Protein Metabolism

PROF. DR. MOHAMED

NAGUIB

Dietary protein
Pepsin
Stomach liver

Polypeptides and amino acids

Pancreas

To liver

Trypsin Chymotrypsin Carboxypeptidase Elastase

Oligopeptides and amino acids

Small intestine

Aminopeptidases Tripeptidase Dipeptidase

Amino acids

Digestion of dietary proteins by the proteolytic enzymes of the gastro-intestinal tract.

Enzymes are secreted inactive to avoid autodigetion Chronic pancreatitis :maldigetion

Pepsin

H 2N-CH-COHN-CH-CONH-CH-CO NH-CH-CONH-CH-CONH-CH-CONH-CH-COOH R1 R2 R3 R4
Phenyalanine Tyrosine

R5

R6

R7

Amino acids

N.B. :
The digestion destroys its antigenicity. If absorbed as polypeptide, produces allergy in the form of urticaria , bronchial asthma and hay's fever.

Absorption
From lumen to intestinal cell By a.a or peptide transport system (carrier) ATP  Against concentration gradient  Needs Na ion as cotransporter


ACTIVE PROCESS Inside the cell complete dig by Aminopeptidase , Di &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 pathway
a) Urea: formed in the liver, is considered as the main metabolic end product of protein catabolism. energy: b) Supplying energy: cal, 1 gram protein yields 4.1 K cal, only if there is 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.

Nitrogen balance:
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 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: A condition in which there is increase in the N2 intake over the output.

N2 INTAKE

>

N2 LOST
Nitrogen output Nitrogen intake

It may occur in growth, pregnancy or convalescence from diseases. diseases.

Negative nitrogen balance: A condition in which there is either decreased N2 intake as in :  starvation  malnutrition,maldigestion, malabsorption,  severe vomiting, severe diarrhea Or increased N2 lost as in  hemorrhage, burns,  old age or debilitating disease. N2 LOST > N2 INTAKE

General Metabolism of Proteins : Complete breakdown of proteins and amino acids give rise to

Urea + Co2 + H2O + Energy. Energy.

The major pathway for amino acids excess  after protein synthesis is the removal of the amino group and its conversion to ammonia . The liver is the major site of removal of amino group from amino acids..


The amino group is removed by different mechanisms:

1. Transamination

2. Oxidative deamination  3. Non-oxidative deamination  Non4. Transdeamination 

I . Transamination :
 It

transfers the amino group from an amino acid to -keto acid. the amino acids participate in the reaction of transamination except threonine and lysine. Vitamin B6 is required as a coenzyme. enzymes are termed transaminases

 All

 Its

a) Aspartate transaminase: (AST) or(GOT)

COOH CHNH2 + CH2 CH2 COOH

COOH C O CH2 COOH

GOT

B6

COOH C O CH2 + CH2 COOH

COOH CHNH2 CH2 COOH

Glutamic acid Oxaloacetic acid

-Ketoglutaric acid Aspartic acid

b) Alanine transaminase: (ALT)or(GPT)

COOH CHNH2 CH2 CH2 COOH
Glutamic acid Pyruvic acid

COOH C O CH3
GPT B6

COOH C O CH2 CH2 COOH

-Ketoglutaric acid

COOH CHNH2 CH3

Alanine

Transaminases are cytosolic and mitochondrial enzymes. It is a freely reversible process.

Biological importance of Transamination

1- Synthesis of new non-essential amino acids. non2- Degradation of most amino acids except lysine and threonine. 3- Formation of components of citric acid cycle (filling up reaction of citric acid cycle). 4-Transaminase enzymes are used in diagnosis and prognosis of the diseases.

N.B. Transaminase enzymes are present  inside the cells and small traces are present in the blood ( 5 - 40 IU/L). The increase in their level denote cell  damage with the release of enzymes from the destructed cells. E.g.  in cardiac infarction SGOT is increased in hepatic infection, SGPT is increased above the normal levels. levels.

II. Oxidative deamination: It is catalyzed by : Amino acid oxidases  Occur in liver and kidney. It includes removal of hydrogen (oxidation) and  removal of NH3 (deamination). There are D- and L-amino acid oxidases that  Loxidizes D- and L-amino acids respectively, to DLthe corresponding -keto acids and the amino group is released as ammonia (NH3).

Oxidative deamination
NH2 R-CH-COOH
Aminoacid Flavin

NH
Amino acid oxidase

R-C-COOH
Iminoacid

1
Flavin-H2

H2O
2

NH3
H2O2 Catalase
1/2 O2

O2

O R-C-COOH
E -Ketoacid

H2O

 D-amino

acid oxidase uses FAD as coenzyme which is of limited occurance in mammals and of high activity, activity,

 L-amino

acid oxidase uses FMN as coenzyme which is of high occurrance in mammals, but of low activity. Imp for Lysine activity.  L-Glutamate dehydrogenase uses NAD OR NADP as coenzyme .For Glutamic acid the only a.a undergo O.D in high rate.

III - Non-oxidative deamination Non(direct deamination):

 The

- amino group of serine and threonine ( amino acids containing hydroxyl group) can be group) directly converted to NH3 without removal of hydrogen.  This reaction is catalyzed by serine and threonine dehydratase which need pyriodoxal phosphate as coenzyme.

NonNon-oxidative deamination (direct deamination)

OH NH2 CH 2-CH-COOH
L-serine

H2O

NH 2
Serine

NH CH3-C-COOH H2O NH 3 CH 3-CO-COOH

dehydratase

CH2=C-COOH

PLP

NonNon-oxidative deamination

pyruvic acid

IV .Transdeamination (L-Glutamate dehydrogenase): (L-

Vit B6 1 1

NAD NADP

COOH CHNH2 CH2 CH2 COOH

Oxidative
L-glutamic acid dehydrogenase

COOH deamination COOH C O C NH CH2 CH2 COOH Iminoacid H2 O NH 3 CH2 CH2 COOH

NADP (NAD)

NADPH+H NADH+H+

Glutamic acid

-ketoglutaric acid

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.

Metabolism of ammonia

Blood level: 100 ug per dl

Sources of blood ammonia: 1.From amino acids :

  

Transdeamination Oxidative deamination NonNon-oxidative deamination .

2.From glutamine :
 

Renal glutaminase Intestinal glutaminase

3.From amines : whether dietary amine or monoamine hormones by amine oxidase. 4. From catabolism of purines and pyrimidines . 5.From bacterial action in the intestine either from dietary protein residue or from urea diffuses into the intestine
(This is of significance in cases of kidney failure ) This

Fates of ammonia (Removal of ammonia):



form non-essential amino acids and other biosynthetic nonreactions. Glutamine synthesis in the brain, liver, muscle and renal tissues (4%). The majority of NH3 (90%) will produce urea in the liver 90%) by urea cycle. Excretion in urine upto 1 gm /24 hours urine. /24 Traces in blood (up to 100 ug / dl).

Oxidative Deamination

Non Oxidative Deamination

Transdeamination

.From

amines
NH3

From bacterial action in the intestine on protein

Glutamine

Purine and pyrimidine

1%

4%

90 %
New aminoacid
Excretion in urine upto 1 gm /24 hours urine /24

Urea Traces in the blood up to 100 ug / dl

Sources and Fates of ammonia

Glutamine synthesis and ammonia formation

In the liver,brain and muscle

Glutamine synthetase

In the kidney Glutaminase

+
ATP ADP+p

H2O

Glutamic acid

Glutamine

Glutamic acid

Mechanism of ammonia excretion by the kidney:

Glutamine

NaHCO3

NH4CL

N.B. Ammonia excretion increases in cases of Metabolic acidosis and decrease in cases of alkalosis.

Ammoniacal Encephalopathy
Interfere with CAC  Manifistation  Causes:Congenital Aquired: liver failiure portocaval shunt gastrointestinal bleeding  Treatment:glu,alpha ketoglu,benzoic acid , phenyl acitic restriction of protiens,frequent small meals dialysis


Krebs urea cycle or ornithine cycle for urea formation

 Urea

is formed in the liver mainly , some in the brain and renal tubules

one molecule of CO2 and two molecules of NH3 using 3 ATP's.

Urea
O H2N- C - NH2

It is released into the blood with a level of

20 - 40 mg/dL


It is the major end product of nitrogen catabolism in humans representing 80-90% 80-90% of the nitrogen excreted.

Urea formation
NH2 NH2 3ATP CO2 +2 NH3 CO NH2 NH2
urea

+ H2O

Five reactions each of them utilises specific enzyme in urea cycle. The first 2 reactions of urea cycle are mitochondrial and the rest 3 reactions are cytoplasmic.

mitochondria

cytoplasm

Five enzymes of urea cycle:

 Carbamoyl  Ornithine

phosphate synthetase 1

transcarbamoylase (citrulline synthase) synthetase.

 Argininosuccinate

 Argininosuccinase.  Arginase.

cytoplasm

mitochondria

Urea Cycle

Urea Cycle

Reactions (steps) of the urea cycle: 1. Carbamoylphosphate formation: Using active CO2 , NH3 , 2 ATP and carabmoylphosphate synthetase I, which is I, a mitochondrial enzyme active in presence of N-acetylglutamic acid.
carabmoylphosphate synthetase I

CO2 + NH3 + 2ATP

H2N.CO. P + 2 ADP + P
Carbamoyl phosphate

2. Formation of citrulline:


By transfer of carbamoyl group from its phosphoric anhydride to the amino group of ornithine. It is done by mitochondrial ornithine transcarbamoylase. Citrulline then diffuses from the mitochondria to the cytosol where the rest of the urea cycle occurs.

Formation of citrulline:
Carbamoyl

Carbamoyl phosphate

H2N.CO. P
2
ornithine transcarbamoylase

ornithine

Citrulline

3. Formation of argininosuccinate:


Citrulline plus aspartate forms argininoargininosuccinate by argininosuccinate synthetase. This requires ATP that changes to AMP+PPi because the ureido group (-NH -CO-NH2) is (COvery stable and requires energy for activtion.

Formation of argininosuccinate:
aspartate

argininosuccinate synthetase

ATP

AMP+ PPi

Citrulline

argininoarginino-succinate

4. Cleavage of argininosuccinate:


To form arginine and fumarate by argininosuccinase. This enzyme is present in liver and kidney of humans.

Cleavage of argininosuccinate:
fumarate

argininosuccinase

argininoarginino-succinate

arginine

5. Formation of urea:


Liver arginase enzyme cleaves arginine to form urea and regenerates ornithine and thus completes the urea cycle.

Formation of urea
urea

arginase

arginine

ornithine

UREA CYCLE

LINK BETWEEN KREBS' UREA CYCLE AND KREBS' TRICARBOXYLIC ACID CYCLE:
1

2ATP CO2 + NH3 2

LINK BETWEEN KREBS' UREA CYCLE AND KREBS' TRICARBOXYLIC ACID CYCLE:

1. The fumarate resulting from reaction number 4 (in Krebs urea cycle), under the influence of argininosuccinase, undergoes conversion to malate by fumarase enzyme in citric acid cycle. This malate forms oxaloacetate by malate dehydrogenase.

2.The CO2 used in urea cycle comes mainly from Krebs' tricarboxylic acid cycle. 3. The oxaloacetate from CAC undergoes Transamination by SGOT to form aspartate in cytoplasm. cytoplasm. This aspartate is needed in urea cycle 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 CYCLE:

 1.

Excess ammonia formation stimulates urea formation. High arginine level stimulates N-acetyl Nglutamate synthase enzyme, thus increases urea formation.

 2.

 3.

High urea level inhibits carbamoylphosphate synthase (reaction 1), ornithine transcarbamoylase (reaction 2) and arginase enzymes (reaction 5).

 4.

Carbamoylphosphate synthetase is inactive in the absence of activator, N-acetylglutamate.

Metabolic fate of the carbon skeleton of amino acids

According to the body need. The Carbon skeleton after removal of the amino group is :

oxidized  or converted to glucose  ketone bodies and fat



Catabolism of Amino Acids

Amino Acid is composed of

Amino group

AND

Carbon skeleton

OR Transferred to a keto acid to form anew amino acid

Released as ammonia

Converted to Glucose, Or ketone bodies

OR Oxidized to CO2 +H2O Energy

According to the metabolic fate Aminoacids are classified into:

1. Ketogenic amino acids 2. Glucogenic amino acids
3. Ketogenic-glucogenic (mixed) amino acids

1- Glucogenic Amino Acids: They produce Pyruvate Intermediates of citric acid cycle Glucose. This group includes most amino acids as glycine,alanine,cysteine,glutamic acid,aspartic acid,serine

  

2- Ketogenic Amino Acids:



This group includes leucine. leucine. It produces Acetyl CoA Acetoacetate which give ketone bodies and fat.

3- Both Ketogenic and Glucogenic Amino Acids:  This group includes phenylalanine, tyrosine, tryptophan, isoleucine and lysine. lysine. Their products can give both, glucose and ketone bodies.

Fate of carbon skeleton

Ketogenic Amino Acids

Both Ketogenic and Glucogenic Amino Acids

Glucogenic Amino Acids

Fate of carbon skeleton

MCQ
The coenzyme for serine dehydratase is:
   

a. Thiamine pyrophosphate. b. Pyridoxal phosphate. c. Adenosine triphosphate. d. Nicotinamide mononucleotide.

MCQ
Urea cycle consume:  a. 1 ATP  b. 2 ATP  c. 3 ATP  d. 4 ATP

The urea cycle



a. Supplies the body requirement for arginine in infants. b. Converts urea to uric acid. c. Converts ammonia into urea. d. Acts as an energy-supplying mechanism by energyoxidizing waste materials. e. Converts urea to ammonia and carbon dioxide.

  

Urea formation ocurs mainly in:  a. Liver.

 b.  c.

Blood. Kidney. d. Spleen. 

An amino acid not involved in urea cycle is:



a. Arginine. b. Histidine. c. Ornithine. d. Aspartic acid.

L-amino acid oxidase:



  

a) Catalyses an oxidation coupled to the production of ATP b) Is present in large amounts in normal cells with high activity c) In vivo catalyses a reaction producing H2O2 d) Uses pyridoxal phosphate as its coenzyme e) Transferes the amino group of an amino acid to an acceptor molecule

The following statements on ammonia are incorrect except:

 

 

a) Its blood level is about 1mg/dl b) It is produced in the brain which is unable to detoxify it c) It is mainly converted to glutamine d) Its blood level increase in case of hepatic failure e) Its excretion in urine in the form of NH4CL is decreased in case of acidosis

In the urea cycle : 1. Carbamoyl phosphate is derived directly from glutamine and CO2 2. Ornithin reacts with aspartate to generate arginosuccinate. 3. The -amino group of arginine forms one of nitrogens of urea. 4. N-acetylglutamate is a positive allosteric Neffector of ornithine transcarbamoylase. 5. Aspartate provides nitrogen for synthesis of arginine.

The first step in the catabolism of most amino acids is the transfer of the alphaalphaamino group to:  A.Alpha-ketoglutarate to form oxaloacetate. A.Alpha B.Alpha-ketoglutarate to form aspartate. B.Alpha C.Alpha-ketoglutarate to from alanine. C.Alpha D.Alpha-ketoglutarate to from glutamate D.Alpha-

Which of the following enzyme reaction take place during the synthesis of urea from ammonium ion and glutamate? a.Carbamoyl phosphate + citrulline = ornithine. b.Aspartate + citrulline + ATP = argininosuccinate + AMP + PPi. c.Argininosuccinate = aspartate + arginine. d.CO2 + NH3+ + 2ADP = carbamoyl phosphate + 2ATP. d.CO2

Place (T) if it is TRUE of (F) if it is FLASE: Carbamoyl-phosphate synthetase I is a rate-limiting Carbamoylratestep for urea synthesis.() Ammonia excretion decreases in cases of Metabolic acidosis.()
 

Ammonia is the major end product of nitrogen catabolism  in humans() in cardiac infarction SGOT is increased and  in hepatic infection, SGPT is increased above the normal levels. levels. ()

1 mg protein yields 4.1 K cal.()  Excess ammonia formation stimulates  urea formation. . ()

COOH CHNH2 CH2 CH2 COOH

+

COOH C O CH3
GPT B6

COOH C O CH2 CH2 COOH

+

COOH CHNH2 CH3

Serine

Non-essential amino acid derived from the amino acid glycine.

Serine Serine

CH2 OH
amino

CH COOH NH2

hydroxy propionic acid

Biosynthesis of serine
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).

I.Biosynthesis of serine
1.From glycolytic intermediates (3-phosphoglycerate)

2.From glycine by serine hydroxymethyl transferase

Glycine

H-CH- COOH I NH2

THF ~ CH2OH
PLP

Serine hydroxymethyl transferase

THF

Serine

CH2-CH-COOH I I OH NH2

Conversion of Serine to Pyruvate

.
CH2-CH-COOH I I OH NH2 CH2=C-COOH NH2 H2O CH3C-COOH II NH H 2O NH3

Serine
O CH3C-COOH

Pyruvic acid
(Glucogenic)

II- Catabolism of serine: II1- Conversion to glycine, then by glycine cleavage system, it is cleaved to CO2 & NH3 2- Conversion to pyruvate by serine dehydratase (serine is glucogenic amino acid).

Catabolism of serine
CH2 CH COOH NH2
THF PLP NH3
H2O

Serine OH
Serine dehydratase
PLP

Serine hydroxymethyl transferase

THF ~ CH2OH

Pyruvate
(Glucogenic)

Glycine
glycine cleavage system

CO2 +NH3

III- Functions and derivatives: IIIIncorporated into proteins. 1.It provides the carbon skeleton of cysteine. 2.It forms glycine by serine hydroxymethyltransferase. 3.Synthesis of ceramide (conjugation with palmitoyl CoA). 4.Synthesis of ethanolamine by decarboxylation. Thus it is essential for the synthesis of phospholipids. (It is a lipotropic factor). 5.It is a source for one carbon moiety.

Cysteine
 It

is non essential sulfur containing and glucogenic amino acid.

SH NH2 CH2-CH-COOH

I- Synthesis:
 Cysteine

is formed in the body from 1.homocysteine (provides the thiol group) 2. serine provides the carbon skeleton. Homocysteine is provided by methionine.

NH2

II-Functions and Derivatives: II1.It is one of the 20 primary amino acids of proteins. 2.Cysteine is converted to pyruvate and thus it is a glucogenic amino acid. acid. 3- Formation of thioethanolamine. thioethanolamine. 4. Formation of bile salts: salts: Cysteine forms taurine which shares in formation of bile acids and salts e.g. sodium taurocholate.

 Thioethanolamine

1.Provides the thiol group of ACP

component of fatty acid Synthase multienzyme complex.

2.Is a component of CoASH.

5- Synthesis of cystine:

+ NAD NADH+H

The disulfide bond of cystine stabilize tertiary structure of proteins.e.g. insulin, Keratin and immunoglobulins.

6- Synthesis of Glutathione
Tripeptide : Glu- Cys- Gly Glu- Cys-

Glu

Cys

Gly

It is an important reducing agent, since it is present in reduced (G-SH) and oxidized forms (G-S-S-G). (G(G-

7- H2S formed by the action of desulfhydrase is the source of active sulfate (PAPS) which is used for synthesis of sulfur containing compounds e.g. sulfolipids.PAPS is also used in detoxification reactions as in case of indole and skatole.

Cysteine
Cysteine desulfhydrase

NH3

H2 S

(PAPS)

Pyruvate

active sulfate

SH Pyruvic

8- The thiol group of cysteine forms the active group of many enzymes e.g. 1.glyceraldehyde-3-phosphate dehydrogenase, .glyceraldehyde2.fatty acid synthase multienzyme complex.
SH NH2 CH2-CH-COOH

Methionine
 It

is essential sulfur containing and glucogenic amino acid

I- Functions and Derivatives:

1- Methionine condenses with ATP forming S-adenosyl Smethionine (active methionine (SAM) which is the main methyl donor in the body. The activated methyl group may transfer to various acceptors in transmethylation reactions.

Active methionine (SAM)

ATP Active methionine

After transmethylation, the remaining part, homocysteine, has 3 routes of metabolism, depending on the physiological needs of the body: I

homocysteine desulfhydrase

II
-Ketobutyrate, ammonia and H2S

III

2- SAM is used in many transmethylation reactions (a) Phosphatidyl Ethanolamine Choline CH3 (b) Norepinephrine CH3 (c) Guanidoacetic acid (d) N-acetyl serotonin NCH3 CH3 creatine melatonin Epinephrine
CH3

Phosphatidyl

(e)Nicotinamide

methylnicotinamide

II- Metabolism of Homocysteine: IIAfter transmethylation, the remaining part, homocysteine, has 3 routes of metabolism, depending on the physiological needs of the body:

1..If methionine is needed, homocysteine is remethylated (salvage pathway).

2.If cysteine is needed, it is synthesized via cystathionine , homoserine is further metabolized to form propionyl CoA. thus, methionine is glucogenic.

3. When methionine and cysteine are present in adequate amounts, cystathionase activates homocysteine desulfhydrase which hydrolyzes homocysteine to E -Ketobutyrate, ammonia and H2S.

Homocysteine desulfhydrase which hydrolyzes homocysteine to E -Ketobutyrate, ammonia and H2S

Amino Acids with Aromatic Side Chain

CH2 CH-COOH I NH2 CH2 CH-COOH I NH2

Phenylalanine

Tyrosine I OH

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

II- Catabolic pathways of phenylalanine: IIThere are 2 pathways for catabolism of phenylalanine:phenylalanine:1- Direct pathway (minor) where phenylalanine by (minor) transamination reaction forms phenylpyruvic acid which is excreted in urine via its metabolites. 2- Phenylalanine is transformed to tyrosine (major pathway) in the liver then tyrosine is catabolized to fumaric acid and acetoacetic acid i.e. phenylalanine and tyrosine are both glucogenic and ketogenic.

Catabolism of Phenylalanine
.

Major Catabolic Pathway

Minor Catabolic Pathway

Minor Catabolic Pathway of Phenylalanine

Major Catabolic Pathway of Phenylalanine

L-Phenylalanine
Phenylalanine hydroxylase Tetrahydrobiopterin + O2 Dihydrobiopterrin + H2O NADP+ Reductase NADPH+H+

L-Tyrosine

Fumarate
Glucogenic

Acetoacetate
Ketogenic

III- Functions and derivatives: III1)Melanin: in the melanocytes (pigment cells) in the skin, )Melanin: hair and eye. Tyrosinase Tyrosine Dopa condensation and cyclization dopaquinone melanin

2. Synthesis of thyroid hormones T4

I HO I CH2 CH COOH NH2
3-5-Diiodotyrosine

HO I

CH2 CH COOH NH2

3-5-Diiodotyrosine

CH3

CH COOH NH2

Alanine

Tetra-iodothyronine (T4, thyroxine).

Synthesis of thyroid T3 hormones

I HO CH2 CH COOH NH2
3-Monoiodotyrosine

HO I

CH2

CH COOH NH2

3-5-Diiodotyrosine

CH3

CH COOH NH2

Alanine

Tri-iodothyronine (T3 )

Both reactions occur in the thyroglobulin, Then T3 T3 and T4 are released. T4

3) Tyrosine forms catecholamines This occurs in cells of neural origin and in the adrenal medulla. .

III
Minor Catabolic Pathway

II

Major Catabolic Pathway

Catabolism of Phenylalanine

Functions of Phenylalanine and Tyrosine

1. Synthesis of catecholamines; a. Adrenaline (epinephrine). b. Noradrenaline (norepinephrine). c. Dopamine. 2. Synthesis of thyroid hormones; a. Tri-iodothyronine (T3). Tri(T3 b. Tetra-iodothyronine (T4, thyroxine). Tetra(T4 3. Synthesis of melanin pigments. 4. Synthesis of tissue proteins. 5. Source of energy.

Synthesis of Catecholamines (Dopamine, Adrenaline and Noradrenaline) L-Phenylalanine

Phenylalanine hydroxylase Tetrahydrobiopterin (BH4) + O2 Dihydrobiopterrin (BH2) + H2O Tetrahydrobiopterin (BH4) + O2 Dihydrobiopterrin (BH2) + H2O NADP+ BH2 Reductase NADPH

L-Tyrosine
Tyrosine hydroxylase

BH2 Reductase

DOPA

Catecholamines

III- Metabolic Disorders of phenylalanine and Tyrosine IIIcatabolism:catabolism:-

1.Phenylketonuria (PKU): 2. Tyrosinemia or tyrosinosis 3.Alkaptonuria 4.Albinism

1.Phenylketonuria (PKU):


It is an inherited metabolic disorder of phenylalanine caused by defective liver phenylalanine hydroxylase or dihydrobiopterin reductase. The disease is characterized by phenylpyruvic, phenylacetic and phenyllactic acid in blood and urine.

*both parents must be carriers of the gene

The signs and symptoms include:include:1. Mental retardation. 2. Eczema of the skin. 3. Mousy odour of urine. 4. Hypopigmentation
Hypopigmentation as a result of decreased melanin pigment will lead to fair skin and hair and blue eyes.

The disease could be diagnosed by

1. increased plasma phenylalanine levels (>20 mg/dl) (>20 (normal: 0.7 4 mg/dl); and by 2. using ferric chloride test which gives a blue-green bluecolour with urine.

Treatment is through a diet low in phenylalanine and rich in tyrosine.

2.Tyrosinemia or tyrosinosis:
 

Inherited metabolic disorders characterized by high levels of plasma tyrosine. tyrosine. Death usually occurs early from liver failure.

Treatment is by low tyrosine and phenylalanine diet.

The most important types are:are: Hepatorenal

type (Type I tyrosinemia) due to fumaryl acetoacetate hydrolase deficiency. deficiency. type (Type II tyrosinemia) due to hepatic tyrosine transaminase deficiency. deficiency. tyrosinemia due to defective phydroxy phenyl pyruvate hydroxylase.

 Oculocutaneous

 Neonatal

3.Alkaptonuria:
Inherited metabolic disorder due to defect in homogentisate oxidase.
 

This causes accumulation of homogentisate in blood and urine. Homogentisate is oxidized into brownish black pigment that causes 1.darkening of urine on standing in air. 2.There is also arthritis and 3.generalized pigmentation of connective tissue (Ochronosis).

4.Albinism:.Albinism:

Albinism is due to deficiency of tyrosinase enzyme in the skin, hair and eyes. So, melanin pigments will not be formed leading to

1. white colour of skin and make it sensitive to light that may lead to burn and carcinoma. 2. Lack of pigments in hair cause fair hair, and 3. lack of pigments in the eyes cause photophobia. The patient is called Albino.

Symptoms: Absence of color in skin , hair & iris of the eyes

Albino
Treatment: Protection of the skin and eyes from the sun by Avoiding the sun and using sun screen with high sun protection factor.

Phenylalanine hydroxylase

Phenylalanine
O2 H2O

Tyrosine
E-KG

Phenylketonuria
Tyrosinemia II

PLP

Tyrosine transaminase
Glu

P-Hydroxyphenyl-pyruvate hydroxylase N .Tyrosinemia Homogentisate PO2 Ascorbate + Cu2+ CO2 O2 Homogentisate Alkaptonuria dioxygenase Maleylacetoacetatecis- trans Ascorbate Fe2+ isomerase

Hydroxyphenyl pyruvate

Maleylacetaoacetate

Fumarylacetoacetate
Fumarylacetoacetate hydrolase Tyrosinemia I GSH H2O

Major Catabolic Pathway of Phenylalanine

Fumarate

Acetoacetate

Tryptophan
 It

is an essential, glucogenic and ketogenic, heterocyclic amino acid.

NH2 CH2-CH-COOH N H

I- Catabolic pathway:
 Tryptophan

is catabolized to acetoacetyl CoA (ketogenic) and alanine is developed through this pathway (glucogenic). niacin can be synthesized through this pathway.

 Also

Catabolic pathway

Tryptophan
B6

CH2-CH-COOH N H NH2

Alanine
(Glucogenic)

Acetoacetyl CoA
(Ketogenic) (vit. B3 ) B3

Niacin

XANTHURENIC

OH

N OH

COOH

Biological Functions of Tryptophan

1.

Formation of niacin.

2. Formation of serotonin. 3. Formation of melatonin.

1- Convesion to niacin:niacin:Tryptophan will form niacin which is one of the B vitamins.  Niacin enters in the formation of NAD and NADP. 

. 1mg niacin.

60 mg Tryptophan

Lack of niacin causes pellagra

Pellagra:Pellagra:Pellagra is a disease caused by severe niacin deficiency. It is characterised by:by:Disturbance in lipid, carbohydrate and protein metabolism.

3 Ds:
* Diarrhea, alternating with constipation. * Dermatitis in the sunexposed areas, especially the V-shaped chest area. V* Dementia or progressive loss of all cerebral functions.

Causes of Pellagra:Pellagra:1- Diet poor in both niacin and tryptophan e.g. eating maize as the sole diet which contains protein called zein that is low in tryptophan. 2- Malignant carcinoid syndrome in which tryptophan metabolism is directed into the formation of serotonin. 3- Hartnup disease in which there is impairment of tryptophan absorption. 4- Vitamin B6 deficiency potentiates niacin deficiency as in isoniazid drug, used in treatment of tuberculosis.

Metabolic disorders
 1-Hartnup

disease  2-B6 deficiency excretion of xanthurenic acid in urine due to inhibition of kinurininase enzyme

Glutamate (Glu.)
 It

is an acidic, nonessential and acidic,

glucogenic amino acid. I- Synthesis of Glutamic acid:

 1-

It is synthesized by E-Ketoglutarate

by glutamate transaminase or glutamate dehydrogenase which are reversible reactions.

E KA COOH CHNH2 CH2 CH2 COOH

NAD(P)+ H2O

E AA
COOH C O

Glutamate transaminase

CH2 Glutamate dehydrogenase CH2 COOH

NAD(P)H + H+ NH3

II- Significance of Glutamate: II 

  

one of the 20 primary aa of protein synthesis. It is deaminated to -Ketoglutaric acid which can form glucose (glucogenic) or oxidized for (glucogenic) energy. It is important constituent of glutathione. glutathione. It is important constituent of folic acid. acid. N-acetyl glutamate is an activator for carbamoyl phosphate synthetase 1 in urea synthesis. It is precursor of -aminobutyrate (GABA), an neurotransmitter. B6 important inhibitory neurotransmitter. In B6 deficiency, diminished GABA leads to convulsions in children.

GABA

Synthesis & Catabolism of Glutamine.

Significance of Glutamine:
  

one of the primary amino acids used for protein synthesis. synthesis. It plays a role in ammonia detoxification in the brain and liver. It is important in some detoxification reactions e.g. With phenylacetate, it forms phenylacetylglutamine; phenylacetylglutamine; a urinary metabolite. In the kidney, glutaminase activity is increased in cases of acidosis. Excretion of NH4+ is one acidosis. NH4 of the renal mechanism for excretion of H+ in acidosis.

The amide group of glutamine is used for:for: Synthesis of amino sugars.  Synthesis of purines (N3 and N9). (N3 N9  Synthesis of pyrimidines (N3 and NH2 (N3 NH2 of cytosine [UTP CTP])  Conversion of XMP GMP  Synthesis of asparagine.

Aspartate (ASP)

It is an acidic, nonessential, glucogenic amino acid. It can be formed from oxaloacetate.

Functions and derivatives of Aspartate:1.

2.

Asp is transaminated or deaminated to oxaloacetate, which can form glucose (glucogenic) or oxidized to give energy. It is one of the 20 primary amino acids of protein synthesis.

3. Synthesis of urea (formation of argininosuccinate). 4. Pyrimidine synthesis, it supplies N1, C4, N1 C4 C5 and C6. C6 5. Purine synthesis (N1) and in conversion (N1 of IMP to adenylosuccinate. 6. Decarboxylation of aspartate, yields Balanine (H2N-CH2- CH2-COOH) which is (H2 CH2 CH2 a component of coenzyme A.

7. It is a precursor of asparagine, a primary asparagine, amino acid in protein synthesis.

MCQ
 Required

for tyrosine biosynthesis:

1.Serotonin. 2.Dihydrobiopetrin. 3.Hydroxybutyrate. 4.Inositol.

A pellagra like skin rash may be seen in:in:1.Phenylketonuria. 2.Homogentisic aciduria. 3.Hartnup disease. 4.Methylmalonic academia.

Tyrosine would be an essential amino acid in the diet of a child with: a) Lesch Nyhan Syndrome  b) defective tyrosine aminotransferase  c) deficiency of pyridoxine.  d) classical phenylketonuria.  e) Galactosemia


In patient with alkaptonuria, which one of the following enzyme is absent: A. B. C. D. E. homogentisic acid oxidase tyrosine transaminase tryptophan hydroxylase phenylalanine decarboxylase leucine transaminase

    

Absorption of which one of the following aminoacids is defective in Hartnup's disease: A. B. C. D. E. glycine lysine leucine tyrosine tryptophan