Amino Acid Catabolism PDF

FATE OF THE CARBON SKELETON OF AMINO ACIDS PRINCE ADOBA 1 CATABOLISM OF BRANCHED CHAIN AMINO ACIDS 3 common steps 1 - Transamination 2 – Oxidative decarboxylation BCKD - (Branched chain) ɑ-ketoacid dehydrogenase compex 3 - Dehy...

FATE OF THE CARBON SKELETON OF AMINO ACIDS PRINCE ADOBA 1 CATABOLISM OF BRANCHED CHAIN AMINO ACIDS 3 common steps 1 - Transamination 2 – Oxidative decarboxylation BCKD - (Branched chain) ɑ-ketoacid dehydrogenase compex 3 - Dehydrogenation Acyl CoA dehydrogenase 4  LEUCINE, ISOLEUCINE & VALINE The main site for the catabolism of the branched chain amino acids (all essential AAs) is the skeletal muscle However, it has also been demonstrated in the adipose, kidney and brain tissues The catabolism commences with a specific aminotransferase (higher in muscles than liver) which converts the respective amino acids into α-keto acids in the cytosol where α-ketoglutarate is the acceptor (transamination reaction)  CATABOLISM OF LEUCINE, ISOLEUCINE & VALINE The α-keto acids are then acted on by branched chain α-keto acid dehydrogenase complex in the mitochondria (oxidative decarboxylation reaction) to produce the corresponding Acyl CoA thioesters 5 coenzymes used: Thiamine pyrophosphate (TPP), CoASH, Lipoamide, FAD, NAD+ 3 enzymes: decarboxylase, a transacylase, and a dihydrolipoyl dehydrogenase 5  CATABOLISM OF LEUCINE, ISOLEUCINE & VALINE The α-keto acid dehydrogenase complex is regulated by covalent modification This is in response to the presence of branched chain amino acids in the diet The enzyme complex is inactivated by phosphorylation and activated by dephosphorylation (via kinase and phosphatase respectively) 6  Maple Syrup Urine Disease The deficiency of α-keto acid dehydrogenase complex has been associated with the Maple Syrup Urine Disease (MSUD) This condition is characterized by the accumulation of α-keto acids in the blood and their excretion in the urine – also called branched chain ketonuria The urine and sweat of affected individuals have the odour of maple syrup (or burnt sugar) The accumulation of BCAAs impairs transport & function of other AAs – even protein synthesis affected  Maple Syrup Urine Disease There is an associated abnormal development of the brain leading to mental retardation and death in infancy. The condition may be managed by restricting the intake of branched chain amino acids. Some cases respond to the administration of large doses of thiamine. Diagnosis: urinary branched amino acids and keto acids & enzyme analysis. 8  Intermittent Branched Chain Ketonuria This condition is a variant of MSUD It is characterized by a less severe deficiency of the α-keto acid dehydrogenase complex In this variant, the symptoms appear later in life and occur only intermittently Restriction of the intake of branched chain amino acids is more effective 9  ISOVALERIC ACIDAEMIA This condition is due to the deficiency of Isovaleryl CoA dehydrogenase required for the catabolism of leucine (i.e. isovaleryl CoA to β- methylcrotonyl CoA is impaired) The accumulation and excretion of isovalerate (isovaleric acid) is high in urine The breath and urine (body fluids) of affected subjects have a 'cheesy' odour Affected subjects present with a mild mental retardation  ISOVALERIC ACIDAEMIA When affected subjects are fed with protein they may present with vomiting, acidosis and coma. It may be managed by the restriction of the intake of leucine 11 CATABOLISM OF PHENYLALANINE 12  CATABOLISM OF PHENYLALANINE Phenylalanine is usually hydroxylated to tyrosine in a reaction catalyzed by phenylalanine hydroxylase (present in the liver) The cofactor for this reaction is tetrahydrobiopterin 13  PHENYLKETONURIA The deficiency of the phenylalanine hydroxylase, the cofactor or the dihydrobiopterin reductase which regenerates the cofactor (dihydrobiopterin → tetrahydrobiopterin) may lead to Phenylketonuria (PKU)***?? 14  PHENYLKETONURIA It is characterized by the accumulation of phenylalanine and phenylketones (from alternative pathway) in the blood and their excretion in the urine Alternative pathway 15  PHENYLKETONURIA The urine of affected subjects has a `mousy’ odour (due to phenylacetate) Affected subjects present with;  severe mental retardation  a low IQ  failure to grow  dilution of hair and skin pigmentation (hypopigmentation) 16  PHENYLKETONURIA Management of the condition requires the restriction of phenylalanine containing diets The diet of subjects should however be high in tyrosine (essential now)* for the first 4-5 years (prevent the damage to brain) Protein diet restriction should be enforced for several years The diets of subjects should contain high levels of tetrahydrobiopterin 17  PHENYLKETONURIA Diagnosis of PKU: – Guthrie test???: for phenylalanine in blood (bacterial inhibition assay; β-2-thienylalanine inhibits growth of Bacillus subtilis) – Ferric chloride test: for phenylpyruvate in urine 18  METABOLISM OF TYROSINE The metabolic fate of tyrosine are as follows: Catecholamines Thyroid Hormones Melanin pigment 19  Catabolism of Tyrosine Tyrosine is catabolized through a series of reactions leading to the synthesis of acetoacetate and fumarate The reactions include transamination, dioxygenation, isomerisation & hydrolysis reactions Occurs mostly in the liver 20 Catabolism of Tyrosine 21  TYROSINAEMIA This condition is characterized by the accumulation and excretion of tyrosine and its metabolites. About 10% of neonates may have temporarily elevated levels of tyrosine This temporary elevation may be due to Vit C deficiency or immature liver enzymes (prematured babies more affected) 22  TYROSINAEMIA If untreated, tyrosine and its metabolites may build up in tissues and organs leading to serious medical problems This condition affects both males and females equally There are three distinct types of tyrosinaemia 23 Vit C 24  Type I Tyrosinaemia This condition is characterized by the deficiency of fumarylacetoacetase (fumaryl acetoacetate hydrolase) It is associated with the accumulation of maleyl acetoacetate and fumaryl acetoacetate Fumaryl acetoacetate accumulates in hepatocytes and proximal renal tubal cells and causes oxidative damage and DNA damage leading to cell death Some babies may present with the acute form and others with the chronic form 25  Type I Tyrosinaemia The acute form manifests in the first few months whereas the chronic form manifests around one year The symptoms of the acute form are: – Poor appetite and stunted growth – Vomiting – A cabbage-like odour – Inflammation of the liver (hepatitis) – Jaundice – Irritability – lethargy 27  Type I Tyrosinaemia The symptoms of the chronic form are: – Cirrhosis of the liver – Polyneuropathy – Kidney problems It is otherwise referred to as hepato-renal tyrosinaemia 27  Type II Tyrosinaemia This condition is characterized by the deficiency of tyrosine aminotransferase Accumulation and excretion of tyrosine and its metabolites It is associated with eye and skin lesions as well as mental retardation (rare) 28  Type II Tyrosinaemia The symptoms begin in early childhood and include: – Abnormal sensitivity to light (photophobia) – Eye pain and redness – Painful skin lesions on the palms and soles – About 50% of affected subjects have some degree of intellectual disability It is otherwise referred to as oculo-cutaneous tyrosinaemia or Richner-Hanhart Syndrome 29  Type III It is characterized by the deficiency of para-hydroxy phenylpyruvate dioxygenase Characteristic features include: – Intellectual disability – Seizures – Periodic loss of balance and coordination (intermittent ataxia) 30  HOMOGENTISIC ACIDURIA (Alkaptonuria) This condition is characterized by the deficiency of homogentisate-1,2- dioxygenase Affected subjects excrete large amounts of homogentisic acid in their urine hence the name. On exposure to air, homogentisic acid gets oxidized to the corresponding quinones, which polymerize to give alkapton (black or brown colour) and leads to the darkening of napkins The urine of alkaptonuric patients resembles coke in colour. 32  HOMOGENTISIC ACIDURIA Alkapton is also deposited in the bones, connective tissue and other organs leading to ochronosis Later in life affected subjects present with arthritis 32  HOMOGENTISIC ACIDURIA Diagnosis: – Change in colour of the urine on standing to brown or dark (simple traditional mtd); – Ferric chloride – positive (a green colour is obtained); – Benedict’s test – positive (reducing ability of homogentisate) Treatment: Consumption of protein diet with relatively low phenylalanine 33  MELANIN SYNTHESIS Melanin is the pigment of skin, hair and eye. Melanin synthesis occurs in melanosomes present in melanocytes (pigment-producing cells)  ALBINISM Deficiency of tyrosinase enzyme results in albinism. It is characterized by defective synthesis of melanin in the skin, hair and eyes Caused by autosomal recessive genetic mutation in the tyrosinase gene 36  ALBINISM (cont.) Affected subjects are extremely sensitive to sunlight Lack of pigment in the eyes causes photophobia but does not impaired eyesight They are also highly susceptible to sunburn and skin cancer 37 Albino phenotype  CATABOLISM OF HISTIDINE The first irreversible step in histidine catabolism is its conversion to urocanic acid and NH3 catalysed by histidine ammonia lyase (Histidase) (mostly present in the liver and skin*) The urocanic acid* is subsequentially converted to Formiminoglutamate (FIGlu) FIGlu is also converted in the presence of tetrahydrofolate (THFA) to glutamate and N5- formimino THFA 37 CATABOLISM OF HISTIDINE (cont) Histidase Urocanase 4-imidazolone 5-propionate Histidine Urocanate imidazolone propionase glutamate formiminotransferase Glutamate N5-Formimino-THFA N-Formiminoglutamate (FIGlu) 38  CATABOLISM OF HISTIDINE (cont) Deficiency of folic acid or vitamin B12 in humans results in accumulation of FIGlu and its excessive excretion in urine Histidine load test - excretion of FIGLU in urine is used to assess folic acid deficiency Folate deficiency may be due to malnutrition or may be drug- induced Folate deficiency is characterized by biochemical and haematological changes 40  CATABOLISM OF HISTIDINE (cont) Deficiency of folate results in inadequate synthesis of DNA and abnormal cell division. Can lead to macrocytic RBC formation (megaloblastic anaemia) 41  HISTIDINAEMIA Histidine ammonia lyase (histidase) is deficient in individuals presenting with histidinaemia Histidinaemia is associated with elevated blood and urine levels of histidine In some affected individuals, there are speech defects and mental retardation DIAGNOSIS (A). Absence of: – (1) urocanate detection in sweat or – (2) Histidase in skin biospy confirms the condition OR (B). Blood and urine levels of histidine 42 THE END 42 43