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J. Biol. Chem., Vol. 280, Issue 49, 41101-41110, December 9, 2005

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

Michael A. McDonough1, Kathryn L. Kavanagh1, Danica Butler1, Timothy Searls1, Udo Oppermann, and Christopher J. Schofield2

From the Oxford Centre for Molecular Sciences and Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, United Kingdom, Oxford Structural Genomics Consortium, University of Oxford, Botnar Research Centre, Oxford OX3 7LD, United Kingdom

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 -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 -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.

Received for publication, July 12, 2005 , and in revised form, September 20, 2005.

The atomic coordinates and structure factors (code 2A1X) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by European Union Grant QLG3-CT-2002-00696 and Biotechnology and Biological Research Council Grant 43/B14227. The Structural Genomics Consortium is a registered charity (number 1097737) funded by the Wellcome Trust, GlaxoSmithKline, Genome Canada, the Canadian Institutes of Health Research, the Ontario Innovation Trust, the Ontario Research and Development Challenge Fund, and the Canadian Foundation for Innovation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1S and 2S.

¹ These authors contributed equally to this work (protein purification and crystallization (D. B. and T. S.) and crystallography (M. A. M. and K. L. K.)).

² To whom correspondence should be addressed. Tel.: 44-1865-285110; Fax: 44-1865-285002; E-mail: christopher.schofield{at}chemistry.oxford.ac.uk.

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