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