Inborn errors of amino acid metabolism Editing file Color Index: Objectives: ● Important ● Dr’s notes Identify the amino acid degradation and synthesis of non-essential amino acids ● In females’ slides only ● In males’ slides only Recognize the metabolic defects in amino acid metabolism that lead to genetic diseases Take home message: Degradation of amino acids involves removal of α-amino group followed by degradation of leftover carbon skeleton by various ways to products that can either enter the biosynthetic athways or TCA Glucogenic amino acids whose catabolism yields pyruvate or one of the intermediates of TCA Ketogenic amino acids whose catabolism yields either acetoacetate or one of its precursor. The essential amino acids are provided in the diet and the non-essential amino acids are synthesized in the body Deficiency of the enzymes involved in amino acid metabolism leads to hereditary disorders like: phenylketonuria, alkaptonuria etc. 437 team: According to the type of mutation, the enzyme might be completely lost or just deficient. Inborn errors of amino acid metabolism If the enzyme was completely lost, no products will be produced at all, and the substrates will accumulate in huge amounts, 1. Accumulation of the substrate leading to a very severe Gene mutation Enzyme loss or deficiency disease. 2. Deficiency of the product If the enzyme was not Cofactors completely lost, some Enzyme + Substrate Product substrates will be converted to products and the disease will be less severe. Deficiency of the product is not always present, Excess Deficient because there might be another pathway that results in the same product. Diseases Maple syrup Phenylketonuria Albinism Homocystinuria Alkaptonuria (most common) urine disease 3 Females’ doctor notes: Phenylketonuria (PKU) Tyrosine is normally non-essential (body can make no need to take it from Enzyme Substrate Product diet) (deficient) (accumulated) (deficient) but in case of enzyme deficiency the body can’t produce it so it Phenylalanine Phenylalanine hydroxylase Tyrosine becomes essential ( hyperphenylalaninemia ) (supplements are needed) “it is conditional amino acid” Classical PKU Accumulated Enzymes required for Cofactors (BH4) synthesis Phenylalanine hydroxylase Deficient 4 The pathway of phenylalanine Dr’s notes : * Enzymes required for Cofactors (BH4) synthesis. Thus, in the absence of one of Atypical hyperphenylalaninemia these enzymes deficiency of BH4 Due to deficiency of dihydropteridine reductase, dihydrobiopterin synthetase, Carbinolamine dehydratase enzymes * 1 Conversion of Phe to Tyr requires 2 Even if phenylalanine tetrahydrobiopterin (BH4) hydroxylase level is normal 3 The enzyme will not function 4 Hence Phe is accumulated without BH4 Cofactors Enzyme + Substrate Product phenylalanine hydroxylase phenylalanine BH4 Tyrosine - accumulate Deficient 5 Characteristics of PKU ● Elevated phenylalanine in tissues, plasma, urine. ● Phe is degraded to: phenyllactate, phenylacetate, phenylpyruvate. ● Gives urine a mousy odor. In the absence of BH4 : ❷ ❸ No or less tyrosine/ also inhibited by excess Phe ❶ Phe will not be converted to Tyrosine. ● Melanin will become deficient because Tyrosine is required for synthesis of melanin. ● Deficiency of tyrosinase will lead to albinism. Tyrosine ➔ DOPA ➔ DOPAquinone ➔ ● Causes light skin and photosensitivity in PKU patients. LeucoDOPAchrome➔ DOPAchrome ➔➔ Melanin Tyrosine will not be converted to Catecholamines. No or less melanin Light ❷ Tryptophan will not be converted to Serotonin. skin in PKU patients ★ ❸ Catecholamines & serotonin are neurotransmitters. Amino Acids & Tetrahydrobiopterin 6 Extra info : 1. Seizure: Uncontrolled electrical activity in the brain, which may produce a physical convulsion, minor physical signs, thought disturbances, or a Characteristics of PKU combination of symptoms. 2. Microcephaly: a medical condition in which the brain doesn’t develop properly resulting in a smaller than normal head. CNS symptoms Hypopigmentation Urine “Melanin is not synthesized” Females’ doctor notes: 3. We measure it after birth ● Mental retardation after 24-48 hours NOT ● Fair hair ● Failure to walk or talk musty (mousy) odor. Immediately ● Seizures 1 ● Light skin colour because the mother clears increased blood phenylalanine in 2 ● Blue eyes ● Microcephaly her affected fetus through etc. the placenta. 437 team: If the treatment is Diagnosis Treatment started before 7 days of birth, they might have a near normal life Prenatal detecting gene mutation in fetus. “before birth” Lifelong phenylalanine restricted diet The problem is that phenylalanine is very abundant in most food, so it is 3 difficult to control. Neonatal measuring levels of blood Phenylalanine. “In infants” Tyrosine supplementation 7 Maple Syrup Urine Disease Females’ doctor notes: Maple syrup odor of urine How to differentiate between the classic type and deficiency of Thiamine-responsive form? The enzyme decarboxylates These amino acids branched chain α-ketoacid leucine, isoleucine and valine accumulate in blood You give the patient thiamine dehydrogenase supplement and see if it works. Treatment: Limited intake of leucine, isoleucine and valine “to prevent toxic effects.” Symptoms 1 Mental retardation 2 Metabolic acidosis 3 Physical disability ..etc Types Intermediated and Thiamine-responsive Classic type intermittent forms form ● Most common ● Higher enzyme activity ● high doses of thiamine increases ●Little or no activity of the enzyme ● Symptoms are milder the enzyme activity 8 Maple Syrup Urine Disease Degradation of branched-chain amino acids: valine, isoleucine and leucine. Deficiency of branched chain a-keto acid dehydrogenase leads to MSUD. α- ketoglutarate is the universal acceptor of amino group 437 team: In our body we have certain branched chain amino acids. The α- keto acids are acted on by their α- keto acid These amino acids are leucine, isoleucine and valine. dehydrogenases. The first step in their degradation is deamination If The α- keto acid dehydrogenase is deficient, it will lead to “Removal of an amino group and introduce a ketone group at accumulation of the amino acids and their α- keto acid, Leucine and their keto acids the alpha carbon”. leading to maple syrup urine disease (MSUD). By the end of this step, each amino acid is converted to its [α- keto acid]. 9 Extra info : Albinism 1. DihydrOxyPhenylAlanine: is present in nervous tissue as a precursor of dopamine, used in the treatment of Parkinson's disease. Albinism Tyrosine Melanin ● A disease of tyrosine ● Involved in melanin production ● A pigment of : metabolism hair, skin and eyes. ➔ Due to tyrosinase deficiency ★ Melanin is absent in albino patients: Hair Skin ● Appear white ● Appear white Eyes Photophobia ● Appear white or Prone to skin cancer. red ● Vision defects 10 Homocystinuria Females’ doctor notes: 1. Increased amounts of Defects in homocysteine metabolism homocysteine causes oxidative Causes stress which lead to these diseases ● Deficiency of cystathionine β-synthase (converts homocysteine to cystathionine) 2. When vit B6 and B12 and folate are low homocystine is Clinical High plasma and urine levels of homocysteine and methionine increased “the exact relation isn’t known” presentations Low plasma and urine levels of cysteine Risk factor for Atherosclerosis and heart diseases 1 ● Skeletal abnormalities, ● Osteoporosis Symptomes ● Mental retardation ● Displacement of eye lens 2 ● Oral administration of vitamins B6,B12 and folate (folic acid) Treatment ➔ Vitamin B6 is a cofactor of cystathionine β-synthase ● Methionine-restricted diet Hyperhomocysteinemia ● Is associated with: Neural tube defect Vascular diseases 1 2 3 Heart diseases (spina bifida) (Atherosclerosis) 11 Homocystinuria 12 Important to know The pathway of this disease is Alkaptonuria the one in the middle where tyrosine is converted to p-hydroxyphenylpyruvate. Definition Cause Fate of tyrosine Tyrosine is mentioned in 3 diseases: Rare disease of tyrosine degradation ● homogentisic acid oxidase 1- Alkaptonuria 2- PKU deficiency 3- Albinism Catechol Melanin amine P-hydroxy phenylpyruvatec Homogentisic acid is accumulated Homogentisic in tissue and cartilage acid Homogentisic acid oxidase TCA Fumarate cycle 13 Characteristics of Alkaptonuria Black Homogentisic Arthritis pigmentation aciduria Elevated homogentisic acid Of cartilage and tissues. in urine which is oxidized to dark pigment Later; 40 years and beyond over time Diagnosis Treatment ● Restricted intake of tyrosine and phenylalanine reduces homogentisic acid and dark pigmentation Usually asymptomatic until adulthood ● Treat symptoms of arthritis beyond on 14 Summary Huge thanks to TEAM 437! Disease Enzyme Substrate Product Symptoms Treatment (deficient) (Accumulated) (Deficient) Classical Phenylalanine Phenylalanine Tyrosine CNS symptoms Life long phenylalanine restricted diet and phenylketonuria hydroxylase Melanin tyrosine supplementation Catecholamines Mousy(musty) odor of urine Hypopigmentation Atypical 1. Dihydropteridine Phenylalanine BH4 leading to Same as the Same as the classical PKU nonfunctional phenylketonuria reductase phenylalanine classical PKU hydroxylase. 2. Dihydrobiopterin synthetase Which will lead to tyrosine,catecholamine ,serotonin,melanin 3. Carbinolamine deficiency. dehydratase Maple syrup Branched chain 1. Leucine Mental retardation,physical Limited intake of disability,metabolic leucine,isoleucine,valine urine disease α-ketoacid 2. Isoleucine acidosis,maple syrup odor dehydrogenase 3. valine of urine. And their