TY - JOUR
T1 - Crystal structure of tyrosine hydroxylase at 2.3 Å and its implications for inherited neurodegenerative diseases
AU - Goodwill, Kenneth E.
AU - Sabatier, Christelle
AU - Marks, Cara
AU - Raag, Reetta
AU - Fitzpatrick, Paul F.
AU - Stevens, Raymond C.
PY - 1997
Y1 - 1997
N2 - Tyrosine hydroxylase (TyrOH) catalyzes the conversion of tyrosine to L- DOPA, the rate-limiting step in the biosynthesis of the catecholamines dopamine, adrenaline, and noradrenaline. TyrOH is highly homologous in terms of both protein sequence and catalytic mechanism to phenylalanine hydroxylase (PheOH) and tryptophan hydroxylase (TrpOH). The crystal structure of the catalytic and tetramerization domains of TyrOH reveals a novel α-helical basket holding the catalytic iron and a 40 Å long anti-parallel coiled coil which forms the core of the tetramer. The catalytic iron is located 10 Å below the enzyme surface in a 17 Å deep active site pocket and is coordinated by the conserved residues His 331. His 336 and Glu 376. The structure provides a rationale for the effect of point mutations in TyrOH that cause L-DOPA responsive parkinsonism and Segawa's syndrome. The location of 112 different point mutations in PheOH that lead to phenylketonuria (PKU) are predicted based on the TyrOH structure.
AB - Tyrosine hydroxylase (TyrOH) catalyzes the conversion of tyrosine to L- DOPA, the rate-limiting step in the biosynthesis of the catecholamines dopamine, adrenaline, and noradrenaline. TyrOH is highly homologous in terms of both protein sequence and catalytic mechanism to phenylalanine hydroxylase (PheOH) and tryptophan hydroxylase (TrpOH). The crystal structure of the catalytic and tetramerization domains of TyrOH reveals a novel α-helical basket holding the catalytic iron and a 40 Å long anti-parallel coiled coil which forms the core of the tetramer. The catalytic iron is located 10 Å below the enzyme surface in a 17 Å deep active site pocket and is coordinated by the conserved residues His 331. His 336 and Glu 376. The structure provides a rationale for the effect of point mutations in TyrOH that cause L-DOPA responsive parkinsonism and Segawa's syndrome. The location of 112 different point mutations in PheOH that lead to phenylketonuria (PKU) are predicted based on the TyrOH structure.
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U2 - 10.1038/nsb0797-578
DO - 10.1038/nsb0797-578
M3 - Article
C2 - 9228951
AN - SCOPUS:0031010420
VL - 4
SP - 578
EP - 585
JO - Nature Structural Biology
JF - Nature Structural Biology
SN - 1545-9993
IS - 7
ER -