Structure of Human Phytanoyl-CoA 2-Hydroxylase Identifies Molecular Mechanisms of Refsum Disease

Refsum disease (RD), a neurological syndrome characterized by adult onset retinitis pigmentosa, anosmia, sensory neuropathy, and phytanic acidaemia, is caused by elevated levels of phytanic acid. Many cases of RD are associated with mutations in phytanoyl-CoA 2-hydroxylase (PAHX), an Fe(II) and 2-ox...

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Veröffentlicht in:The Journal of biological chemistry 2005-12, Vol.280 (49), p.41101-41110
Hauptverfasser: McDonough, Michael A., Kavanagh, Kathryn L., Butler, Danica, Searls, Timothy, Oppermann, Udo, Schofield, Christopher J.
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container_end_page 41110
container_issue 49
container_start_page 41101
container_title The Journal of biological chemistry
container_volume 280
creator McDonough, Michael A.
Kavanagh, Kathryn L.
Butler, Danica
Searls, Timothy
Oppermann, Udo
Schofield, Christopher J.
description Refsum disease (RD), a neurological syndrome characterized by adult onset retinitis pigmentosa, anosmia, sensory neuropathy, and phytanic acidaemia, is caused by elevated levels of phytanic acid. Many cases of RD are associated with mutations in phytanoyl-CoA 2-hydroxylase (PAHX), an Fe(II) and 2-oxoglutarate (2OG)-dependent oxygenase that catalyzes the initial α-oxidation step in the degradation of phytenic acid in peroxisomes. We describe the x-ray crystallographic structure of PAHX to 2.5 Å resolution complexed with Fe(II) and 2OG and predict the molecular consequences of mutations causing RD. Like other 2OG oxygenases, PAHX possesses a double-stranded β-helix core, which supports three iron binding ligands (His175, Asp177, and His264); the 2-oxoacid group of 2OG binds to the Fe(II) in a bidentate manner. The manner in which PAHX binds to Fe(II) and 2OG together with the presence of a cysteine residue (Cys191) 6.7 Å from the Fe(II) and two further histidine residues (His155 and His281) at its active site distinguishes it from that of the other human 2OG oxygenase for which structures are available, factor inhibiting hypoxia-inducible factor. Of the 15 PAHX residues observed to be mutated in RD patients, 11 cluster in two distinct groups around the Fe(II) (Pro173, His175, Gln176, Asp177, and His220) and 2OG binding sites (Trp193, Glu197, Ile199, Gly204, Asn269, and Arg275). PAHX may be the first of a new subfamily of coenzyme A-binding 2OG oxygenases.
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Many cases of RD are associated with mutations in phytanoyl-CoA 2-hydroxylase (PAHX), an Fe(II) and 2-oxoglutarate (2OG)-dependent oxygenase that catalyzes the initial α-oxidation step in the degradation of phytenic acid in peroxisomes. We describe the x-ray crystallographic structure of PAHX to 2.5 Å resolution complexed with Fe(II) and 2OG and predict the molecular consequences of mutations causing RD. Like other 2OG oxygenases, PAHX possesses a double-stranded β-helix core, which supports three iron binding ligands (His175, Asp177, and His264); the 2-oxoacid group of 2OG binds to the Fe(II) in a bidentate manner. The manner in which PAHX binds to Fe(II) and 2OG together with the presence of a cysteine residue (Cys191) 6.7 Å from the Fe(II) and two further histidine residues (His155 and His281) at its active site distinguishes it from that of the other human 2OG oxygenase for which structures are available, factor inhibiting hypoxia-inducible factor. Of the 15 PAHX residues observed to be mutated in RD patients, 11 cluster in two distinct groups around the Fe(II) (Pro173, His175, Gln176, Asp177, and His220) and 2OG binding sites (Trp193, Glu197, Ile199, Gly204, Asn269, and Arg275). 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Of the 15 PAHX residues observed to be mutated in RD patients, 11 cluster in two distinct groups around the Fe(II) (Pro173, His175, Gln176, Asp177, and His220) and 2OG binding sites (Trp193, Glu197, Ile199, Gly204, Asn269, and Arg275). 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subjects Aspartic Acid - metabolism
Binding Sites - genetics
Coenzyme A - metabolism
Crystallization
Crystallography, X-Ray
Cysteine - metabolism
Escherichia coli - genetics
Ferrous Compounds - metabolism
Histidine - metabolism
Humans
Ketoglutaric Acids - metabolism
Mixed Function Oxygenases - chemistry
Mixed Function Oxygenases - genetics
Models, Molecular
Mutation
Peroxisomes - enzymology
Phytanic Acid - analogs & derivatives
Phytanic Acid - metabolism
Protein Binding
Protein Structure, Secondary
Recombinant Proteins
Refsum Disease - drug therapy
Refsum Disease - enzymology
Structure-Activity Relationship
Transfection
title Structure of Human Phytanoyl-CoA 2-Hydroxylase Identifies Molecular Mechanisms of Refsum Disease
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