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 alpha-oxidation step in the degradation of
phytenic acid in peroxisomes. We describe the x-ray crystallographic structure of PAHX to 2.5 A 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 beta-helix core, which supports three
iron binding
ligands (His(175), Asp(177), and His(264)); 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 (Cys(191)) 6.7 A from the Fe(II) and two further
histidine residues (His(155) and His(281)) 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) (Pro(173), His(175), Gln(176), Asp(177), and His(220)) and 2OG binding sites (Trp(193), Glu(197), Ile(199), Gly(204), Asn(269), and Arg(275)). PAHX may be the first of a new subfamily of
coenzyme A-binding 2OG
oxygenases.