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Transcript
Catabolism of the branched-chain amino acids • The branched-chain amino acids, isoleucine, leucine, and valine, are essential amino acids. • In contrast to other amino acids, they are metabolized primarily by the peripheral tissues (particularly muscle), rather than by the liver. • They are oxidized as fuels primarily in muscle, adipose, kidney, and brain. • These extrahepatic tissues contain an aminotransferase, absent in liver, that acts on all three branched-chain amino acids to produce the corresponding α-keto acids. • These three amino acids have a similar route of catabolism. • The initial steps in valine, leucine, and isoleucine degradation are identical. All three are first deaminated to a-keto acids, which are then oxidatively decarboxylated to form CoA derivatives. 1. Transamination: Removal of the amino groups of all three amino acids is catalyzed by a single, vitamin B6–requiring enzyme, branched-chain α-amino acid aminotransferase. 2. Oxidative decarboxylation: Removal of the carboxyl group of the α-keto acids derived from leucine, valine, and isoleucine is catalyzed by a single multienzyme complex, branched-chain α-keto acid dehydrogenase complex. • This complex uses five cofactors: thiamine pyrophosphate, lipoic acid, FAD, NAD+, and CoA as its coenzymes. • Degradation of leucine, valine, and isoleucine. • TPP = thiamine pyrophosphate. 3. Dehydrogenation: Oxidation of the products formed in the above reaction yields α-β-unsaturated acyl CoA derivatives. 4. End products: • isoleucine ultimately yields acetyl CoA and succinyl CoA, rendering it both ketogenic and glucogenic. • Valine yields succinyl CoA and is glucogenic. • Leucine is ketogenic, being metabolized to acetoacetate and acetyl CoA. • [Note: Branched-chain amino acid catabolism also results in glutamine and alanine being sent out into the blood from muscle.] Maple syrup urine disease • It is a hereditary defect in the oxidative decarboxylation of these branched-chain a-keto acids. • Due to the deficiency of branched-chain α-keto acid dehydrogenase complex. • The metabolic block created by this defect leads to elevated levels of valine, leucine, and isoleucine (and their corresponding branched-chain a-keto acids) in the blood and urine. • The accumulation of the branched-chain α-keto acid substrates in urine give their sweet odor and prompted the name maple syrup urine disease. • If untreated, the disease results in abnormal development of the brain, mental retardation, and death in early infancy. • Treatment by rigid control of the diet, limiting the intake of valine, isoleucine, and leucine to the minimum required to permit normal growth. Catabolic pathways of three branched chain amino acids Inherited Disorders of A.A Catabolism Inborn Errors Of Metabolism Phenylketonuria • Phenylketonuria (PKU), caused by a deficiency of phenylalanine hydroxylase, PKU is the most common clinically encountered inborn error of amino acid metabolism (prevalence 1:15,000). • Hyperphenylalaninemia may also be caused by deficiencies in any of the several enzymes required to synthesize BH4, or in dihydropteridine (BH2) reductase, which regenerates BH4 from BH2. • Biochemically, it is characterized by: • accumulation of phenylalanine in blood & urine (and a deficiency of tyrosine) [phenylalanine in the blood that is 30-50 times higher than normal ]. • Excretion of large amounts of phe, phenylpyruvate, phenylacetate and phenyllactate in urine. • Phenylacetate gives a characteristic mousy odor to the urine. Phenylketonuria The most important symptoms of the disease are: • 1) Mental retardation. 2) Hypopigmentation. • Mental retardation results unless treatment begins immediately after birth. • Treatment consists of limiting phenylalanine intake to levels barely adequate to support growth. Tyrosine, an essential nutrient for individuals with phenylketonuria, must be supplied in the diet. Alternative pathways for catabolism of phenylalanine in phenylketonuria: • The high level of phenylalanine leads to the production of phenylalanine metabolites such as phenylpyruvate, phenylacetate and phenyllactate, all of which are associated with the observed neurological and developmental problems. PKU cont…. • Tyrosine is used not only for protein synthesis, but tyrosine is also the precursor for neurotransmitter dopamine, as well as, skin pigments (melanins) and epinephrine. • Why patients with PKU have hypopigmentation ? Albinism • Albinism refers to a group of conditions in which a defect in tyrosine metabolism results in a deficiency in the production of melanin. • These defects result in the partial or full absence of pigment from the skin, hair, and eyes. • Albinism appears in different forms ,Complete albinism (also called tyrosinase-negative oculocutaneous albinism) results from a deficiency of tyrosinase, causing a total absence of pigment from the hair, eyes, and skin. • It is the most severe form of the condition. In addition to hypopigmentation, affected individuals have vision defects and photophobia (sunlight hurts their eyes). They are at increased risk for skin cancer. Alkaptonuria • Alkaptonuria is a rare metabolic disease involving a deficiency in homogentisic acid oxidase, resulting in the accumulation of homogentisic acid. [This reaction occurs in the degradative pathway of tyrosine] • There are three characteristic symptoms: - homogentisic aciduria (the patient's urine contains elevated levels of homogentisic acid, which is oxidized to a dark pigment on standing. - Joint arthritis. - Black ochronotic pigmentation of cartilage and collagenous tissue. • Patients with alkaptonuria are usually asymptomatic until about age 40. • Dark staining of the diapers sometimes can indicate the disease in infants. • Diets low in protein—especially in phenylalanine and tyrosine—help reduce the levels of homogentisic acid, and decrease the amount of pigment deposited in body tissues. Alkaptonuria: It is characterized by dark color urine, large arthritis with dark cartilage.