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Amino Acid Metabolism-3

Biosynthesis of Nonessential Amino Acid Inborn Errors of Amino Acid Metabolism

Faisal Khatib MD;PhD Faculty of Medicine, University of Jordan

Biosynthesis of Nonessential Amino Acids

• From α-keto acids

– Alanine, Aspartate, Glutamate

– Serine

• From essential amino acids

– Cysteine, Tyrosine

• From other amino acids

– Amidation of Glutamine, Asparagine

– Proline

– Interconversion of Serine and Glycine

Production of Serine From 3- phosphoglycer ate 2
Production of Serine From 3- phosphoglycer ate

Production of

Serine

From

3-

phosphoglycer

ate

Tyrosine can be Produced by Hydroxylation of Phenylalanine

Tyrosine can be Produced by Hydroxylation of Phenylalanine

Cysteine can be Produced from Methionine

Methionine

Homocysteine

SerineCysteine can be Produced from Methionine Methionine Homocysteine Cyst a thionine α ketobutyrate Cysteine

Cystathionine

α ketobutyrateCysteine can be Produced from Methionine Methionine Homocysteine Serine Cyst a thionine Cysteine

Cysteine

Asparagine is Produced by Amidation of Aspartate Glutamine is the Donor of Amide Group 4
Asparagine is Produced by Amidation of Aspartate Glutamine is the Donor of Amide Group

Asparagine is Produced by Amidation of Aspartate

Asparagine is Produced by Amidation of Aspartate Glutamine is the Donor of Amide Group

Glutamine is the Donor of Amide Group

Defects of Amino Acid Metabolism • Inborn errors of amino acid metabolism • Mutant gene

Defects of Amino Acid Metabolism

• Inborn errors of amino acid metabolism

• Mutant gene >>> Abnormal Enzyme

• Mostly recessive

• Most of them are rare 1:250,000

• Few are common

• Total or Partial Loss of Activity

Defects of Amino Acid Metabolism

Loss of enzyme activity

Accumulation of metabolites

Mental retardation (in many diseases)

of Amino Acid Metabolism Loss of enzyme activity Accumulation of metabolites Mental retardation (in many diseases)

Phenylketonuria (PKU)

• Relatively common

• Can be easily detected

• More than one form exist

• Can respond to dietary treatment

BH 2 Reductase BH 2 Synthetase
BH 2 Reductase BH 2 Synthetase

BH 2

Reductase

BH 2 Synthetase
BH 2
Synthetase

Tetrahydrobiopterin is required in the synthesis of some neurotransmitters

Tetrahydrobiopterin is required in the synthesis of some neurotransmitters

PKU is characterized by high plasma level of phenylalanine and its metabolites

PKU is characterized by high plasma level of phenylalanine and its metabolites

Diagnosis of PKU

• Early diagnosis is important

• Neonatal diagnosis 48 hours after birth

• Testing at birth >>>False negative

• Antenatal diagnosis

– Genetic methods

– Forty mutations or more are known

>>>False negative • Antenatal diagnosis – Genetic methods – Forty mutations or more are known 9

Treatment of PKU

• Most natural proteins contain Phenylalanine

• Synthetic amino acid preperations with some natural food of low Phe content.

• Repeated measurement of plasma phe level

• Tyrosine must be supplied

Must begin early after birth to prevent mental retardation

Treatment of PKU

Must begin early after birth to prevent mental retardation Treatment of PKU

Treatment of PKU

Life long management is necessary

Treatment of PKU Life long management is necessary

Maternal PKU

• Fetus can be affected if untreated mother

– CNS manifestations

– Congenital heart defects

• Dietary control should start prior to conception and throughout pregnancy

Maple Syrup Urine Disease

• Deficiency of branched- chain α-keto acid dehydogenase

• Val, Leu, Ile

• Accumulation of Amino Acids and α-keto acid

• Fatal disease

• Val, Leu, Ile transaminase

• α-keto acid analogs

dehydrogenase

• Acyl CoA

Maple Syrup Urine Disease

Classification

• Classic type

– Little or no Enzyme activity – Symptoms within first several days

• Intermediate form

– Enzyme 3-15% of normal – Onset from infancy to childhood

• Thiamine responsive form

• Large doses of thiamine

Maple Syrup Urine Disease Diagnosis and Management

• Measurement of enzyme in leukocytes

• Early diagnosis is essential

• Treatment should start from day 1

• Synthetic formula low in branched amino acids

Albinism

• Defect in tyrosine metabolism

• Tyrosine →→→ Melanin

• Partial or full absence of the enzyme

• Different forms, different modes of inheritance

Complete albinism

Complete albinism

Homocystineuria

High plasma and urinary level of homocysteine methionine Low level of cysteine

Premature arteriosclerosis

Some patients are responsive to B 6

Restriction of methionine

Supplementation with vit. B 6 , B 12

folate

Some patients are responsive to B 6 Restriction of methionine Supplementation with vit. B 6 ,

Alkaptonuria

Rare but has historical importance

Homogentisic acid oxidase

Accumulation of homogenitisic and excretion in urine

→→ Black pigment

Not life threatening

Homogentisic acid oxidase Accumulation of homogenitisic and excretion in urine →→ Black pigment Not life threatening
acid oxidase Accumulation of homogenitisic and excretion in urine →→ Black pigment Not life threatening 15