Sandbox Reserved 1734: Difference between revisions

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The major regulatory mechanisms of phenylalanine hydroxylase include activation of phenylalanine inhibition by BH4, and additional activation by phosphorylation. Phosphorylation acts as a mediator of phenylalanine activation by decreasing phenylalanine concentration required to activate enzyme phosphorylation at Ser16. Substrate activation and positive homotropic allosterics for phenylalanine binding involves all three functional domains and all four subunits in the holoenzyme. The hypothesized cause of the phenylalanine activation mechanism is that homotropic binding of phenylalanine at the active site and the regulatory domain is involved in cooperativity through the interactions with the catalytic and oligomerization domains. Phenylalanine binds to an allosteric site, besides the active site, on the regulatory domain, which induces large conformational changes. The allosteric regulation is necessary to maintain phenylalanine levels below neurotoxic levels. BH4 acts as a negative allosteric regulator by blocking phenylalanine activation, however, BH4 binding to a Phe-activated form of PAH results in positive cooperativity.

== Phenylketonuria == L-Tyrosine is the precursor to neurotransmitters such as epinephrine, dopamine, and serotonin. PAH depletion or mutation leads to excessive accumulation of toxic L-Phe levels (physiological plasmatic levels <120 micromolar~~) This causes of~~ the autosomal recessive metabolic disorder Phenylketonuria (PKU). PKU is a congenital disorder characterized by excessive amounts of L-~~Phenylalanine~~ that buildup to neurotoxic amounts leading to cognitive disability and neurological impairment- profound mental retardation, seizures, microcephaly, and delayed development. The severity of ~~mutation indicated~~ the severity of ~~PKU that leaded to increase~~ the ~~accumulation of phenylalanine in the patient blood with toxic effect~~. PAH secreted from the liver, and a variety of deficiency syndromes causing various levels of hyperphenylalaninemia have been observed in PKU patient. (Shebl 2019) finds, the most severe PKU was a 14-year-old female followed by a 6-month-old male and a 16-year-old male. Tyrosine biosynthesis as liver enzyme associated with melanin-associated physiological processes. Treatments include a lifelong diet avoiding foods containing phenylalanine and supplementation of synthetic formations of the cofactor tetrahydrobiopterin (BH4) PAH mutations result in reduced enzyme activity and stability and some alter its oligomeric state. ~~Mutations~~ spread throughout 3D structure, but most located in catalytic domain. Loss of enzymatic function caused mainly by folding defects ~~leading~~ to decreased stability. ~~PAH proteins found in hepatocytes~~ (~~liver cells~~). ~~Found on chromosome 12 with 13 exons.~~

== Phenylketonuria == L-Tyrosine is the precursor to neurotransmitters such as epinephrine, dopamine, and serotonin. It is essential that L-phenylalanine is converted into L-tyrosine by the hydroxylation reaction. In order for this conversion to be successful, the enzyme phenylalanine hydroxylase needs to be able to function properly. PAH depletion or mutation leads to excessive accumulation of toxic L-Phe levels. However, normal physiological plasmatic levels of L-phenylalanine are less than 120 micromolar. When the enzyme PAH doesn’t function currently, the autosomal recessive metabolic disorder Phenylketonuria (PKU) occurs. PKU is a congenital disorder characterized by excessive amounts of L-phenylalanine that buildup to neurotoxic amounts leading to cognitive disability and neurological impairment, including profound mental retardation, seizures, microcephaly, and delayed development. The severity of PKU is dependent upon the severity of the enzyme’s mutation. PAH mutations result in reduced enzyme activity and stability and some alter its oligomeric state. These mutations spread throughout the 3D structure, but most are located in the catalytic domain. Loss of enzymatic function is caused mainly by folding defects that lead to decreased protein stability.

Treatments for phenylketonuria include a lifelong diet avoiding foods containing phenylalanine and supplementation of synthetic formations of the cofactor tetrahydrobiopterin (BH4).

Sandbox Reserved 1734: Difference between revisions

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 The major regulatory mechanisms of phenylalanine hydroxylase include activation of phenylalanine inhibition by BH4, and additional activation by phosphorylation. Phosphorylation acts as a mediator of phenylalanine activation by decreasing phenylalanine concentration required to activate enzyme phosphorylation at Ser16. Substrate activation and positive homotropic allosterics for phenylalanine binding involves all three functional domains and all four subunits in the holoenzyme. The hypothesized cause of the phenylalanine activation mechanism is that homotropic binding of phenylalanine at the active site and the regulatory domain is involved in cooperativity through the interactions with the catalytic and oligomerization domains. Phenylalanine binds to an allosteric site, besides the active site, on the regulatory domain, which induces large conformational changes. The allosteric regulation is necessary to maintain phenylalanine levels below neurotoxic levels. BH4 acts as a negative allosteric regulator by blocking phenylalanine activation, however, BH4 binding to a Phe-activated form of PAH results in positive cooperativity.
-== Phenylketonuria == L-Tyrosine is the precursor to neurotransmitters such as epinephrine, dopamine, and serotonin. PAH depletion or mutation leads to excessive accumulation of toxic L-Phe levels (physiological plasmatic levels <120 micromolar) This causes of the autosomal recessive metabolic disorder Phenylketonuria (PKU). PKU is a congenital disorder characterized by excessive amounts of L-Phenylalanine that buildup to neurotoxic amounts leading to cognitive disability and neurological impairment- profound mental retardation, seizures, microcephaly, and delayed development. The severity of mutation indicated the severity of PKU that leaded to increase the accumulation of phenylalanine in the patient blood with toxic effect. PAH secreted from the liver, and a variety of deficiency syndromes causing various levels of hyperphenylalaninemia have been observed in PKU patient. (Shebl 2019) finds, the most severe PKU was a 14-year-old female followed by a 6-month-old male and a 16-year-old male. Tyrosine biosynthesis as liver enzyme associated with melanin-associated physiological processes. Treatments include a lifelong diet avoiding foods containing phenylalanine and supplementation of synthetic formations of the cofactor tetrahydrobiopterin (BH4) PAH mutations result in reduced enzyme activity and stability and some alter its oligomeric state. Mutations spread throughout 3D structure, but most located in catalytic domain. Loss of enzymatic function caused mainly by folding defects leading to decreased stability. PAH proteins found in hepatocytes (liver cells). Found on chromosome 12 with 13 exons.
+== Phenylketonuria == L-Tyrosine is the precursor to neurotransmitters such as epinephrine, dopamine, and serotonin. It is essential that L-phenylalanine is converted into L-tyrosine by the hydroxylation reaction. In order for this conversion to be successful, the enzyme phenylalanine hydroxylase needs to be able to function properly. PAH depletion or mutation leads to excessive accumulation of toxic L-Phe levels. However, normal physiological plasmatic levels of L-phenylalanine are less than 120 micromolar. When the enzyme PAH doesn’t function currently, the  autosomal recessive metabolic disorder Phenylketonuria (PKU) occurs. PKU is a congenital disorder characterized by excessive amounts of L-phenylalanine that buildup to neurotoxic amounts leading to cognitive disability and neurological impairment, including profound mental retardation, seizures, microcephaly, and delayed development. The severity of PKU is dependent upon the severity of the enzyme’s mutation. PAH mutations result in reduced enzyme activity and stability and some alter its oligomeric state. These mutations spread throughout the 3D structure, but most are located in the catalytic domain. Loss of enzymatic function is caused mainly by folding defects that lead to decreased protein stability.
+Treatments for phenylketonuria include a lifelong diet avoiding foods containing phenylalanine and supplementation of synthetic formations of the cofactor tetrahydrobiopterin (BH4).