METABOLISM OF INDIVIDUAL

AMINO ACIDS, BIOSYNTHESIS OF

NON-ESSENTIAL AMINO ACIDS.
AND INBORN ERROR OF
METABOLISM

BY: DARWISH
 AROMATIC AMINO ACIDS

A.PHENYALANINE
• PHENYLALANINE IS A KETOGENIC AND GLYCOGENIC ESSENTIAL
AMINO ACID.
FUNCTIONS:
• PHENYLALANINE IS THE PRECURSOR FOR TYROSINE
• PHENYLALANINE CAN BE CONVERTED TO TYROSINE MAINLY IN
LIVER.
• THIS REACTION NEEDS PHENYLALANINE HYDROXYLASE ENZYME
AND TETRAHYDROBIOPTERIN AS COENZYME.
• DEFICIENCY OF EITHER PHENYLALANINE HYDROXYLASE OR
DIHYDROBIOPTERIN RESULTS IN A DISEASE CALLED
PHENYLKETONURIA
B. TYROSINE:
• TYROSINE IS A KETOGENIC AND GLYCOGENIC NON-
ESSENTIAL AMINO ACID.
• TYROSINE AND PHENYLALANINE ARE SIMILAR
STRUCTURE BUT TYROSINE HAS ADDITIONAL OH-
GROUP AT PARA POSITION OF BENZINE RING.
FUNCTIONS:
• TYROSINE IS DEGRADED TO PRODUCE AS END
PRODUCTS FUMARATE AND ACETOACETATE.
• FUMARATE IS GLUCOGENIC , WHEREAS
ACETOACETATE IS KETOGENIC
• PHENYLALANINE IS CATABOLIZED VIA TYROSINE.
HENCE BOTH PHENYLALANINE AND TYROSINE ARE
GLUCOGENIC AND KETOGENIC.
• TYROSINE THROUGH IT IS DISPENSABLE (NON-
ESSENTIAL AMINO ACID) BUT IT IS GREAT
COMPOUNDS IN HUMAN BODY.
• MANY BIOLOGICAL COMPOUNDS OF IMPORTANCE ARE
SYNTHESIS FORM TYROSINE AND ARE:
a. SYNTHESIS OF THYROID HORMONES : THYROXINE (T4) AND
TRIIODOTHYRONINE (T3).
b. SYNTHESIS OF CATECHOLAMINES
c. SYNTHESIS OF MELANINE PIGMENT
 SIMPLE, HYDROXY AND
SULFUR CONTAINING
AMINO ACIDS
(GLYCINE, SERINE,THREONINE, METHIONINE,
CYSTEINE)
• SULPHUR CONTAINING AMINO ACIDS ARE THE FOLLOWING :
 L –METHIONINE ( ESSENTIAL)
 L- CYSTEINE(NON-ESSENTIAL)
 L- CYSTINE
• METHIONINE ,CYSTEINE AND CYSTINE ARE PRINCIPAL SOURCE OF
SULPHUR IN THE BODY
• DEMETHYLATION AND METHIONINE PRODUCES HOMOCYSTEINE WHICH
MAY BE REMETHYLATED TO FORM METHIONINE AGAIN
• CYSTEINE IS REVERSIBLE CONVERTIBLE TO CYSTINE AND HOMO CYSTEINE
TO HOMOCYSTINE BY OXIDATION REDUCTASE
• BOTH METHIONINE AND CYSTEINE CAN UNDERGO TRANSAMINATION
REACTION.
• METHIONINE IS ESSENTIAL AMINO ACID AND
HAS TO BE SUPPLIED IN THE DIET.
• CYSTEINE IS NOT ESSENTIAL AMINO ACID AND
CAN BE SYNTHESIZED IN THE BODY FROM
METHIONINE.
GLYCINE, SERINE,THREONINE
SEE THE PAGE N0.183
( BIOCHEMISTRY TEXTBOOK, BY DM VASUDEVAN
 CATABOLISM OF THE CARBON SKELETONS
OF AMINO ACIDS (FATE OF Α-KETO ACIDS)

• THE Α-KETOACIDS (THE CARBON SKELETON) REMAINING AFTER THE

REMOVAL OF THE AMINO GROUP (NH2) BY TRANSAMINATION AND
DEAMINATION OF AMINO ACIDS MAY UNDERGO :
a. REAMINATION : BY AMMONIA (NH3) TO FORM AGAIN THE
CORRESPONDING AMINO ACID ( BY GLUTAMATE DEHYROGENASE).

b. CATABOLISED : TO FORM SEVEN PRODUCTS : PYRUVATE , ACETY COA,

ACETOACETYL COA, FUMARATE,OXALO-ACETATE, Α-
KETOGLUTARATE AND SUCCINYL COA
c. THESE PRODUCTS ENTER DIFFERENT PATHWAYS WHICH LEAD TO :
i. SYNTHESIS OF GLYCOGEN OR GLUCOSE
ii. SYNTHESIS OF LIPIDS
iii. COMPLETE OXIDATION INTO CO2 AND H2O.
CATABOLISM OF AMINO ACIDS INTO Α-KETO
ACIDS

A. AMINO ACIDS FORMING OXALOACETATE:

a. ASPARAGINE : IS HYDROLYSED BY THE ENZYME
ASPARAGINASE, GIVING NH3 AND ASPARTATE.
b. ASPARTATE : LOSES ITS AMINO GROUP BY TRANSAMINATION TO
FORM OXALOACETATE

B. AMINO ACIDS FORMING Α-KETOGLUTARATE:

1. GLUTAMINE :IS CONVERTED TO GLUTAMATE AND AMMONIA BY
ENZYME GLUTAMINASE
2. GLUTAMATE : IS CONVERTED TO Α-KETOGLUTARATE BY
TRANSAMINATION OR THROUGH OXIDATIVE DEAMINATION BY
GLUTAMATE DEHYDROGENASE.
3. PROLINE : IS OXIDIZED TO GLUTAMATE. THEN GLUTAMATE IS
THEN CONVERTED TO Α-KETOGLUTARATE
 BIOSYNTHESIS OF NON-ESSENTIAL AMINO ACIDS

INTRODUCTION :
• ALL KNOWN 20 AMINO ACIDS ARE VERY IMPORTANT TO HUMAN
• THEY ARE CLASSIFIED NUTRITIONALLY INTO ESSENTIAL AMINO
ACIDS,WHICH CANNOT BE FORMED IN THE BODY AND SHOULD
BE TAKEN IN DIET AND NON-ESSENTIAL AMINO ACIDS WHICH
CAN BE SYNTHESIZED IN THE BODY.
1. SYNTHESIS OF ALANINE, ASPARTATE AND GLUTAMATE: THEY ARE
SYNTHESIZED FROM THE CORRESPONDING Α-KETOACIDS:
PYRUVATE,OXALOACETATE AND Α-KETOGLUTARATE RESPECTIVELY BY
TRANSAMINATION
2. GLUTAMATE IS UNSUAL IN THAT IT CAN ALSO BE SYNTHESIZED BY THE
REVERSE OF OXIDATIVE DEAMINATION CATALYZED BY GLUTAMATE
DEHYDROGENASE
3. SYNTHESIS OF GLUTAMINE AND ASPARAGINE: THEY ARE
SYNTHESIZED BY AMIDATION IN REACTIONS CATALYZED BY
GLUTAMINE SYNTHETASE AND ASPARAGINE SYNTHETASE
4. SYNTHESIS OF PROLINE: GLUTAMATE IS CONVERTED INTO PROLINE
BY FORMING GLUTAMATE SEMI-ALDEHYDE
5. SYNTHESIS OF GLYCINE,CYSTEINE AND SERINE:
a. GLYCINE : IS SYNTHESIZED FROM SERINE BY REMOVAL OF A
METHYLENE GROUP
b. CYSTEINE IS SYNTHESIZED BY 2 SUCCESSIVE REACTIONS
HOMOCYSTEINE COMBINES WITH SERINE TO FORM CYSTATHIONINE
• CYSTATHIONINE IS HYDROLYZED TO CYSTEINE AND HOMOSERINE
• HOMOCYSTEINE IS DERIVED FROM METHIONINE
C. SERINE: IS SYNTHESIZED FROM 3
PHOSPHOGLYCERATE
6. SYNTHESIS OF TYROSINE : IS SYNTHESIZED
FROM PHENYLALANINE BY REACTION
CATALYZED BY PHENYLALANINE
HYDROYLASE ENZYME .
 IEM OF AMINO ACIDS

• SEVERAL ENZYME DEFECTS IN

PHENYLALANINE/TYROSINE DEGRADATION
LEADING TO METABOLIC DISORDERS ARE
KNOWN.
• LNFIG.L5.19, THE DEFICIENT ENZYMES AND THE
RESPECTIVE INBORN ERRORS ARE DEPICTED
AND THEY ARE DISCUSSED HERE UNDER
 PHENYLKETONURIA( PKU)
INTRODUCTION:
• PHENYLALANINE(P HE,F ) AND TYROSINE( TYR , Y) ARE
STRUCTURALLY RELATED AROMATIC AMINO ACIDS.
• PHENYLALANINE IS AN ESSENTIAL AMINO ACID WHILE
TYROSINE IS NON-ESSENTIAL.
• BESIDES ITS INCORPORATION INTO PROTEINS, THE ONLY
FUNCTION OF PHENYLALANINE IS ITS CONVERSION TO
TYROSINE.
• FOR THIS REASON, INGESTION OF TYROSINE CAN REDUCE
THE DIETARY REQUIREMENT OF PHENYLALANINE
• THE PREDOMINANT METABOLISM OF
PHENYLALANINE OCCURS THROUGH TYROSINE.
• TYROSINE IS INCORPORATED INTO PROTEINS
AND IS INVOLVED IN THE SYNTHESIS OF A
VARIETY OF BIOLOGICALLY IMPORTANT
COMPOUNDS-EPINEPHRINE, NOREPINEPHRINE,
DOPAMINE (CATECHOLAMINES), THYROID
HORMONES AND THE PIGMENT MELANIN
• PHENYLKETONURIA( PKU) IS THE MOST COMMON METABOLIC
DISORDER IN AMINO ACID METABOLISM.
• THE INCIDENCE OF PKU IS 1 IN 10,000 BIRTHS.
• IT IS DUE TO THE DEFICIENCY OF THE HEPATIC ENZYME,
PHENYLALANINE HYDROXYLASE, CAUSED BY AN AUTOSOMAL
RECESSIVE GENE.
• THIS ENZYME DEFICIENCY IMPAIRS THE SYNTHESIS OF
TETRAHYDROBIOPTERIN REQUIRED FOR THE ACTION OF
PHENYLALANINE HYDROXYLASE .
• THE NET OUTCOME IN PKU IS THAT PHENYLALANINE IS NOT
CONVERTED TO TYROSINE
• PHENYLALANINE METABOLISM IN PKU :
• PHENYLKETONURIA PRIMARILY CAUSES THE
ACCUMULATION OF PHENYLALANINE IN TISSUES AND
BLOOD, AND RESULTS IN ITS INCREASED EXCRETION
IN URINE.
• DUE TO DISTURBANCES IN THE ROUTINE
METABOLISM, PHENYLALANINE IS DIVERTED TO
ALTERNATE PATHWAYS, RESULTING IN THE EXCESSIVE
PRODUCTION OF PHENYLPYRUVATE, PHENYLLACTATE
AND PHENYLGLUTAMINE.
• AII THESE METABOLITES ARE EXCRETED IN URINE IN
HIGH CONCENTRATION IN PKU.
• PHENYLACETATE GIVES THE URINE A MOUSEY ODOR
• THE NAME PHENYLKETONURIA IS COINED
DUE TO THE FACT THAT THE METABOLITE
PHENYLPYRUVATE IS A KETO ACID (C6H5CH2-
CO-COO-) EXCRETED IN URINE IN HIGH
AMOUNTS
 CLINICAL MANIFESTATIONS
1. EFFECTS ON CENTRAL NERVOUS SYSTEM:
• MENTAL RETARDATION , FAILURE TO WALK OR TALK,
FAILURE OF GROWTH ,SEIZURES AND TREMOR ARE THE
CHARACTERISTIC FINDINGS IN PKU
• ACCUMULATION OF PHENYLALANINE IN BRAIN
IMPAIRS THE TRANSPORT AND METABOLISM OF OTHER
AMINO ACIDS (TRYPTOPHAN AND TYROSINE)
• DEFECT IN MYELIN FORMATION IS OBSERVED IN PKU
PATIENTS
2. EFFECTS ON PIGMENTATION : MELANIN IS THE PIGMENT
SYNTHESIZED FROM TYROSINE BY TYROSINASE
 DIAGNOSIS OF PKU
• PKU IS MOSTLY DETECTED BY SCREENING THE NEWBORN BABIES
FOR THE INCREASED PLASMA LEVELS OF PHENYLALANINE( PKU,
20-65 MG/ DL; NORMAL 1-2MG/DL).
• THIS IS USUALLY CARRIED OUT BY GUTHRIE TEST, WHICH IS A
BACTERIAL (BACILLUS SUBTILIS) BIOASSAY FOR PHENYLALANINE.
• THE TEST IS USUALLY PERFORMED AFTER THE BABY IS FED WITH
BREAST MILK FOR A COUPLE OF DAYS.
• ALL THE BABIES BORN IN USA ARE SCREENED FOR PKU BY TESTING
ELEVATED LEVELS OF PHENYLALANINE.
• PHENYLPYRUVATE IN URINE CAN BE DETECTED BY FERRIC
CHLORIDE TEST (A GREEN COLOUR IS OBTAINED).
• THIS TEST IS NOT SPECIFIC, SINCE MANY OTHER COMPOUNDS GIVE
A FALSE POSITIVE TEST
 TREATMENT OF PKU
• TREATMENT OF PKU : THE MAINTENANCE OF PLASMA
PHENYLALANINE CONCENTRATION WITHIN THE NORMAL RANGE
IS A CHALLENGING TASK IN THE TREATMENT OF PKU.
• THIS IS DONE BY SELECTING FOODS WITH LOW PHENYLALANINE
CONTENT AND/OR FEEDING SYNTHETIC AMINO ACID
PREPARATIONS, LOW IN PHENYLALANINE.
• DIETARY INTAKE OF PHENYLALANINE SHOULD BE ADJUSTED BY
MEASURING PLASMA LEVELS.
• EARLY DIAGNOSIS (IN THE FIRST COUPLE OF MONTHS OF BABY'S
LIFE) AND TREATMENT FOR 4-5 YEARS CAN PREVENT THE
DAMAGE TO BRAIN.
 TYROSINEMIA II
• THIS DISORDER-ALSO KNOWN AS RICHNER- HANHART SYNDROME,
IS DUE TO A DEFECT IN THE ENZYME TYROSINE TRANSAMINASE.
• THE RESULT IS A BLOCKAGE IN THE ROUTINE DEGRADATIVE
PATHWAY OF TYROSINE.
• ACCUMULATION AND EXCRETION OF TYROSINE AND ITS
METABOLITES-NAMELY P-HYDROXYPHENYLPYRUVATE, P-
HYDROXYPHENYLLACTATE, N-ACETYLTYROSINE-AND TYRAMINE
ARE OBSERVED.
• TYROSINEMIA TYPE LI IS CHARACTERIZED BY SKIN (DERMATITIS)
AND EYE LESIONS AND, RARELY, MENTAL RETARDATION.
• A DISTURBED SELF-COORDINATION IS SEEN IN THESE PATIENTS
ALKAPTONURIA ( BLACK URINE DISEASE)

• ALKAPTONURIA HAS GREAT HISTORICAL IMPORTANCE.

• IT WAS FIRST DESCRIBED BY LUSITANUSI N 1649 AND
CHARACTERIZED IN 1859.
• GARROD CONCEIVED THE IDEA OF INBORN ERRORS OF
METABOLISM FROM HIS OBSERVATION ON
ALKAPTONURIA.
• THE PREVALANCE OF THIS AUTOSOMAL RECESSIVE
DISORDER IS 1 IN 25,000
• ENZYME DEFECT : THE DEFECTIVE ENZYME IN
ALKAPTONURIA IS HOMOGENTISATE OXIDASE IN
TYROSINE METABOLISM.
• HOMOGENTISATE ACCUMULATES IN TISSUES AND
BLOOD, AND IS EXCRETED INTO URINE.
• HOMOGENTISATE, ON STANDING, GETS OXIDIZED
TO THE CORRESPONDING QUINONES,WHICH
POLYMERIZE TO GIVE BLACK OR BROWN COLOR.
• FOR THIS REASON, THE URINE OF ALKAPTONURIC
PATIENTS RESEMBLES COKE IN COLOR.
 CLINICAL MANIFESTATIONS

• BIOCHEMICAL MANIFESTATIONS : HOMOGENTISATE GETS

OXIDIZED BY POLYPHENOL OXIDASE TO BENZOQUINONE
ACETATE WHICH UNDERGOES POLYMERIZATION TO PRODUCE A
PIGMENT CALLED ALKAPTON.
• ALKAPTON DEPOSITION OCCURS IN CONNECTIVE TISSUE,
BONES AND VARIOUS ORGANS (NOSE, EAR ETC.) RESULTING IN A
CONDITION KNOWN AS OCHRONOSIS.
• MANY ALKAPTONURIC PATIENTS SUFFER FROM ARTHRITIS AND
THIS IS BELIEVED TO BE DUE TO THE DEPOSITION OF PIGMENT
ALKAPTON (IN THE JOINTS), PRODUCED FROM HOMOGENTISATE
 DIAGNOSIS AND TREATMENT

• CHANGE IN COLOR OF THE URINE ON STANDING TO BROWN OR

DARK HAS BEEN THE SIMPLE TRADITIONAL METHOD TO
IDENTIFY ALKAPTONURIA.
• THE URINE GIVES A POSITIVE TEST WITH FERRIC CHLORIDE
• AND SILVER NITRATE.
• THIS IS DUE TO THE STRONG REDUCING ACTIVITY OF
HOMOGENTISATE.
• BENEDICT'S TEST-EMPLOYED FOR THE DETECTION OF GLUCOSE
AND OTHER REDUCING SUGARS-IS ALSO POSITIVE WITH
HOMOGENTISATE
• ALKAPTONURIA IS NOT A DANGEROUS
DISORDER AND, THEREFORE, DOES NOT
REQUIRE ANY SPECIFIC TREATMENT.
• HOWEVER, CONSUMPTION OF PROTEIN DIET
WITH RELATIVELY LOW PHENYLALANINE
CONTENT IS RECOMMENDED
 ALBINISM

• INTRODUCTION:
 ALBINISM (GREEK: ALBINO-WHITE) IS AN INBORN ERROR, DUE TO THE
LACK OF SYNTHESIS OF THE PIGMENT MELANIN
 IT IS AN AUTOSOMAL RECESSIVE DISORDER WITH A FREQUENCY OF 1 IN
20,000.
 IT IS A HEREDITARY DEFICIENCY OF TYROSINE HYDROXYLASE ENZYME
IN MELANOCYTES.
 THIS RESULTS IN DEFECTIVE SYNTHESIS OF MELANIN PIGMENTS
 EYE ,SKIN AND HAIR ARE AFFECTED

a. EYE :OCULAR ALBINISM

b. SKIN : CUTANEOUS ALBINISM

c. EYE AND SKIN : OCULO-CUTANEOUS ALBINISM

 BIOCHEMICAL CAUSES

• THE COLOR OF SKIN AND HAIR IS CONTROLLED BY A LARGE

NUMBER OF GENES.
• ABOUT 150 GENES HAVE BEEN IDENTIFIED IN MICE
• THE MELANIN SYNTHESIS CAN BE INFLUENCED BY A VARIETY
OF FACTORS.
• MANY POSSIBLE CAUSES FOR ALBINISM HAVE BEEN
IDENTIFIED:
a. DEFICIENCY OR LACK OF ENZYME TYROSINASE
b. DECREASE IN MELANOSOMES OF MELANOCYTES
c. LACK OF PROTEIN MATRIX IN MELANOSOMES
d. PRESENCE OF INHIBITORS OF TYROSINASE
 CLINICAL MANIFESTATION

• THE MOST IMPORTANT FUNCTION OF MELANIN IS THE

PROTECTION OF THE BODY FROM SUN RADIATION.
• LACK OF MELANIN IN ALBINOS MAKES THEM SENSITIVE TO
SUNLIGHT.
• INCREASED SUSCEPTIBILITY TO SKIN CANCER
( CARCINOMA) IS OBSERVED.
• PHOTOPHOBIA ( INTOLERANCE OF LIGHT) IS ASSOCIATED WITH
LACK OF PIGMENT IN THE EYES.
• HOWEVER THERE IS NO IMPAIRMENT IN THE EYESIGHT OF
ALBINOS