Death usually occurs early from liver failure.
Treatment is by low tyrosine and Treatment is by low tyrosine and phenylalanine diet.phenylalanine diet.
The most important types areThe most important types are-:-:
Hepatorenal typeHepatorenal type (Type I tyrosinemia) (Type I tyrosinemia) due to due to fumaryl acetoacetate hydrolase deficiencyfumaryl acetoacetate hydrolase deficiency..
OculocutaneousOculocutaneous type (Type II tyrosinemia) type (Type II tyrosinemia) due to due to hepatic tyrosine transaminase deficiencyhepatic tyrosine transaminase deficiency..
Neonatal tyrosinemiaNeonatal tyrosinemia due to defective due to defective p-p-hydroxy phenyl pyruvate hydroxylase.hydroxy phenyl pyruvate hydroxylase.
33..AlkaptonuriaAlkaptonuria::
Inherited metabolic disorder due to defect in Inherited metabolic disorder due to defect in homogentisate oxidase.homogentisate oxidase.
This causes accumulation of homogentisate in blood This causes accumulation of homogentisate in blood and urine.and urine.
Homogentisate is oxidized into brownish black Homogentisate is oxidized into brownish black pigment that causes pigment that causes
1.darkening of urine on standing in air. 1.darkening of urine on standing in air. 2.There is also arthritis and 2.There is also arthritis and 3.generalized pigmentation of connective tissue 3.generalized pigmentation of connective tissue (Ochronosis).(Ochronosis).
44..AlbinismAlbinism-:-:
AlbinismAlbinism is due to deficiency of is due to deficiency of tyrosinase enzymetyrosinase enzyme in the skin, hair and eyes. So, melanin pigments in the skin, hair and eyes. So, melanin pigments will not be formed leading to will not be formed leading to
1. white colour of skin and make it sensitive to light that 1. white colour of skin and make it sensitive to light that may lead to burn and carcinoma. may lead to burn and carcinoma.
2. Lack of pigments in hair cause fair hair, and 2. Lack of pigments in hair cause fair hair, and
3. lack of pigments in the eyes cause photophobia.3. lack of pigments in the eyes cause photophobia.
The patient is called Albino.The patient is called Albino.
Symptoms:Absence of color in skin , hair & iris of the eyes
Symptoms:Absence of color in skin , hair & iris of the eyes
AlbinoAlbino
Treatment:Protection of the skin and eyes from the sun by Avoiding the sun and using sun screen with high sun protection factor.
Treatment:Protection of the skin and eyes from the sun by Avoiding the sun and using sun screen with high sun protection factor.
P- Hydroxyphenylpyruvate
PhenylalanineO2
O2
H2O
Tyrosine-KG
Tyrosine transaminase
PLP
Glu
HomogentisateCO2
Ascorbate + Cu2+O2
Ascorbate Fe2+
Maleylacetaoacetate
GSH
Fumarylacetoacetate
H2O
Fumarylacetoacetate hydrolase
AcetoacetateFumarate
Phenylketonuria
Alkaptonuria
Phenylalanine hydroxylasePhenylalanine hydroxylase
Homogentisatedioxygenase
Homogentisatedioxygenase
Maleylacetoacetatecis- transisomerase
Maleylacetoacetatecis- transisomerase
P-Hydroxyphenyl-pyruvate hydroxylaseP-Hydroxyphenyl-pyruvate hydroxylase
Major Catabolic Pathway of PhenylalanineMajor Catabolic Pathway of Phenylalanine
Tyrosinemia II Tyrosinemia II
Tyrosinemia I Tyrosinemia I
N .Tyrosinemia N .Tyrosinemia
TryptophanTryptophan
It is an essential, glucogenic and It is an essential, glucogenic and ketogenic, heterocyclic amino acid.ketogenic, heterocyclic amino acid.
N
CH2-CH-COOH
NH2
H
I- Catabolic pathwayI- Catabolic pathway::
Tryptophan is catabolized to acetoacetyl CoA Tryptophan is catabolized to acetoacetyl CoA (ketogenic) and alanine is developed through (ketogenic) and alanine is developed through this pathway (glucogenic).this pathway (glucogenic).
Also Also niacinniacin can be synthesized through this can be synthesized through this
pathway. pathway.
TryptophanTryptophan
NiacinNiacin
AlanineAlanine
(Ketogenic)(Ketogenic)
(Glucogenic)(Glucogenic)
Acetoacetyl CoAAcetoacetyl CoA
Catabolic pathwayCatabolic pathway
B6B6
(vit. B3 )(vit. B3 )(vit. B3 )(vit. B3 )
N
CH2-CH-COOH
H
NH2
OHOH
XANTHURENICXANTHURENIC
NN
OHOH
COOHCOOH
Biological Functions of TryptophanBiological Functions of Tryptophan
1.1. Formation of niacin.Formation of niacin.
22 . .Formation of serotoninFormation of serotonin..
33 . .Formation of melatoninFormation of melatonin..
11 - -Convesion to niacinConvesion to niacin-:-:
Tryptophan will form niacin which is one of the B vitaminsTryptophan will form niacin which is one of the B vitamins . .
Niacin enters in the formation of NAD and NADPNiacin enters in the formation of NAD and NADP..
..
6060 mg Tryptophan mg Tryptophan 1mg niacin1mg niacin..
Lack of niacin causes pellagra
Lack of niacin causes pellagra
PellagraPellagra-:-:
Pellagra is a disease caused by severe niacin Pellagra is a disease caused by severe niacin deficiencydeficiency..
It is characterised byIt is characterised by-:-:
Disturbance in lipid, carbohydrate and protein Disturbance in lipid, carbohydrate and protein metabolismmetabolism..
33 D’sD’s::
* * Diarrhea, alternating with constipationDiarrhea, alternating with constipation..
* *Dermatitis in the sunexposed areasDermatitis in the sunexposed areas,,
especially the V-shaped chest areaespecially the V-shaped chest area..
* *Dementia or progressive loss of all cerebralDementia or progressive loss of all cerebral
functionsfunctions..
Causes of PellagraCauses of Pellagra-:-:1- Diet poor in both niacin and tryptophan e.g. 1- Diet poor in both niacin and tryptophan e.g.
eating eating maize maize as the sole diet which contains as the sole diet which contains protein called zein that is low in tryptophan.protein called zein that is low in tryptophan.
2- 2- Malignant carcinoidMalignant carcinoid syndrome in which syndrome in which tryptophan metabolism is directed into the tryptophan metabolism is directed into the formation of serotonin.formation of serotonin.
3- 3- Hartnup diseaseHartnup disease in which there is impairment in which there is impairment of tryptophan absorption.of tryptophan absorption.
4- 4- Vitamin BVitamin B66 deficiency potentiates niacin deficiency potentiates niacin deficiency as in isoniazid drug, used in deficiency as in isoniazid drug, used in treatment of tuberculosis.treatment of tuberculosis.
Metabolic disordersMetabolic disorders
1-Hartnup disease1-Hartnup disease 2-B6 deficiency excretion of 2-B6 deficiency excretion of
xanthurenic acid in urine due to inhibition xanthurenic acid in urine due to inhibition of kinurininase enzymeof kinurininase enzyme
Glutamate (Glu.)Glutamate (Glu.)
It is an It is an acidicacidic, , nonessentialnonessential and and
glucogenicglucogenic amino acid. amino acid.
I- Synthesis of Glutamic acid:I- Synthesis of Glutamic acid:
1- It is synthesized by 1- It is synthesized by -Ketoglutarate-Ketoglutarate
by by glutamate transaminaseglutamate transaminase or or glutamate glutamate
dehydrogenasedehydrogenase which are reversible which are reversible
reactions.reactions.
COOH COOH
CHNH2 C O
CH2 CH2
CH2 CH2
COOH COOH
KA AA
Glutamate transaminase
NAD(P)+
H2O
NAD(P)H + H+
NH3
Glutamate dehydrogenase
II- Significance of Glutamate:II- Significance of Glutamate: one of the 20 primary aa of one of the 20 primary aa of protein synthesis.protein synthesis. It is It is deaminated to -Ketoglutaric aciddeaminated to -Ketoglutaric acid which can form which can form
glucose (glucose (glucogenicglucogenic) or oxidized for energy.) or oxidized for energy. It is important constituent of It is important constituent of glutathioneglutathione.. It is important constituent of It is important constituent of folicfolic acidacid.. N-acetyl glutamateN-acetyl glutamate is an activator for carbamoyl is an activator for carbamoyl
phosphate synthetase 1 in urea synthesis.phosphate synthetase 1 in urea synthesis. It is It is precursor of -aminobutyrate (GABA),precursor of -aminobutyrate (GABA), an important an important
inhibitory neurotransmitterinhibitory neurotransmitter. In B6 deficiency, . In B6 deficiency, diminished GABA leads to convulsions in children.diminished GABA leads to convulsions in children.
GABAGABA
Synthesis & Catabolism of Synthesis & Catabolism of Glutamine.Glutamine.
Significance of Glutamine:Significance of Glutamine: one of the primary amino acids used for one of the primary amino acids used for protein protein
synthesissynthesis.. It plays a role in It plays a role in ammonia detoxificationammonia detoxification in the in the
brain and liver.brain and liver. It is important in some It is important in some detoxification detoxification reactions e.g. reactions e.g.
With phenylacetate, it forms With phenylacetate, it forms phenylacetylglutaminephenylacetylglutamine; a urinary metabolite.; a urinary metabolite.
In the kidney, In the kidney, glutaminaseglutaminase activity is activity is increased in increased in cases of acidosiscases of acidosis. . Excretion of NH4+Excretion of NH4+ is one of the is one of the renal mechanism for excretion of H+ in renal mechanism for excretion of H+ in acidosis.acidosis.
The amide group of glutamine is used for:-The amide group of glutamine is used for:- Synthesis of amino sugars.Synthesis of amino sugars. Synthesis of purines (N3 and N9).Synthesis of purines (N3 and N9). Synthesis of pyrimidines (N3 and NH2 Synthesis of pyrimidines (N3 and NH2
of cytosine [UTP of cytosine [UTP CTP]) CTP]) Conversion of XMP Conversion of XMP GMPGMP Synthesis of asparagine.Synthesis of asparagine.
Aspartate (ASP)Aspartate (ASP)
•It is an acidic, nonessential, glucogenic amino acid. It can be formed from oxaloacetate.
Functions and derivatives of Functions and derivatives of AspartateAspartate-:-:
1.1. Asp is transaminated or deaminated Asp is transaminated or deaminated to oxaloacetate, which can form to oxaloacetate, which can form glucose (glucogenic) or oxidized to glucose (glucogenic) or oxidized to give energy.give energy.
2.2. It is one of the 20 primary amino acids It is one of the 20 primary amino acids of protein synthesis.of protein synthesis.
3. 3. Synthesis of Synthesis of ureaurea (formation of (formation of argininosuccinate).argininosuccinate).
4. 4. PyrimidinePyrimidine synthesis, it supplies N1, C4, synthesis, it supplies N1, C4, C5 and C6.C5 and C6.
5. 5. PurinePurine synthesis (N1) and in conversion synthesis (N1) and in conversion of IMP to adenylosuccinate.of IMP to adenylosuccinate.
6. 6. DecarboxylationDecarboxylation of aspartate, yields of aspartate, yields B-B-
alaninealanine (H2N-CH2- CH2-COOH) which is (H2N-CH2- CH2-COOH) which is
a component of a component of coenzyme A.coenzyme A.
7. 7. It is a precursor of It is a precursor of asparagineasparagine, a primary , a primary amino acid in protein synthesis.amino acid in protein synthesis.
MCQMCQ
Required for tyrosine biosynthesis:Required for tyrosine biosynthesis:
1.Serotonin.1.Serotonin.
2.Dihydrobiopetrin.2.Dihydrobiopetrin.
3.Hydroxybutyrate.3.Hydroxybutyrate.
4.Inositol.4.Inositol.
A pellagra – like skin rash may be seen inA pellagra – like skin rash may be seen in-:-:
1.Phenylketonuria.1.Phenylketonuria.
2.Homogentisic aciduria.2.Homogentisic aciduria.
3.Hartnup disease.3.Hartnup disease.
4.Methylmalonic academia.4.Methylmalonic academia.
Tyrosine would be an essential amino Tyrosine would be an essential amino acid in the diet of a child withacid in the diet of a child with::
a) Lesch Nyhan Syndromea) Lesch Nyhan Syndrome b) defective tyrosine aminotransferaseb) defective tyrosine aminotransferase c) deficiency of pyridoxine.c) deficiency of pyridoxine. d) classical phenylketonuria.d) classical phenylketonuria. e) Galactosemia e) Galactosemia
- In patient with alkaptonuria, which one of In patient with alkaptonuria, which one of the following enzyme is absent:the following enzyme is absent:
A. homogentisic acid oxidaseA. homogentisic acid oxidase B. tyrosine transaminaseB. tyrosine transaminase C. tryptophan hydroxylaseC. tryptophan hydroxylase D. phenylalanine decarboxylaseD. phenylalanine decarboxylase E. leucine transaminaseE. leucine transaminase
Absorption of which one of the following Absorption of which one of the following aminoacids is defective in Hartnup's aminoacids is defective in Hartnup's diseasedisease::
A. glycineA. glycineB. lysineB. lysineC. leucineC. leucineD. tyrosineD. tyrosineE. tryptophanE. tryptophan