Disease relevance of PHYH

• Molecular basis of Refsum disease: sequence variations in phytanoyl-CoA hydroxylase (PHYH) and the PTS2 receptor (PEX7) [1].
• The protein also corresponds to the mouse protein LN1, which could be involved in the progress of lupus nephritis [2].
• Both pro and mature forms of recombinant PAHX were produced in Escherichia coli, highly purified, and shown to have a requirement for iron(II) as a co-factor and 2-oxoglutarate as a co-substrate [3].
• Dynamics of human immunodeficiency virus transcription: P-TEFb phosphorylates RD and dissociates negative effectors from the transactivation response element [4].
• Each of the antibodies marked a small percentage of paraffin-embedded T-cell lymphomas: L26, 4.7%; LN1, 4.7%; LN2, 7.1% [5].

High impact information on PHYH

• Identification of PAHX, a Refsum disease gene [6].
• Radiation hybrid data place PAHX on chromosome 10 between the markers D10S249 and D10S466, a region previously implicated in Refsum disease by homozygosity mapping [6].
• We initially identified the human PAHX and mouse Pahx genes as expressed sequence tags (ESTs) capable of encoding PTS2 proteins [6].
• Sequence analysis of PHYH fibroblast cDNA from five patients with Refsum disease revealed distinct mutations, including a one-nucleotide deletion, a 111-nucleotide deletion and a point mutation [7].
• We have purified PhyH from rat-liver peroxisomes and determined the N-terminal amino-acid sequence, as well as an additional internal amino-acid sequence obtained after Lys-C digestion of the purified protein [7].

Chemical compound and disease context of PHYH

• Patients affected with Refsum disease (RD) have elevated levels of phytanic acid due to a deficiency of the peroxisomal enzyme phytanoyl-CoA hydroxylase (PhyH) [8].
• With formalin-fixed tissue, the percentages of B-cell lymphoma reacting with the antibodies were: L26, 89.1%; LN1, 26.2%; LN2, 57.8% [5].
• We investigated the myotoxicities of T-91485 and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in a human rhabdomyosarcoma cell line, RD, and in human skeletal myocytes [9].
• In children with a progressive neurological illness, with liver disease, retinal disease, unexplained neuropathy or deafness, detailed studies of fatty acid metabolism are indicated, including lipoproteins, serum phytanic acid, C26:C22 long-chain fatty acid ratios, serum pipecolic acid and phytanic acid oxidase levels [10].

Biological context of PHYH

• Linkage analysis of a few patients diagnosed with RD, but without mutations in PHYH, suggested a second locus on chromosome 6q22-24 [8].
• To enable mutation analysis of RD at the genome level, we have elucidated the genomic organization of the PHYH gene [11].
• The A2 domain (337-740 amino acids) of factor VIII (FVIII-A2) was used as a bait and phytanoyl-CoA alpha-hydroxylase (PAHX) was identified as a binding protein of FVIII-A2 [12].
• The middle portion (amino acids 83-264) of PAHX was used as a bait and a mouse brain cDNA library was searched [13].
• Six mutations, including a large in-frame deletion and five missense mutations, were expressed in the yeast Saccharomyces cerevisiae to study their effect on PhyH activity [11].

Anatomical context of PHYH

• In seven cases (4 NS, 2 LP, 1 LD) the monomorphic growths possessed a B-cell phenotype (LCA, L26, and LN1 positive; Leu-M1 and UCHL1 negative) [14].
• The panel included four reagents recognizing probable T-cell and B-cell restricted leukocyte common moieties (UCHL1, MT1, MB1, 4KB5), three antibodies to B-cell-related antigens (KiB3, MB2, LN1), and one to a macrophage-related antigen (Mac411) [15].
• Anti-alpha 6 antibodies inhibited adhesion to the LN-1/E8 fragment, but not to whole laminin or heat-denatured Laminin-1, indicating that chondrocytes utilize at least two beta 1-integrins for laminin adhesion, one of which is alpha 6 beta 1 recognizing the LN-1/E8 fragment [16].
• Several polyclonal antibodies raised against laminin-1 or the LN-1/E8 fragment revealed a strong pericellular reaction in sections of human fetal epiphyseal cartilage and adult articular cartilage [16].
• Binding of BSp73AS-1B1 to LN5 and, less markedly, LN1 induced spreading, lamellipodia formation and migration [17].

Associations of PHYH with chemical compounds

• Patients with RD are unable to degrade phytanic acid due to a deficient activity of phytanoyl-CoA hydroxyl-ase (PhyH), a peroxisomal enzyme catalysing the first step of phytanic acid alpha-oxidation [11].
• Sequence analysis in the light of crystallographic data for other members of the 2-oxoglutarate-dependent oxygenase super-family led to secondary structural predictions for PAHX, which were tested by site-directed mutagenesis [3].
• 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 [18].
• PAHX may be the first of a new subfamily of coenzyme A-binding 2OG oxygenases [18].
• 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 [18].

Other interactions of PHYH

• Immunophilins, Refsum disease, and lupus nephritis: the peroxisomal enzyme phytanoyl-COA alpha-hydroxylase is a new FKBP-associated protein [2].
• This observation suggests that PAHX is a serious candidate for studying the cellular signaling pathway(s) involving FKBP52 in the presence of immunosuppressant drugs [2].
• The elevated expression of von Willebrand factor had no effect on the suppression of FVIII secretion by PAHX [12].
• Utilization of sterol carrier protein-2 by phytanoyl-CoA 2-hydroxylase in the peroxisomal alpha oxidation of phytanic acid [19].
• All patients, with the exception of those with the X-linked form of adrenoleukodystrophy are deficient in phytanic acid oxidase activity [20].

Analytical, diagnostic and therapeutic context of PHYH

• Northern and Western blot analyses demonstrated a unique pattern of developmental PAHX-AP #1 expression which was targeted to the adult brain, but ubiquitous expressions of PAHX were observed in all examined tissues [13].
• We have identified a novel protein (PAHX-AP #1) associated with phytanoyl-CoA alpha-hydroxylase (PAHX), a Refsum disease gene product, using the yeast-based two-hybrid assay [13].
• Subcellular localization studies using equilibrium density centrifugation showed that PhyH is indeed a peroxisomal protein in rat [21].
• We have purified PhyH from rat liver to apparent homogeneity as judged by SDS-PAGE [21].
• The monoclonal antibodies LN1, LN2, and L26 have been recently developed to recognize B-cell-specific antigens that survive routine tissue processing and paraffin embedding [5].

References