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Phenylketonurics:Contains phenylalanine H3N CH O H N H C O O O CH3 O H3N = O O O O + H 3N O HO Aspartame Aspartate Phenylalanine protein X X phenylalanine hydroxylase X CO2 NH3 O2 HO CO2 NH3 phenylalanine tyrosine CO2 O phenylpyruvate CO2 + H2O + energy Phenylketonuria (PKU) First desc ribed in 1934 by Fљlling. Diagnost ic symptom is high leve l of pheny lalanine in blood. Autoso mal recess ive d isease. Occurs in 1 out of 10,000 b irths in European and O rienta l popu lations (1% must be carriers.) Due to lack of suff icient pheny lalanine hydroxy lase. Diagnosed sho rtly afte r birth when a c ouple of d rops of b lood d rawn from a hee l prick revea l a high leve l of pheny lalanine in the b lood. Effects of untreated PKU Progressive, severe mental retardation Seizures, tremors or jerking movements in the a rms and legs Behavioral or social problems Rocking Hyperactivity Stunte d growth Skin ra shes (eczema) Small head size (microcephaly) Vomiting A musty odor in the child's breath, skin or urine, caused by too much phenylalanine in the body Fair skin and blue eyes, because phenylalanine cannot transform into melanin С the pigment responsible for hair and skin tone Dietary treatment for PKU Limited phenylalanine. Meat, fish, eggs, cheese, milk products, legumes, and bread, high in phenylalanine are eliminated or greatly r educed. (No Diet Coke.) Artificial protein substitute s are given which contain amino acids wi thout phenylalanine. These come in formulas, such as Phenex-1 and Phenylfree. Some phenylalanine is necessary i n the diet, taken as a specific amount of b reast milk or regular infant fo rmula for babies, or food exchang es in older children. For example 1Ъ 4 cup of fresh or cooked carrots is equivalent to one exchange. A new-born baby with classic P KU may require 20 exchanges a day, a five y ear old requires between 14 and 30 exchang es, and an adult woman requires between 15 and 50 exchanges a day. This photo was taken at my wedding a few years ago. I have PKU. I was diagnosed on the 3rd day of my life when treatment with the diet began. I stayed on the diet for 16 years. After I married and when my husband and I decided we would like to have a child, I went back on the diet before conception and I stayed on it throughout the pregnancy. Our daughter Stephanie was born without any evidence of maternal PKU effects. She is now in her second year and passing all her developmental milestones in style. The other woman in the picture is my older sister. She also has PKU but when she was born there was no newborn screening program for PKU. The diagnosis of her disease was made late in her first year of life when she developed convulsions. It was too late for treatment and she has never known the benefits of early diagnosis and treatment as I know them. Our picture is on this web site so that parents of newly-diagnosed infants with PKU will have some evidence of good news. (Irene, May 1998) Stephanie, age 2 years. protein X X phenylalanine hydroxylase X CO2 NH3 O2 HO CO2 NH3 phenylalanine tyrosine CO2 O phenylpyruvate CO2 + H2O + energy 531 mutations causing PKU known as of 2007: 62% missense (wrong amino acid, seldom in active site) 13% deletion (base pair omitted) 11% splicing (exons joined incorrectly 6% silent (no change in amino acids) 5% nonsense (protein ends too soon) 2% insertion (extra base pair) 14% are in introns and donХt affect amino acid sequence Structure of the human phenylalanine hydroxylase gene ~125,000 base pairs codes for a protein of 454 amino acids only 1362 base pairs code for amino ac ids 13 exons containing 41-184 base pairs coding for protein 12 introns from 1, 200 to 23,500 base pairs in length Mutations in phenylalanine hydroxylase have a variety of effects Inactive enzyme unstable protein partially active protein Enzyme kinetics describes how fast an enzym e makes a reaction go describes how much su bstrate is needed for the reaction A substrate is the molecule which binds in the active site of an enzyme and reacts Vmax is the fastest rate for the enzyme Km is the concentration of the substrate at which the rate is one-half as large as Vmax A mutation which decreases Vmax will result in a less active protein A mutation which increases Km will result in less active protein. Phenylalanine hydroxylase contains iron Example of a cofactor Required part of a protein which is not an amino acid metals small molecules derived from vitamins such as riboflavin Structure of the human phenylalanine hydroxylase gene Pterin-dependent enzymes H H N H H H H3 C C C N OH OH H H NH2 N H R NH O H H N NH 2 N N H H O O H N tetrahydrobiopterin phenylalanine hydroxylase HO CO2 CO2 NH3 NH3 phenylalanine tyrosine HO tyrosine hydroxylase HO HO CO2 CO2 NH3 NH 3 DOPA tyrosine CO2 N H NH3 tryptophan Removes excess phenylalanine in dietmutations cause phenylketonuria tryptophan HO hydroxylase CO2 N H NH3 5-hydroxytryptophan Catalyzes first step information of dopamine, epinephrine, and norepinephrinemutations are lethal or cause dystonia Catalyzes first step in formation of serotoninmutations cause depression Domain structurally independent portion of a longer protein typically ~100-200 amino acids long Phenylalanine hydroxylase Tryptophan hydroxylase Tyrosine hydroxylase