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Ronald J.a. Wanders - One of the best experts on this subject based on the ideXlab platform.
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Identification and diagnostic value of phytanoyl- and pristanoyl-carnitine in plasma from patients with peroxisomal disorders.
Molecular Genetics and Metabolism, 2017Co-Authors: Katharina Herzog, Ronald J.a. Wanders, Hans R Waterham, Henk Van Lenthe, Frédéric M. Vaz, Sacha FerdinandusseAbstract:Phytanic acid is a branched-chain fatty acid, the level of which is elevated in patients with a variety of peroxisomal disorders, including Refsum disease, and Rhizomelic chondrodysplasia punctata type 1 and 5. Elevated levels of both phytanic and pristanic acid are found in patients with Zellweger Spectrum Disorders, and pristanic acid is elevated in patients with α-methylacyl-CoA racemase deficiency. For the diagnosis of peroxisomal disorders, a variety of metabolites can be measured in blood samples from suspected patients, including very long-chain fatty acids, phytanic and pristanic acid. Based on the fact that very long-chain fatty acylcarnitines are elevated in tissues and plasma from patients with certain peroxisomal disorders, we investigated whether phytanoyl- and pristanoyl-carnitine are also present in plasma from patients with different peroxisomal disorders. Our study shows that phytanoyl- and pristanoyl-carnitine are indeed present in plasma samples from patients with different types of peroxisomal disorders, but only when the total plasma levels of their corresponding fatty acids, phytanic acid and pristanic acid, are markedly elevated. We conclude that the measurement of phytanoyl- and pristanoyl-carnitine is not sensitive and specific enough to use these acylcarnitines as conclusive diagnostic markers for peroxisomal disorders.
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CHAPTER 14:Phytanoyl-CoA Hydroxylase: A 2-Oxoglutarate-Dependent Dioxygenase Crucial for Fatty Acid Alpha-Oxidation in Humans
2-Oxoglutarate-Dependent Oxygenases, 2015Co-Authors: Ronald J.a. Wanders, Merel S. Ebberink, Sacha Ferdinandusse, Hans R WaterhamAbstract:Phytanoyl-CoA hydroxylase belongs to the family of 2-oxoglutarate-dependent dioxygenases and plays a crucial role in the α-oxidation of fatty acids. The complete α-oxidation pathway involves five different enzymes localized in peroxisomes. Thus far, Phytanoyl-CoA hydroxylase deficiency has remained the only genetically determined inborn error of metabolism affecting the α-oxidation pathway. In this chapter we describe the current state of knowledge on fatty acid α-oxidation with special emphasis on Phytanoyl-CoA hydroxylase and its deficiency in Refsum disease.
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Chapter 163 - Peroxisomal disorders
Handbook of Clinical Neurology, 2013Co-Authors: Patrick Aubourg, Ronald J.a. WandersAbstract:The peroxisomal disorders represent a group of genetic diseases in man in which there is an impairment in one or more peroxisomal functions. The peroxisomal disorders are subdivided into three subgroups comprising: (1) the peroxisome biogenesis disorders (PBDs); (2) the single peroxisomal (enzyme-) protein deficiencies; and (3) the single peroxisomal substrate transport deficiencies. The PBD group comprises four different disorders that include Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and rhizomelic chondrodysplasia punctata (RCDP). ZS, NALD, and IRD are clearly distinct from RCDP and are usually referred to as the Zellweger spectrum with ZS being the most severe, and IRD the less severe disorder, with sometimes onset in adulthood. The single peroxisomal enzyme deficiency group comprises seven different disorders, of which D-bifunctional protein and Phytanoyl-CoA hydroxylase (adult Refsum disease) deficiencies are the most frequent. The single peroxisomal substrate transport deficiency group consists of only one disease, X-linked adrenoleukodystrophy. It is the purpose of this chapter to describe the current state of knowledge about the clinical, biochemical, cellular, and molecular aspects of peroxisomal diseases, and to provide guidelines for their post- and prenatal diagnosis. Therapeutic interventions are mostly limited to X-linked adrenoleukodystrophy.
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Comparative profiling of the peroxisomal proteome of wildtype and Pex7 knockout mice by quantitative mass spectrometry
International Journal of Mass Spectrometry, 2012Co-Authors: Sebastian Wiese, Rob Ofman, Ronald J.a. Wanders, Pedro Brites, Thomas Gronemeyer, Christian Bunse, Christian Renz, Helmut E. Meyer, Bettina WarscheidAbstract:Abstract We present a label-free quantitative proteomic approach for the study of kidney peroxisomes of Pex7 knockout mice which is a bona-fide model for the human disease rhizomelic chondrodysplasia punctata (RCDP). RCDP is an autosomal recessive human disorder caused by mutations in the PEX7 gene encoding for Pex7, the cytosolic receptor protein that is essential for the import of proteins containing a functional peroxisomal targeting signal (PTS)-type 2. In this work, we quantitatively followed hundreds of proteins through high density gradient fractions of wildtype (WT) and Pex7 knockout ( Pex7 −/− ) mice by high resolution mass spectrometry. A set of candidate proteins with altered abundance was defined via statistical and quantitative assessment of protein profiles obtained from WT and Pex7 −/− mice. The results obtained demonstrate the feasibility of this approach to identify proteins specifically affected in abundance by the deletion of Pex7. All three known PTS2 proteins, including acetyl-Coenzyme A acyltransferase, alkylglycerone phosphate synthase and Phytanoyl-CoA hydroxylase were determined to be virtually absent in these fractions whereas KIAA0564, a so far uncharacterized protein, was barely detectable in peroxisomal fractions of Pex7 −/− mice. Furthermore, we report numerous PTS1 proteins with increased abundance levels in Pex7 −/− mice that fulfill essential functions in the β-oxidation of very long-chain fatty acids or the biosynthesis of ether-phospholipids in peroxisomes.
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Phytanic acid metabolism in health and disease.
Biochimica et Biophysica Acta, 2011Co-Authors: Ronald J.a. Wanders, Jasper C. Komen, Sacha FerdinandusseAbstract:Abstract Phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) is a branched-chain fatty acid which cannot be beta-oxidized due to the presence of the first methyl group at the 3-position. Instead, phytanic acid undergoes alpha-oxidation to produce pristanic acid (2,6,10,14-tetramethylpentadecanoic acid) plus CO2. Pristanic acid is a 2-methyl branched-chain fatty acid which can undergo beta-oxidation via sequential cycles of beta-oxidation in peroxisomes and mitochondria. The mechanism of alpha-oxidation has been resolved in recent years as reviewed in this paper, although some of the individual enzymatic steps remain to be identified. Furthermore, much has been learned in recent years about the permeability properties of the peroxisomal membrane with important consequences for the alpha-oxidation process. Finally, we present new data on the omega-oxidation of phytanic acid making use of a recently generated mouse model for Refsum disease in which the gene encoding Phytanoyl-CoA 2-hydroxylase has been disrupted.
Christopher J Schofield - One of the best experts on this subject based on the ideXlab platform.
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Crystal structure of PHYHD1A, a 2OG oxygenase related to Phytanoyl-CoA hydroxylase.
Biochemical and biophysical research communications, 2011Co-Authors: Zhihong Zhang, Christopher J Schofield, Grazyna Kochan, Kathryn L. Kavanagh, Udo Oppermann, Michael A. McdonoughAbstract:Abstract Phytanoyl-CoA hydroxylase (PAHX) catalyzes an important step in the metabolism of the fatty acid side chain of chlorophyll. PHYHD1 exists in three isoforms and is the closest human homologue of PAHX. We show that like PAHX, the PHYHD1A but likely not the PHYHD1B/C isoforms, is a functional Fe(II) and 2-oxoglutarate (2OG) dependent oxygenase. Crystallographic and biochemical analyses reveal that PHYHD1A has the double-stranded β-helix fold and Fe(II) and cosubstrate binding residues characteristic of the 2-oxoglutarate dependent oxygenases and catalyzes the conversion of 2-oxoglutarate to succinate and CO2 in an iron-dependent manner. However, PHYHD1A did not couple 2OG turnover to the hydroxylation of acyl-coenzyme A derivatives that are substrates for PAHX, implying that it is not directly involved in phytanoyl coenzyme-A metabolism.
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Structural and mechanistic studies on the peroxisomal oxygenase Phytanoyl-CoA 2-hydroxylase (PhyH).
Biochemical Society Transactions, 2007Co-Authors: Christopher J Schofield, Michael A. McdonoughAbstract:Phytanic acid (PA) is an epimeric metabolite of the isoprenoid side chain of chlorophyll. Owing to the presence of its epimeric β-methyl group, PA cannot be metabolized by β-oxidation. Instead, it is metabolized in peroxisomes via α-oxidation to give pristanic acid, which is then oxidized by β-oxidation. PhyH (Phytanoyl-CoA 2-hydroxylase, also known as PAHX), an Fe(II) and 2OG (2-oxoglutarate) oxygenase, catalyses hydroxylation of Phytanoyl-CoA. Mutations of PhyH ablate its role in α-oxidation, resulting in PA accumulation and ARD (adult Refsum9s disease). The structure and function of PhyH is discussed in terms of its clinical importance and unusual selectivity. Most point mutations of PhyH causing ARD cluster in two distinct groups around the Fe(II)- and 2OG-binding sites. Therapaeutic possibilities for the treatment of Refsum9s disease involving PhyH are discussed.
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Structure of Human Phytanoyl-CoA 2-Hydroxylase Identifies Molecular Mechanisms of Refsum Disease
The Journal of biological chemistry, 2005Co-Authors: Michael A. Mcdonough, Timothy Searls, Danica Butler, Kathryn L. Kavanagh, Udo Oppermann, Christopher J SchofieldAbstract:Abstract 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 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 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 A 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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Studies on the specificity of unprocessed and mature forms of Phytanoyl-CoA 2-hydroxylase and mutation of the iron binding ligands
Journal of lipid research, 2005Co-Authors: Timothy Searls, Matthew D Lloyd, Mridul Mukherji, Winnie Chien, Danica Butler, Christopher J SchofieldAbstract:The mature form of phytanoyl-coenzyme A 2-hydroxylase (PAHX), a nonheme Fe(II)- and 2-oxoglutarate-dependent oxygenase, catalyzes the alpha-hydroxylation of Phytanoyl-CoA within peroxisomes. Mutations in PAHX result in some forms of adult Refsum's disease. Unprocessed PAHX (pro-PAHX) contains an N-terminal peroxisomal targeting sequence that is cleaved to give mature PAHX (mat-PAHX). Previous studies have implied a difference in the substrate specificity of the unprocessed and mature forms of PAHX. We demonstrate that both forms are able to hydroxylate a range of CoA derivatives, but under the same assay conditions, the N-terminal hexa-His-tagged unprocessed form is less active than the nontagged mature form. Analyses of the assay conditions suggest a rationale for the lack of activity previously reported for some substrates (e.g. isovaleryl-CoA) for the (His)6pro-PAHX. Site-directed mutagenesis was used to support proposals for the identity of the iron binding ligands (His-175, Asp-177, His-264) of the 2-His-1-carboxylate motif of PAHX. Mutation of other histidine residues (His-213, His-220, His-259) suggested that these residues were not involved in Fe(II) binding.
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Role of Phytanoyl-CoA 2-hydroxylase in phytanic acid metabolism
Advances in experimental medicine and biology, 2003Co-Authors: Matthew D Lloyd, Anthony S Wierzbicki, Mridul Mukherji, Nadia J Kershaw, Winnie Chien, Christopher J SchofieldAbstract:Phytanic acid is a 3-methyl branched fatty acid that cannot be degraded by P-oxidation. Instead, one carbon atom is removed to give pristanic acid by a single round of peroxisomal a-oxidation. Phytanoyl-CoA 2- hydroxylase (PAHX), an iron(II) and 2-oxoglutarate oxygenase, catalyses the first step in this pathway. Defects in PAHX cause some forms of adult Refsum’s disease, in which phytanic acid accumulates (Wanders et al., 2001; Wierzbicki et al., 2002).
Matthew D Lloyd - One of the best experts on this subject based on the ideXlab platform.
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Studies on the specificity of unprocessed and mature forms of Phytanoyl-CoA 2-hydroxylase and mutation of the iron binding ligands
Journal of lipid research, 2005Co-Authors: Timothy Searls, Matthew D Lloyd, Mridul Mukherji, Winnie Chien, Danica Butler, Christopher J SchofieldAbstract:The mature form of phytanoyl-coenzyme A 2-hydroxylase (PAHX), a nonheme Fe(II)- and 2-oxoglutarate-dependent oxygenase, catalyzes the alpha-hydroxylation of Phytanoyl-CoA within peroxisomes. Mutations in PAHX result in some forms of adult Refsum's disease. Unprocessed PAHX (pro-PAHX) contains an N-terminal peroxisomal targeting sequence that is cleaved to give mature PAHX (mat-PAHX). Previous studies have implied a difference in the substrate specificity of the unprocessed and mature forms of PAHX. We demonstrate that both forms are able to hydroxylate a range of CoA derivatives, but under the same assay conditions, the N-terminal hexa-His-tagged unprocessed form is less active than the nontagged mature form. Analyses of the assay conditions suggest a rationale for the lack of activity previously reported for some substrates (e.g. isovaleryl-CoA) for the (His)6pro-PAHX. Site-directed mutagenesis was used to support proposals for the identity of the iron binding ligands (His-175, Asp-177, His-264) of the 2-His-1-carboxylate motif of PAHX. Mutation of other histidine residues (His-213, His-220, His-259) suggested that these residues were not involved in Fe(II) binding.
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Role of Phytanoyl-CoA 2-hydroxylase in phytanic acid metabolism
Advances in experimental medicine and biology, 2003Co-Authors: Matthew D Lloyd, Anthony S Wierzbicki, Mridul Mukherji, Nadia J Kershaw, Winnie Chien, Christopher J SchofieldAbstract:Phytanic acid is a 3-methyl branched fatty acid that cannot be degraded by P-oxidation. Instead, one carbon atom is removed to give pristanic acid by a single round of peroxisomal a-oxidation. Phytanoyl-CoA 2- hydroxylase (PAHX), an iron(II) and 2-oxoglutarate oxygenase, catalyses the first step in this pathway. Defects in PAHX cause some forms of adult Refsum’s disease, in which phytanic acid accumulates (Wanders et al., 2001; Wierzbicki et al., 2002).
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utilization of sterol carrier protein 2 by phytanoyl coa 2 hydroxylase in the peroxisomal α oxidation of phytanic acid
Chemistry & Biology, 2002Co-Authors: Mridul Mukherji, Anthony S Wierzbicki, Christopher J Schofield, Nadia J Kershaw, Matthew D LloydAbstract:Since it possesses a 3-methyl group, phytanic acid is degraded by a peroxisomal α-oxidation pathway, the first step of which is catalyzed by Phytanoyl-CoA 2-hydroxylase (PAHX). Mutations in human PAHX cause phytanic acid accumulations leading to Adult Refsum's Disease (ARD), which is also observed in a sterol carrier protein 2 (SCP-2)-deficient mouse model. Phytanoyl-CoA is efficiently 2-hydroxylated by PAHX in vitro in the presence of mature SCP-2. Other straight-chain fatty acyl-CoA esters were also 2-hydroxylated and the products isolated and characterized. Use of SCP-2 increases discrimination between straight-chain (e.g., hexadecanoyl-CoA) and branched-chain (e.g., Phytanoyl-CoA) substrates by PAHX. The results explain the phytanic acid accumulation in the SCP-2-deficient mouse model and suggest that some of the common symptoms of ARD and other peroxisomal diseases may arise in part due to defects in SCP-2 function caused by increased phytanic acid levels.
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refsum s disease a peroxisomal disorder affecting phytanic acid α oxidation
Journal of Neurochemistry, 2002Co-Authors: Anthony S Wierzbicki, Matthew D Lloyd, Christopher J Schofield, M D Feher, Brian F GibberdAbstract:Refsum's disease (hereditary motor sensory neuropathy type IV, heredopathia atactica polyneuritiformis) is an autosomal recessive disorder the clinical features of which include retinitis pigmentosa, blindness, anosmia, deafness, sensory neuropathy, ataxia and accumulation of phytanic acid in plasma- and lipid-containing tissues. The transport and biochemical pathways of phytanic acid metabolism have recently been defined with the cloning of two key enzymes, Phytanoyl-CoA 2-hydroxylase (PAHX) and 2-hydroxyPhytanoyl-CoA lyase, together with the confirmation of their localization in peroxisomes. PAHX, an iron(II) and 2-oxoglutarate-dependent oxygenase is located on chromosome 10p13. Mutant forms of PAHX have been shown to be responsible for some, but not all, cases of Refsum's disease. Certain cases have been shown to be atypical mild variants of rhizomelic chondrodysplasia punctata type 1a. Other atypical cases with low-plasma phytanic acid may be caused by α-methylacyl-CoA racemase deficiency. A sterol-carrier protein-2 (SCP-2) knockout mouse model shares a similar clinical phenotype to Refsum's disease, but no mutations in SCP-2 have been described to-date in man. This review describes the clinical, biochemical and metabolic features of Refsum's disease and shows how the biochemistry of the α-oxidation pathway may be linked to the regulation of metabolic pathways controlled by isoprenoid lipids, involving calcineurin or the peroxisomal proliferator activating α-receptor.
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Refsum's disease: a peroxisomal disorder affecting phytanic acid α‐oxidation
Journal of neurochemistry, 2002Co-Authors: Anthony S Wierzbicki, Matthew D Lloyd, Christopher J Schofield, M D Feher, F Brian GibberdAbstract:Refsum's disease (hereditary motor sensory neuropathy type IV, heredopathia atactica polyneuritiformis) is an autosomal recessive disorder the clinical features of which include retinitis pigmentosa, blindness, anosmia, deafness, sensory neuropathy, ataxia and accumulation of phytanic acid in plasma- and lipid-containing tissues. The transport and biochemical pathways of phytanic acid metabolism have recently been defined with the cloning of two key enzymes, Phytanoyl-CoA 2-hydroxylase (PAHX) and 2-hydroxyPhytanoyl-CoA lyase, together with the confirmation of their localization in peroxisomes. PAHX, an iron(II) and 2-oxoglutarate-dependent oxygenase is located on chromosome 10p13. Mutant forms of PAHX have been shown to be responsible for some, but not all, cases of Refsum's disease. Certain cases have been shown to be atypical mild variants of rhizomelic chondrodysplasia punctata type 1a. Other atypical cases with low-plasma phytanic acid may be caused by α-methylacyl-CoA racemase deficiency. A sterol-carrier protein-2 (SCP-2) knockout mouse model shares a similar clinical phenotype to Refsum's disease, but no mutations in SCP-2 have been described to-date in man. This review describes the clinical, biochemical and metabolic features of Refsum's disease and shows how the biochemistry of the α-oxidation pathway may be linked to the regulation of metabolic pathways controlled by isoprenoid lipids, involving calcineurin or the peroxisomal proliferator activating α-receptor.
Anthony S Wierzbicki - One of the best experts on this subject based on the ideXlab platform.
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Disorders of peroxisomal metabolism in adults
Oxford Textbook of Medicine, 2020Co-Authors: Anthony S WierzbickiAbstract:The peroxisome is a specialized organelle which employs molecular oxygen in the oxidation of complex organic molecules including lipids. Enzymatic pathways for the metabolism of fatty acids, including very long-chain fatty acids (VLCFAs), enable this organelle to carry out β-oxidation in partnership with mitochondria. A peroxisomal pathway for isoprenoid lipids derived from chlorophyll, such as phytanic acid, utilizes α-oxidation, but a default mechanism involving ω-oxidation may also metabolize phytanic acid and its derivatives. The biochemical manifestations, molecular pathology, and diverse clinical features of many peroxisomal disorders have now been clarified, offering the promise of prompt diagnosis, better management, and useful means to provide appropriate genetic counselling for affected families. At the same time, specific treatments including rigorous dietary interventions and plasmapheresis to remove undegraded toxic metabolites offer credible hope of improvement and prevention of disease in affected individuals. X-linked adrenoleukodystrophy (X-ALD)—due to mutations in the gene for an ATP-binding cassette (ABC) protein of unknown function and characterized by accumulation of unbranched saturated VLCFAs, particularly hexacosanoate (C26), in the cholesterol esters of brain white matter, adrenal cortex, and certain sphingolipids of the brain. The disease has multiple phenotypes. Most cases develop increasing handicap; management is palliative and supportive in most instances. Adult Refsum’s disease—due in most cases to mutations in the gene for Phytanoyl-CoA hydroxylase (PHYH) such that patients are unable to detoxify phytanic acid by α-oxidation and have greatly elevated levels of this in their plasma. Usually presents in late childhood with progressive deterioration of night vision, the occurrence of progressive retinitis pigmentosa, and anosmia. Treatment is by restriction of dietary phytanic acid, with or without its elimination by plasmapheresis or apheresis.
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The Challenges of a Successful Pregnancy in a Patient with Adult Refsum's Disease due to Phytanoyl-CoA Hydroxylase Deficiency.
JIMD reports, 2016Co-Authors: Karolina M. Stepien, Hans R Waterham, Anthony S Wierzbicki, Bwee Tien Poll-the, Christian J. HendrikszAbstract:We describe the management and outcomes of pregnancy in a 27-year-old woman with infantile-onset Adult Refsum’s disease (ARD). She presented in infancy but was diagnosed with ARD at the age of 10 on basis of phytanic acidaemia and later confirmed to have the Phytanoyl-CoA hydroxylase ((PHYH) c.164delT, p.L55fsX12) mutation. Despite repeated plasmapheresis sessions and strict dietary surveillance for 20 years, her phytanic acid levels persistently stayed above the ideal target level of 100 μmol/L but remained below 400 μmol/L. Initially the pregnancy was uncomplicated but in the third trimester of pregnancy the patient was admitted to the hospital with fluctuating hypertension, sinus tachycardia and breathlessness. The patient was compliant with diet during pregnancy and her phytanic levels were remained well controlled: 177 and 188 μmol/L in the first and second trimester, respectively. Peri-partum management required a coordinated team approach including a high-calorie and restricted diet to reduce the risk of acute metabolic decompensation. During the induced labour she required 10% dextrose infusions.
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Peroxisomal disorders affecting phytanic acid α-oxidation: a review
Biochemical Society Transactions, 2007Co-Authors: Anthony S WierzbickiAbstract:Peroxisomes are involved in the synthesis and degradation of complex fatty acids. They contain enzymes involved in the α-, β- and ω-oxidation pathways for fatty acids. Investigation of these pathways and the diseases associated with mutations in enzymes involved in the degradation of phytanic acid have led to the clarification of the pathophysiology of Refsum9s disease, rhizomelic chondrodysplasia and AMACR (α-methylacyl-CoA racemase) deficiency. This has highlighted the role of an Fe(II)- and 2-oxoglutarate-dependent oxygenases [PhyH (Phytanoyl-CoA 2-hydroxylase), also known as PAHX], thiamin-dependent lyases (Phytanoyl-CoA lyase) and CYP (cytochrome P450) family 4A in fatty acid metabolism. The differential regulation and biology of these pathways is suggesting novel ways to treat the neuro-ophthalmological sequelae of Refsum9s disease. More recently, the discovery that AMACR and other peroxisomal β-oxidation pathway enzymes are highly expressed in prostate and renal cell cancers has prompted active investigation into the role of these oxidation pathways and the peroxisome in the progression of obesity- and insulin resistance-related cancers.
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Identification of PEX7 as the Second Gene Involved in Refsum Disease
American journal of human genetics, 2003Co-Authors: Daan M. Van Den Brink, G A Jansen, Hans R Waterham, Anthony S Wierzbicki, John Mitchell, Jacqueline De Belleroche, Pedro Brites, Janet Haasjes, Michelle Lambert-hamill, Ronald J.a. WandersAbstract:Patients affected with Refsum disease (RD) have elevated levels of phytanic acid due to a deficiency of the peroxisomal enzyme Phytanoyl-CoA hydroxylase (PhyH). In most patients with RD, disease-causing mutations in the PHYH gene have been identified, but, in a subset, no mutations could be found, indicating that the condition is genetically heterogeneous. Linkage analysis of a few patients diagnosed with RD, but without mutations in PHYH, suggested a second locus on chromosome 6q22-24. This region includes the PEX7 gene, which codes for the peroxin 7 receptor protein required for peroxisomal import of proteins containing a peroxisomal targeting signal type 2. Mutations in PEX7 normally cause rhizomelic chondrodysplasia punctata type 1, a severe peroxisomal disorder. Biochemical analyses of the patients with RD revealed defects not only in phytanic acid α-oxidation but also in plasmalogen synthesis and peroxisomal thiolase. Furthermore, we identified mutations in the PEX7 gene. Our data show that mutations in the PEX7 gene may result in a broad clinical spectrum ranging from severe rhizomelic chondrodysplasia punctata to relatively mild RD and that clinical diagnosis of conditions involving retinitis pigmentosa, ataxia, and polyneuropathy may require a full screen of peroxisomal functions.
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Role of Phytanoyl-CoA 2-hydroxylase in phytanic acid metabolism
Advances in experimental medicine and biology, 2003Co-Authors: Matthew D Lloyd, Anthony S Wierzbicki, Mridul Mukherji, Nadia J Kershaw, Winnie Chien, Christopher J SchofieldAbstract:Phytanic acid is a 3-methyl branched fatty acid that cannot be degraded by P-oxidation. Instead, one carbon atom is removed to give pristanic acid by a single round of peroxisomal a-oxidation. Phytanoyl-CoA 2- hydroxylase (PAHX), an iron(II) and 2-oxoglutarate oxygenase, catalyses the first step in this pathway. Defects in PAHX cause some forms of adult Refsum’s disease, in which phytanic acid accumulates (Wanders et al., 2001; Wierzbicki et al., 2002).
Inderjit Singh - One of the best experts on this subject based on the ideXlab platform.
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Restoration of phytanic acid oxidation in Refsum disease fibroblasts from patients with mutations in the phytanoyl‐CoA hydroxylase gene
FEBS letters, 1998Co-Authors: Amarjit Chahal, Ernest Barbosa, Mushfiquddin Khan, Shashidhar Pai, Inderjit SinghAbstract:Abstract Refsum disease (RD) is biochemically characterized by the excessive accumulation of phytanic acid in tissues and body fluids due to deficiency of Phytanoyl-CoA hydroxylase (PAHX). In this study, we screened three RD patients and identified a novel deletion (88 amino acids), and a missense mutation (Arg275Trp) in the previously reported PAHX cDNA (Jansen et al., 1997; Mihalik et al., 1997). Moreover, transfection of skin fibroblasts from two RD patients with wild-type PAHX gene restored the activity for α-oxidation of phytanic acid. Southern analysis on a somatic cell hybrid panel detected the PAHX gene on chromosome 10, corroborating radiation hybrid and homozygosity mapping data (Mihalik et al., 1997; Nadal et al., 1995).
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Phytanic acid oxidation: normal activation and transport yet defective alpha-hydroxylation of phytanic acid in peroxisomes from Refsum disease and rhizomelic chondrodysplasia punctata.
Journal of lipid research, 1996Co-Authors: Kalipada Pahan, Mushfiquddin Khan, Inderjit SinghAbstract:In humans the oxidation of phytanic acid is a per- oxisomal function. To understand the possible mechanisms for the pathognomic accumulation of phytanic acid in plasma and body fluids of Refsum disease (RD) and rhizomelic chon- drodysplasia punctata (RCDP), we investigated activities of various steps (activation, transport, and oxidation) in the metabolism of phytanic acid in peroxisomes isolated from cultured skin fibroblasts from control, RD, and RCDP sub- jects. Activation of phytanic acid was normal in peroxisomes from both RD and RCDP. Transport of phytanic acid or Phytanoyl-CoA in the absence or presence of fatty acid acti- vating cofactors (ATP, MgC12, and CoASH) into peroxisomes isolated from RD and RCDP skin fibroblasts was also similar to that of peroxisomes from control fibroblasts. Defective oxidation of ((2,3)JH)- or (1-14C)phytanic acid, or (l- WlPhytanoyl-CoA (substrate for the first step of a-oxidation) but normal oxidation of ( l-14C)a-hydroxyphytanic acid (sub- strate for the second step of the a-oxidation pathway) in peroxisomes from RD clearly demonstrates that excessive accumulation of phytanic acid in plasma and body fluids of RD is due to the deficiency of phytanic acid a-hydroxylase in peroxisomes. However, in RCDP peroxisomes, in addition to deficient oxidation of ( 1-14Clphytanic acid or Phytanoyl-CoA or ((2,3)sH)phytanic acid, the oxidation of ( l-W)a-hy- droxyphytanic acid was also deficient, indicating that in RCDP the activities both of a-hydroxylation of phytanic acid and decarboxylation of a-hydroxyphytanic acid are deficient. I These observations indicate that peroxisomal membrane functions (phytanic acid activation and transport) in phytanic acid metabolism are normal in both RD and RCDP. The defect in RD is in the a-hydroxylation of phytanic acid; whereas in RCDP both a-hydroxylation of phytanic acid as well as decarboxylation of a-hydroxyphytanic acid are defi- cient.-Pahan, K., M. Khan, and I. Singh. Phytanic acid oxi- dation: normal activation and transport yet defective a-hy- droxylation of phytanic acid in peroxisomes from Refsum disease and rhizomelic chondrodysplasia punctata. J. Lipid Res. 1996.37: 1137-1143.
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Ketoconazole and other imidazole derivatives are potent inhibitors of peroxisomal phytanic acid α-oxidation
FEBS letters, 1995Co-Authors: Kalipada Pahan, Mushfiquddin Khan, Brian T. Smith, Inderjit SinghAbstract:The imidazole antimycotics like ketoconazole, clotrimazole, bifonazole, miconazole and CO, known as powerful inhibitors of cytochrome P-450, are potent inhibitors of peroxisomal phytanic acid α-oxidation to pristanic acid suggesting the possible involvement of the cytochrome P-450 mono-oxygenase system in this oxidation. In contrast to the inhibition of the oxidation of [1-14C]phytanic acid, [1-14C]Phytanoyl-CoA and [(2,3)-3H]phytanic acid, these drugs and CO have no effect on the oxidation of [1-14C]α-hydroxy phytanic acid indicating that these drugs and CO inhibit only the α-hydroxylation of phytanic acid. These studies using purified peroxisomes from liver and cultured human skin fibroblasts and Hep G2 cells clearly demonstrate that α-hydroxylation, an intermediate step in the α-oxidation of phytanic acid found to be impaired in Refsum Disease, is mediated by cytochrome P-450 containing enzyme.
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Phytanic acid oxidation: topographical localization of Phytanoyl-CoA ligase and transport of phytanic acid into human peroxisomes
Journal of lipid research, 1995Co-Authors: Kalipada Pahan, Inderjit SinghAbstract:To understand the possible role of Phytanoyl-CoA li- gase, present in the membrane, in the oxidation of phytanic acid in the matrix of peroxisomes (Pahan, K. and I. Singh. 1993. FEES Lett. 333: 154-158) we examined the transport of phytanic acid/Phytanoyl-CoA into peroxisomes and the topology of the active site of Phytanoyl-CoA ligase in the peroxisomal mem- brane. The increase in lignoceroyl-CoA ligase as compared to no change in the activities of palmitoyl-CoA and Phytanoyl-CoA li- gases when peroxisomes were disrupted with detergent or soni- cation and inhibition of the activities of both palmitoyl-CoA and Phytanoyl-CoA ligase by impermeable inhibitor of acyl-CoA li- gases (mercury-dextran) and trypsin treatment in the intact peroxisomes. On the other hand, the lignoceroyl-CoA ligase ac- tivity was inhibited by mercury-dextran and trypsin only in the disrupted peroxisomes. Taken together, these studies support the conclusion that the enzymatic site of Phytanoyl-CoA ligase is on the cytoplasmic surface of peroxisomal membrane. This implies that Phytanoyl-CoA is synthesized on the cytoplasmic surface of peroxisomal membrane and is translocated through the mem- brane for its a-oxidation to pristanic acid in the matrix of perox- isomes. llilll To delineate the transport for phytanic acid through the peroxisomal membrane, we examined cofactors and energy requirements for its transport into peroxisomes. The similar rates of transport of Phytanoyl-CoA and phytanic acid under conditions favorable for fatty acid activation (presence of ATP, CoASH, and MgC12) and the lack of transport of phytanic acid when ATP and/or CoASH were removed or replaced with their inactive analogues (ATP and/or CoASH) from assay medium clearly demonstrates that the transport of phytanic acid requires prior synthesis of Phytanoyl-CoA by Phytanoyl-CoA ligase. The prerequisite activation of phytanic acid to Phytanoyl-CoA for its a-oxidation only in intact peroxisomes, and oxidation of free phytanic acid in digitonin-permealized peroxisomes or isolated matrix, suggests that Phytanoyl-CoA ligase (in peroxisomal membrane) regulates the oxidation of phytanic acid in peroxi- somes by providing Phytanoyl-CoA for its transport into peroxi- somes.-Pahan, K., and I. Singh. Phytanic acid oxidation: topographical localization of Phytanoyl-CoA ligase and trans- port of phytanic acid into human peroxisomes. J Lipid Res. 1995. 36: 986-997. Phytanic acid (3,7,11,15-tetramethylhexadecanoic acid), a highly branched isoprenoid-derived fatty acid, accumu- lates in excessive amounts in the tissues and body fluids of patients with classical Refsum disease (1) and in pa- tients with defects in the biogenesis of peroxisomes (2, 3). Phytanic acid is not synthesized de novo in humans but is taken exogenously. The ordinary human diet contains 50-100 mg of phytanic acid per day mainly as a consti- tuent of animal, dairy, and plant products. Due to the p- methyl group, phytanic acid cannot be @-oxidized; there- fore, a-oxidation is the only feasible route for its catabolism (1-4). Studies from our laboratory have demonstrated that in humans phytanic acid is a-oxidized to pristanic acid in peroxisomes, but in rodents this process occurs in mitochondria (5, 6). In human skin fibroblasts the rate of phytanic acid oxidation in peroxi- somes was 26 and 130 times greater than that found in mitochondria and microsomes. Moreover, the excessive accumulation of phytanic acid and defective a-oxidation of phytanic acid in peroxisomes, but not mitochondria or microsomes, from cultured skin fibroblasts of patients with Refsum disease (7) and rhizomelic chondrodysplasia punctata (RCDP) (6) also support the conclusion that in humans the major site of a-oxidation of phytanic acid to pristanic acid is the peroxisome. The oxidation of phytanic acid to pristanic acid involves at least four steps: activation of phytanic acid to Phytanoyl-CoA, a-hydroxylation to a-hydroxyphytanic acid, conversion to 2-ketophytanic acid, and finally decar- boxylation to a 19-carbon homologue, pristanic acid. The enzyme for activation of phytanic acid (Phytanoyl-CoA li-
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Phytanic acid α-oxidation in rat liver mitochondria
Biochimica et biophysica acta, 1994Co-Authors: Kalipada Pahan, Sukhvarsha Gulati, Inderjit SinghAbstract:The alpha-oxidation of phytanic acid in rat liver is a mitochondrial function. The inhibition of phytanic acid oxidation activity by inhibitors of acyl-CoA ligases (Naproxen and Triacsin C) and that of carnitine acyltransferase I (2-(5-(4-chlorophenyl)pentyl)oxirane-2 carboxylic acid (POCA) and 2-bromopalmitate) and increase in phytanic acid oxidation activity by the addition of exogenous carnitine and CoA to purified mitochondria suggests that Phytanoyl-CoA ligase and carnitine acyltransferase I are essential for the activation and transport of phytanic acid across the mitochondrial membrane. This was further supported by the fact that activation of phytanic acid to Phytanoyl-CoA was required only in intact mitochondria but not in mitochondria permealized with digitonin. DesulfoCoA, Naproxen and POCA treatment resulted in a significant decrease in phytanic acid oxidation in intact mitochondria but not in digitonin permealized mitochondria. These results show that alpha-oxidation of phytanic acid to pristanic acid, in contrast to beta-oxidation of fatty acids, requires free fatty acid as substrate. The inhibition of alpha-oxidation (approximately 90%) of phytanic acid by different cytochrome P-450 enzyme inhibitors indicated that alpha-oxidation of phytanic acid is mediated through cytochrome P-450 containing enzyme system. Similar to the omega-hydroxylation system in endoplasmic reticulum, alpha-hydroxylation and the subsequent alpha-oxidation of phytanic acid in mitochondria is induced by ciprofibrate, a hypolipidemic drug.