Sandbox Reserved 1734: Difference between revisions

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Quaternary Structure:

The quaternary structure of PAH is a homotetramer, dimer of dimers. It is a multidomain, homo-oligomeric protein with dihedral (D2) symmetry. ~~PAH is an iron (Fe3+) containing enzyme. The iron binds to 2 histidines at the active site.~~

The quaternary structure of PAH is a homotetramer, dimer of dimers. It is a multidomain, homo-oligomeric protein with dihedral (D2) symmetry.

The substrate of phenylalanine hydroxylase is the amino acid L-phenylalanine. The activation of PAH by L-phenylalanine induces a large conformational change, but a slow global conformational change (is it large in magnitude but slow overall?)

~~Activation rate is slower for the BH4-preincubated than for the unbound enzyme, associated to the negative regulation of PAH activation exerted by BH4~~

The substrate of phenylalanine hydroxylase is the amino acid L-phenylalanine. The activation of PAH by L-phenylalanine induces a large conformational change, but a slow global conformational change (is it large in magnitude but slow overall?) Full activation of PAH involves the shift and dimerization of the regulatory domains.

Full activation of PAH involves the shift and dimerization of the ~~RDs~~

PAH is an iron (Fe3+) containing enzyme. The iron binds to 2 histidines at the active site. The cofactors of PAH include 6R-L-erythro-tetrahydrobiopterin (BH4) and oxygen. BH4 is sandwiched between hydrophobic residues and forms several hydrogen bonds with the N-terminal autoregulatory tail. BH4 binding causes a limited conformational change (mostly constrained to the N-terminal tail). PAH lacking this tail is not regulated by either BH4 or L-phenylalanine and is constitutively active. The BH4 binding-site is flanked by the N-terminal (residues 21-32), the active-site lid (130-150), the Fe+2-coordinating residues, the Beta 6-alpha 7 loop (residues 245-251), and F254.

~~Cofactors:~~ 6R-L-erythro-tetrahydrobiopterin (BH4) and oxygen

Tetrahydrobiopterin induces a negative heterotropic allosteric effect on the enzyme, which is observed as the activation rate is slower for the BH4 holoprotein than compared to the unbound enzyme. Prior to BH4 binding, (PAH unbound state) a polar and salt-bridge interaction network links the three PAH domains.

BH4 forms several hydrogen bonds with the N-terminal autoregulatory tail

~~Prior to BH4 binding, (PAH unbound state) a polar and salt-bridge interaction network links the three PAH domains~~

BH4 binding causes a limited conformational change (mostly constrained to the N-terminal tail)

PAH lacking this tail is not regulated by either BH4 or L-phenylalanine and is constitutively active

BH4 binding-site is flanked by the N-terminal (residues 21-32), the active-site lid (130-150), the Fe+2-coordinating residues, the ~~Beta6~~-~~alpha7~~ loop (residues 245-251), and F254

BH4 ~~is sandwiched between hydrophobic residues~~

== Function == PAH is a metabolic enzyme contained in liver cells that catalyzes the hydroxylation reaction of the amino acid L-Phenylalanine to L-Tyrosine. This protein specifically catalyzes the rate-limiting step in the phenylalanine catabolism, which is the para-hydroxylation step of the aromatic side chain. This catalysis is done by hydroxylation of its substrate by incorporation of one oxygen atom into the aromatic ring, and the final reaction includes the reduction of the second oxygen atom to water using electrons supplied by tetrabiopterin (BH4). BH4 functions as a co-substrate that is hydroxylated at each turnover to pterin-4a-carbinolamine (4a-OH-BH4), with consequent dissociation from the enzymes.

Sandbox Reserved 1734: Difference between revisions

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@@ Line 19: / Line 19: @@
 Quaternary Structure:
-The quaternary structure of PAH is a homotetramer, dimer of dimers. It is a multidomain, homo-oligomeric protein with dihedral (D2) symmetry. PAH is an iron (Fe3+) containing enzyme. The iron binds to 2 histidines at the active site.
+The quaternary structure of PAH is a homotetramer, dimer of dimers. It is a multidomain, homo-oligomeric protein with dihedral (D2) symmetry.
-The substrate of phenylalanine hydroxylase is the amino acid L-phenylalanine. The activation of PAH by L-phenylalanine induces a large conformational change, but a slow global conformational change (is it large in magnitude but slow overall?)
-Activation rate is slower for the BH4-preincubated than for the unbound enzyme, associated to the negative regulation of PAH activation exerted by BH4
+The substrate of phenylalanine hydroxylase is the amino acid L-phenylalanine. The activation of PAH by L-phenylalanine induces a large conformational change, but a slow global conformational change (is it large in magnitude but slow overall?) Full activation of PAH involves the shift and dimerization of the regulatory domains.
-Full activation of PAH involves the shift and dimerization of the RDs
+PAH is an iron (Fe3+) containing enzyme. The iron binds to 2 histidines at the active site. The cofactors of PAH include 6R-L-erythro-tetrahydrobiopterin (BH4) and oxygen. BH4 is sandwiched between hydrophobic residues and forms several hydrogen bonds with the N-terminal autoregulatory tail. BH4 binding causes a limited conformational change (mostly constrained to the N-terminal tail). PAH lacking this tail is not regulated by either BH4 or L-phenylalanine and is constitutively active. The BH4 binding-site is flanked by the N-terminal (residues 21-32), the active-site lid (130-150), the Fe+2-coordinating residues, the Beta 6-alpha 7 loop (residues 245-251), and F254.
-Cofactors: 6R-L-erythro-tetrahydrobiopterin (BH4) and oxygen
+Tetrahydrobiopterin induces a negative heterotropic allosteric effect on the enzyme, which is observed as the activation rate is slower for the BH4 holoprotein than compared to the unbound enzyme. Prior to BH4 binding, (PAH unbound state) a polar and salt-bridge interaction network links the three PAH domains.
-BH4 forms several hydrogen bonds with the N-terminal autoregulatory tail
-Prior to BH4 binding, (PAH unbound state) a polar and salt-bridge interaction network links the three PAH domains
-BH4 binding causes a limited conformational change (mostly constrained to the N-terminal tail)
-PAH lacking this tail is not regulated by either BH4 or L-phenylalanine and is constitutively active
-BH4 binding-site is flanked by the N-terminal (residues 21-32), the active-site lid (130-150), the Fe+2-coordinating residues, the Beta6-alpha7 loop (residues 245-251), and F254
-BH4 is sandwiched between hydrophobic residues
 == Function == PAH is a metabolic enzyme contained in liver cells that catalyzes the hydroxylation reaction of the amino acid L-Phenylalanine to L-Tyrosine. This protein specifically catalyzes the rate-limiting step in the phenylalanine catabolism, which is the para-hydroxylation step of the aromatic side chain. This catalysis is done by hydroxylation of its substrate by incorporation of one oxygen atom into the aromatic ring, and the final reaction includes the reduction of the second oxygen atom to water using electrons supplied by tetrabiopterin (BH4). BH4 functions as a co-substrate that is hydroxylated at each turnover to pterin-4a-carbinolamine (4a-OH-BH4), with consequent dissociation from the enzymes.