Refsum Disease
Phytanic Acid
Refsum Disease, Infantile
Peroxisomal Disorders
Phytol
Zellweger Syndrome
Microbodies
Coenzyme A
Mixed Function Oxygenases
Immunophilins, Refsum disease, and lupus nephritis: the peroxisomal enzyme phytanoyl-COA alpha-hydroxylase is a new FKBP-associated protein. (1/54)
FKBP52 (FKBP59, FKBP4) is a "macro" immunophilin that, although sharing high structural and functional homologies in its amino-terminal domain with FKBP12 (FKBP1), does not have immunosuppressant activity when complexed with FK506, unlike FKBP12. To investigate the physiological function of FKBP52, we used the yeast two-hybrid system as an approach to find its potential protein partners and, from that, its cellular role. This methodology, which already has allowed us to find the FK506-binding protein (FKBP)-associated protein FAP48, also led to the detection of another FKBP-associated protein. Determination of the sequence of this protein permitted its identification as phytanoyl-CoA alpha-hydroxylase (PAHX), a peroxisomal enzyme that so far was unknown as an FKBP-associated protein. Inactivation of this enzyme is responsible for Refsum disease in humans. The protein also corresponds to the mouse protein LN1, which could be involved in the progress of lupus nephritis. We show here that PAHX has the physical capacity to interact with the FKBP12-like domain of FKBP52, but not with FKBP12, suggesting that it is a particular and specific target of FKBP52. Whereas the binding of calcineurin to FKBP12 is potentiated by FK506, the specific association of PAHX and FKBP52 is maintained in the presence of FK506. This observation suggests that PAHX is a serious candidate for studying the cellular signaling pathway(s) involving FKBP52 in the presence of immunosuppressant drugs. (+info)Refsum disease diagnostic marker phytanic acid alters the physical state of membrane proteins of liver mitochondria. (2/54)
Phytanic acid (3,7,11,15-tetramethylhexadecanoic acid), a branched chain fatty acid accumulating in Refsum disease to high levels throughout the body, induces uncoupling of rat liver mitochondria similar to non-branched fatty acids (e.g. palmitic acid), but the contribution of the ADP/ATP carrier or the aspartate/glutamate carrier in phytanic acid-induced uncoupling is of minor importance. Possible deleterious effects of phytanic acid on membrane-linked energy coupling processes were studied by ESR spectroscopy using rat liver mitochondria and a membrane preparation labeled with the lipid-specific spin probe 5-doxylstearic acid (5-DSA) or the protein-specific spin probe MAL-TEMPO (4-maleimido-2,2,6, 6-tetramethyl-piperidine-1-oxyl). The effects of phytanic acid on phospholipid molecular dynamics and on the physical state of membrane proteins were quantified by estimation of the order parameter or the ratio of the amplitudes of the weakly to strongly immobilized MAL-TEMPO binding sites (W/S ratio), respectively. It was found, that phytanic acid (1) increased the mobility of phospholipid molecules (indicated by a decrease in the order parameter) and (2) altered the conformational state and/or the segmental mobility of membrane proteins (indicated by a drastic decrease in the W/S ratio). Unsaturated fatty acids with multiple cis-double bonds (e.g. linolenic or arachidonic acid), but not non-branched FFA (ranging from chain length C10:0 to C18:0), also decrease the W/S ratio. It is hypothesized that the interaction of phytanic acid with transmembrane proteins might stimulate the proton permeability through the mitochondrial inner membrane according to a mechanism, different to a protein-supported fatty acid cycling. (+info)Human phytanoyl-CoA hydroxylase: resolution of the gene structure and the molecular basis of Refsum's disease. (3/54)
Refsum's disease (RD) is an inherited neurological syndrome biochemically characterized by the accumulation of phytanic acid in plasma and tissues. 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. To enable mutation analysis of RD at the genome level, we have elucidated the genomic organization of the PHYH gene. The gene is approximately 21 kb and contains nine exons and eight introns. Mutation analysis of PHYH cDNA from 22 patients with RD revealed 14 different missense mutations, a 3 bp insertion, and a 1 bp deletion, which were all confirmed at the genome level. A 111 bp deletion identified in the PHYH cDNA of several patients with RD was due to either one of two different mutations in the same splice acceptor site, which result in skipping of exon 3. 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. The results showed that all these mutations lead to an enzymatically inactive PhyH protein. (+info)Identification of genetic heterogeneity in Refsum's disease. (4/54)
Refsum's disease (MIM 266500) is a recessive disorder characterised by defective peroxisomal alpha-oxidation of phytanic acid. A Refsum's disease gene, phytanoyl-CoA hydroxylase (PAHX), has been localised to chromosome 10p13 between the markers D10S226-D10S223. This study investigated whether all cases of Refsum's disease were linked with chromosome 10p13. Eight genetically informative families comprising 92 individuals including 17 living patients with a Refsum's disease phenotype and initial plasma phytanic acid > 200 micromol/L were recruited. Linkage to the 10pter-10p11.2 region was investigated using a panel of eight dinucleotide repeat markers. Linkage analysis of this phenotypically identical cohort suggested that Refsum's disease was genetically heterogeneous (Zmax = 5.28, alpha = 0.45). Two subgroups were identified. One group of four families with eight affected individuals had a maximum multipoint lod score for linkage of 3.89 in the region D10S547 to D10S191, whilst in another three families with nine affected individuals linkage to this region was definitely excluded. Our results show that Refsum's disease is genetically heterogeneous, with up to 55% of cases not being linked to the PAHX gene locus at D10S547 to D10S223. This suggests that Refsum's disease, in common with other peroxisomal 'diseases', may be more accurately described as a heterogeneous syndrome. (+info)Enhanced expression of a-series gangliosides in fibroblasts of patients with peroxisome biogenesis disorders. (5/54)
Peroxisome biogenesis disorders (PBD) are classified into Zellweger syndrome (ZS), infantile Refsum disease (IRD) and neonatal adrenoleukodystrophy. Disturbances in the differentiation of neural cells such as migration arrest are characteristic of PBD. So far the pathogenesis of these disturbances is not clearly understood. We describe an altered metabolism of glycosphingolipids in PBD which has not yet been investigated. We observed an increased amount of a-series gangliosides, GM2, GM1 and GD1a, in the fibroblasts of patients with ZS and IRD. Gangliosides GM1 and GD1a were not present in detectable amounts in normal subjects. A key step in the synthesis of a-series gangliosides is a transfer of GalNAc to ganglioside GM3, so we determined the level of ganglioside GM3 by immunohistochemical methods. We found a granular structure, which was positive toward anti-ganglioside GM3 antibody in the cytoplasm of the patients' fibroblasts. In control cells, the cell membrane was slightly positive toward anti-GM3 antibody. These results may help to clarify the pathogenesis of PBD with respect to the functional roles of glycosphingolipids in cell differentiation, proliferation and apoptosis. (+info)Structure-function analysis of phytanoyl-CoA 2-hydroxylase mutations causing Refsum's disease. (6/54)
Refsum's disease is a neurological syndrome characterized by adult-onset retinitis pigmentosa, anosmia, sensory neuropathy and phytanic acidaemia. Many cases are caused by mutations in peroxisomal oxygenase phytanoyl-CoA 2-hydroxylase (PAHX) which catalyses the initial alpha-oxidation step in the degradation of phytanic acid. 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. 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. The H175A and D177A mutants did not catalyse hydroxylation of phytanoyl-CoA, consistent with their assigned role as iron(II) binding ligands. The clinically observed P29S, Q176K, G204S, N269H, R275Q and R275W mutants were assayed for both 2-oxoglutarate and phytanoyl-CoA oxidation. The P29S mutant was fully active, implying that the mutation resulted in defective targeting of the protein to peroxisomes. Mutation of Arg-275 resulted in impaired 2-oxoglutarate binding. The Q176K, G204S and N269H mutations caused partial uncoupling of 2-oxoglutarate conversion from phytanoyl-CoA oxidation. The results demonstrate that the diagnosis of Refsum's disease should not solely rely upon PAHX assays for 2-oxoglutarate or phytanoyl-CoA oxidation. (+info)Effects of phytanic acid on the vitamin E status, lipid composition and physical properties of retinal cell membranes: implications for adult Refsum disease. (7/54)
Adult Refsum disease is an inherited disorder in which phytanic acid accumulates in tissues and serum. Two hypotheses have been proposed to explain the pathogenesis of this condition. The molecular distortion hypothesis suggests that phytanic acid may alter membrane composition and structure, thereby affecting membrane function(s). The anti-metabolite hypothesis suggests that an accumulation of phytanic acid in membranes may interfere with vitamin E function. These two hypotheses were investigated by studying the effects of modulating phytanic acid and alpha-tocopherol concentrations on the fatty acid composition and certain physical parameters of cultured retinal cells. Results showed that (a) the phospholipid fraction of retinal cells readily incorporated phytanic acid, (b) the incorporation of phytanic acid increased membrane fluidity, (c) there was no competition for uptake between phytanic acid and alpha-tocopherol, and (d) the incorporation of phytanic acid did not increase the susceptibility of membranes to lipid peroxidation in vitro. These results obtained with cultured retinal cells suggest that the molecular distortion hypothesis, but not the anti-metabolite hypothesis, could explain the pathogenesis of adult Refsum disease. In vitro tissue culture models can, however, only approximate to the much more complex situation that occurs in vivo. (+info)Stereochemistry of the peroxisomal branched-chain fatty acid alpha- and beta-oxidation systems in patients suffering from different peroxisomal disorders. (8/54)
Phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) is a branched-chain fatty acid derived from dietary sources and broken down in the peroxisome to pristanic acid (2,6,10,14-tetramethylpentadecanoic acid) via alpha-oxidation. Pristanic acid then undergoes beta-oxidation in peroxisomes. Phytanic acid naturally occurs as a mixture of (3S,7R,11R)- and (3R,7R,11R)-diastereomers. In contrast to the alpha-oxidation system, peroxisomal beta-oxidation is stereospecific and only accepts (2S)-isomers. Therefore, a racemase called alpha-methylacyl-CoA racemase is required to convert (2R)-pristanic acid into its (2S)-isomer. To further investigate the stereochemistry of the peroxisomal oxidation systems and their substrates, we have developed a method using gas-liquid chromatography-mass spectrometry to analyze the isomers of phytanic, pristanic, and trimethylundecanoic acid in plasma from patients with various peroxisomal fatty acid oxidation defects. In this study, we show that in plasma of patients with a peroxisomal beta-oxidation deficiency, the relative amounts of the two diastereomers of pristanic acid are almost equal, whereas in patients with a defect of alpha-methylacyl-CoA racemase, (2R)-pristanic acid is the predominant isomer. Furthermore, we show that in alpha-methylacyl-CoA racemase deficiency, not only pristanic acid accumulates, but also one of the metabolites of pristanic acid, 2610-trimethylundecanoic acid, providing direct in vivo evidence for the requirement of this racemase for the complete degradation of pristanic acid. (+info)Refsum Disease is a rare inherited neurological disorder characterized by the accumulation of phytanic acid in various tissues of the body due to impaired breakdown of this fatty acid. This is caused by a deficiency in the enzyme phytanoyl-CoA hydroxylase or the transporter protein peroxisomal biogenesis factor 7 (PEX7).
The symptoms of Refsum Disease can vary but often include progressive neurological dysfunction, retinitis pigmentosa leading to decreased vision and night blindness, hearing loss, ichthyosis (dry, scaly skin), and cardiac abnormalities. The onset of symptoms is usually in childhood or adolescence, but milder cases may not become apparent until later in life.
The treatment for Refsum Disease involves a strict diet that limits the intake of phytanic acid, which is found in dairy products, beef, and certain fish. Plasmapheresis, a procedure to remove harmful substances from the blood, may also be used to reduce the levels of phytanic acid in the body. Early diagnosis and treatment can help slow down or prevent the progression of the disease.
Phytanic acid is a branched-chain fatty acid that is primarily found in animal products, such as dairy foods and meat, but can also be present in some plants. It is a secondary plant metabolite that originates from the breakdown of phytol, a component of chlorophyll.
Phytanic acid is unique because it contains a methyl group branching off from the middle of the carbon chain, making it difficult for the body to break down and metabolize. Instead, it must be degraded through a process called α-oxidation, which takes place in peroxisomes.
In some cases, impaired phytanic acid metabolism can lead to a rare genetic disorder known as Refsum disease, which is characterized by the accumulation of phytanic acid in various tissues and organs, leading to neurological symptoms, retinal degeneration, and cardiac dysfunction.
Infantile Refsum Disease (IRD) is a rare inherited neurological disorder that is part of the group of peroxisomal biogenesis disorders. It is caused by mutations in the PHYH gene, which provides instructions for making an enzyme called phytanoyl-CoA hydroxylase. This enzyme plays a critical role in breaking down a type of fat called phytanic acid, which is found in certain foods such as dairy products, ruminant meat (beef, lamb), and some nuts and vegetables.
In IRD, the lack of functional phytanoyl-CoA hydroxylase enzyme leads to an accumulation of phytanic acid in various tissues of the body, including the nervous system. This accumulation can cause progressive neurological symptoms such as difficulty with coordination and movement, muscle weakness, hearing loss, vision problems, and intellectual disability.
IRD typically presents in infancy or early childhood with symptoms such as feeding difficulties, failure to thrive, hypotonia (low muscle tone), seizures, and developmental delays. Over time, the neurological symptoms can worsen, leading to significant disability and reduced life expectancy. Treatment for IRD involves a strict diet that limits the intake of phytanic acid, as well as plasma exchange therapy to remove excess phytanic acid from the bloodstream.
Peroxisomal disorders are a group of inherited metabolic diseases caused by defects in the function or structure of peroxisomes, which are specialized subcellular organelles found in the cells of animals, plants, and humans. These disorders can affect various aspects of metabolism, including fatty acid oxidation, bile acid synthesis, and plasma cholesterol levels.
Peroxisomal disorders can be classified into two main categories: single peroxisomal enzyme deficiencies and peroxisome biogenesis disorders (PBDs). Single peroxisomal enzyme deficiencies are characterized by a defect in a specific enzyme found within the peroxisome, while PBDs are caused by problems with the formation or assembly of the peroxisome itself.
Examples of single peroxisomal enzyme deficiencies include X-linked adrenoleukodystrophy (X-ALD), Refsum disease, and acyl-CoA oxidase deficiency. PBDs include Zellweger spectrum disorders, such as Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease.
Symptoms of peroxisomal disorders can vary widely depending on the specific disorder and the severity of the enzyme or biogenesis defect. They may include neurological problems, vision and hearing loss, developmental delays, liver dysfunction, and skeletal abnormalities. Treatment typically focuses on managing symptoms and addressing any underlying metabolic imbalances.
Phytol is not a medical term, but rather a chemical compound. It is a diterpene alcohol that is a breakdown product of chlorophyll and is found in green plants. It is used in the synthesis of various compounds, including vitamins E and K, and is also used in the production of perfumes and fragrances. In the context of human health, phytol has been studied for its potential anti-cancer properties.
Zellweger Syndrome is a rare genetic disorder that affects the development and function of multiple organ systems in the body. It is part of a group of conditions known as peroxisome biogenesis disorders (PBDs), which are characterized by abnormalities in the structure and function of peroxisomes, which are cellular structures that break down fatty acids and other substances in the body.
Zellweger Syndrome is caused by mutations in one or more genes involved in the formation and maintenance of peroxisomes. As a result, people with this condition have reduced levels of certain enzymes that are necessary for normal brain development, as well as for the breakdown of fats and other substances in the body.
Symptoms of Zellweger Syndrome typically appear within the first few months of life and may include:
* Severe developmental delays and intellectual disability
* Hypotonia (low muscle tone) and poor motor skills
* Vision and hearing problems
* Facial abnormalities, such as a high forehead, wide-set eyes, and a prominent nasal bridge
* Liver dysfunction and jaundice
* Seizures
* Feeding difficulties and failure to thrive
There is no cure for Zellweger Syndrome, and treatment is focused on managing the symptoms of the condition. The prognosis for people with this disorder is generally poor, with most individuals not surviving beyond the first year of life. However, some individuals with milder forms of the condition may live into early childhood or adolescence.
Microbodies are small, membrane-bound organelles found in the cells of eukaryotic organisms. They typically measure between 0.2 to 0.5 micrometers in diameter and play a crucial role in various metabolic processes, particularly in the detoxification of harmful substances and the synthesis of lipids.
There are several types of microbodies, including:
1. Peroxisomes: These are the most common type of microbody. They contain enzymes that help break down fatty acids and amino acids, producing hydrogen peroxide as a byproduct. Another set of enzymes within peroxisomes then converts the harmful hydrogen peroxide into water and oxygen, thus detoxifying the cell.
2. Glyoxysomes: These microbodies are primarily found in plants and some fungi. They contain enzymes involved in the glyoxylate cycle, a metabolic pathway that helps convert stored fats into carbohydrates during germination.
3. Microbody-like particles (MLPs): These are smaller organelles found in certain protists and algae. Their functions are not well understood but are believed to be involved in lipid metabolism.
It is important to note that microbodies do not have a uniform structure or function across all eukaryotic cells, and their specific roles can vary depending on the organism and cell type.
Coenzyme A, often abbreviated as CoA or sometimes holo-CoA, is a coenzyme that plays a crucial role in several important chemical reactions in the body, particularly in the metabolism of carbohydrates, fatty acids, and amino acids. It is composed of a pantothenic acid (vitamin B5) derivative called pantothenate, an adenosine diphosphate (ADP) molecule, and a terminal phosphate group.
Coenzyme A functions as a carrier molecule for acetyl groups, which are formed during the breakdown of carbohydrates, fatty acids, and some amino acids. The acetyl group is attached to the sulfur atom in CoA, forming acetyl-CoA, which can then be used as a building block for various biochemical pathways, such as the citric acid cycle (Krebs cycle) and fatty acid synthesis.
In summary, Coenzyme A is a vital coenzyme that helps facilitate essential metabolic processes by carrying and transferring acetyl groups in the body.
Mixed Function Oxygenases (MFOs) are a type of enzyme that catalyze the addition of one atom each from molecular oxygen (O2) to a substrate, while reducing the other oxygen atom to water. These enzymes play a crucial role in the metabolism of various endogenous and exogenous compounds, including drugs, carcinogens, and environmental pollutants.
MFOs are primarily located in the endoplasmic reticulum of cells and consist of two subunits: a flavoprotein component that contains FAD or FMN as a cofactor, and an iron-containing heme protein. The most well-known example of MFO is cytochrome P450, which is involved in the oxidation of xenobiotics and endogenous compounds such as steroids, fatty acids, and vitamins.
MFOs can catalyze a variety of reactions, including hydroxylation, epoxidation, dealkylation, and deamination, among others. These reactions often lead to the activation or detoxification of xenobiotics, making MFOs an important component of the body's defense system against foreign substances. However, in some cases, these reactions can also produce reactive intermediates that may cause toxicity or contribute to the development of diseases such as cancer.
Peroxisomes are membrane-bound subcellular organelles found in the cytoplasm of eukaryotic cells. They play a crucial role in various cellular processes, including the breakdown of fatty acids and the detoxification of harmful substances such as hydrogen peroxide (H2O2). Peroxisomes contain numerous enzymes, including catalase, which converts H2O2 into water and oxygen, thus preventing oxidative damage to cellular components. They also participate in the biosynthesis of ether phospholipids, a type of lipid essential for the structure and function of cell membranes. Additionally, peroxisomes are involved in the metabolism of reactive oxygen species (ROS) and contribute to the regulation of intracellular redox homeostasis. Dysfunction or impairment of peroxisome function has been linked to several diseases, including neurological disorders, developmental abnormalities, and metabolic conditions.