Lecture 48 Flashcards
What are metabolic defects in amino acid metabolism usually caused by?
1) Inborn errors of metabolism are commonly caused by mutant genes that generally result in abnormal proteins, most often enzymes
2) The inherited defects may be expressed as a total loss of enzyme activity or a partial deficiency in activity
What is a treatment for metabolic defects in amino acid metabolism and what is important about the treatment?
1) Treatment: diets low in the amino acids whose catabolism is impaired
2) Newborn screening and timely initiation off treatment are essential. By law, all states must screen for over 20 disorders. All states screen for PKU
What are common metabolic defects in amino acid metabolism?
Cystinuria, Histidinemia, Phenylketonuria, Methylmalonyl CoA mutase deficiency, & Albinism
What are rare metabolic defects in amino acid metabolism?
Homocystinuria, Alkaptonuria, Maple syrup urine disease, Cystathioninuria, & Cystinosis
What causes phenylketonuria (PKU)?
1) A deficiency in phenylalanine hydroxylase
2) The following reaction cannot occur:
L-phenylalanine + Tetrahydro-bioptern + O2 –> L-Tyrosine + Dihydro-biopterin + H2O (uses Phenylalanine hydroxylase)
What are characteristics of phenylketonuria?
1) Most common clinically encountered inborn error of amino acid metabolism
2) Elevated levels of phenylalanine (10X normal), phenylpyruvate, phenyllactate, & phenylacetate in blood & urine
3) Symptoms: Hypopigmentation, due to inhibition of tyrosinase essential for melanin formation (patients often blond with fair skin & blue eyes)
4) CNS symptoms: intellectual disability by age one, developmental delay, microcephaly, & seizures in untreated PKU patients (now rare due to prenatal testing)
5) Treatment: dietary restriction of Phe
What does phenylalanine normally form?
1) Phenylalanine is normally converted to Tyrosine
2) Tyrosine can be used to produce tissue proteins, melanin, catecholamines, fumarate & acetoacetate
What does phenyalanine form in phenylketonuria?
1) Phenylalanine is converted to Phenylpyruvate
2) Phenylpyruvate is converted to phenyllactate & phenylacetate
What can hyperphenylalanemia be caused by?
1) May be caused by deficiencies in any of the several enzymes required to synthesize Tetrahydrobioptern (BH4) or in dihydropteridine reductase, which regenerates BH4 from BH2
2) These enzymes are used in Tyrosine synthesis, catecholamine synthesis, & serotonin synthesis
3) A deficiency in dihydropteridine reductase or any of the enzymes of BH4 synthesis leads to hyperphenyalanemia and decreased synthesis of catecholamines & serotonin
What is the inheritance pattern of maple syrup urine disease (MSUD)?
1) Autosomal recessive
What causes maple syrup urine disease (MSUD)?
1) Partial or complete deficiency in mitochondrial branched chain alpha-keto acid dehydrogenase (BCKD), that oxidatively decarboxylates Leu, Ile, & Val
2) These BCAAs and their corresponding alpha-keto acids accumulate in blood, casing interference with brain functions (especially Leu & alpha-Kic acid)
What are symptoms of maple syrup urine disease (MSUD)?
1) A characteristic maple syrup odor to the urine due to rise in Ile
2) Feeding problems, vomiting, ketoacidosis, changes in muscle tone, neurologic problems that can result in coma
3) If untreated, disease is fatal
4) If treatment is delayed, intellectual disability results
How is maple syrup urine disease (MSUD) treated?
Synthetic formula free of BCAAs supplmeneted with limited amount of Leu, Ile, & Val to allow normal growth & development without producing toxic levels
What causes albinism?
Results from an absent or defective copper-requiring tyrosinase deficiency
What is the inheritance pattern for albinism?
Albinism appears in different forms: autosomal recessive inheritance is primary mode
What are the symptoms of albinism?
1) White hair, pink eyes, & hypopigmented pale skin
2) Sensitive to sunlight (easy to sunburn and increased skin cancer)
3) Impaired vision & photophobia
How is albinism treated?
Protection from UV exposure
How is eumelanin formed from tyrosine?
1) Tyrosine –> DOPA (uses tyrosinase)
2) DOPA –> DOPAquinone (uses tyrosinase)
3) Series of steps leads to eumelanin
How is pheomelanin formed from tyrosine?
1) Tyrosine –> DOPA (uses tyrosinase)
2) DOPA –> DOPAquinone (uses tyrosinase)
3) DOPAquinone + cysteine –> CysteinylDOPA
4) CysteinylDOPA –> 1,4-benzothiazinyl-alanine
5) Pheomelanin
What is melanin?
1) In humans, melanin is the primary determinant of skin color
2) Melanin is also found in hair, the pigmented tissue underlying the iris of the eye, & the stria vascularis of the inner ear
3) In the brain, tissues with melanin include pigment-bearing neurons within areas of the brainstem, such as the locus coeruleus and the substantia nigra
How is melanin formed?
1) Melanin in the skin is produced by melanocytes, which are found in the basal layer of the epidermis
2) Albinism results from very little or no melanin synthesis in the body
What are two types of melanin?
Pheomelanin & eumelanin are found in human skin & hair, but eumelanin is the most abundant melanin in humans
What is eumelanin?
1) Eumelanin polymers are composed of numerous cross-linked 5,6-dihydroxyindole (DHI) and 5,6-dihydroxyindole-2-carboxylic acid (DHICA) polymers
2) Two types are recognized: black & brown
3) A small amount of black eumelanin in the absence of other pigments causes grey hair
4) A small amount of brown eumelanin in the absence of other pigments results in blond hair
What is pheomelanin?
1) Pheomelanin imparts a pink to red hue and, thus, is found in particularly large quantities in red hair
2) Pheomelanin is particularly concentrated in the lips, nipples, glans of the penis, & vagina
3) In chemical terms, pheomelanin differs from eumelanin in that its oligomer structure incorporates benzothiazine and benzothiazole units that are produced, instead of DHI & DHICA from tyrosine and cysteine
