Disease relevance of PHYTANIC ACID

• Decreased phytanic-acid oxidation is also observed in human cells lacking PEX7, the receptor for the type-2 peroxisomal targetting signal (PTS2; refs 3,4), suggesting that the enzyme defective in Refsum disease is targetted to peroxisomes by a PTS2 [1].
• The rhizomelic form of chondrodysplasia punctata (RCDP) is a peroxisomal disorder characterized biochemically by an impairment of plasmalogen biosynthesis and phytanate catabolism [2].
• We postulate that the abnormal fatty acids in peroxisomal disorders, particularly very long chain fatty acids and phytanic acid, are incorporated into cell membranes and perturb their microenvironments resulting in dysfunction, atrophy and death of vulnerable cells [3].
• 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 [4].
• We found that the serum concentrations of phytanic acid correlated well with the expression of genes encoding peroxisomal beta-oxidation enzymes and liver fatty acid-binding protein, which have all been demonstrated to contain functionally active peroxisome proliferator response elements in their promoter regions [5].

High impact information on PHYTANIC ACID

• Biochemically, the disease is caused by the deficiency of phytanoyl-CoA hydroxylase (PhyH), a peroxisomal protein catalyzing the first step in the alpha-oxidation of phytanic acid [6].
• The defect became evident from up to 10-fold accumulation of the tetramethyl-branched fatty acid phytanic acid in Scp2(-/-) mice [7].
• Phytanic acid oxidation was reduced in fibroblasts from some, but not all, of the patients [8].
• Metabolism of phytanic acid in Refsum's disease [9].
• Patients affected with Refsum disease (RD) have elevated levels of phytanic acid due to a deficiency of the peroxisomal enzyme phytanoyl-CoA hydroxylase (PhyH) [10].

Chemical compound and disease context of PHYTANIC ACID

• Phytol is a branched-chain fatty alcohol that is a naturally occurring precursor of phytanic acid, a fatty acid involved in the pathogenesis of Refsum disease [11].
• Measurement of phytanic acid and pristanic acid and their ratios in stored dried blood collected at neonatal screening can therefore be used in the diagnosis of peroxisomal disorders, especially for those cases in which, owing to early death of the patient, no other material is available for biochemical investigations [12].
• In addition to phytanic acid accumulation (232 mumol/L), the chondrodysplasia punctata patient showed an elevated 2-hydroxyphytanic acid plasma concentration (0.4 mumol/L), whereas the plasma pristanic acid level was in the control range (0.7 mumol/L).(ABSTRACT TRUNCATED AT 250 WORDS)[13]
• Brain pyruvate and 2-oxoglutarate dehydrogenase complexes are mitochondrial targets of the CoA ester of the Refsum disease marker phytanic acid [14].
• Our data indicate that the genetic defect in rhizomelic chondrodysplasia punctata results in abnormalities in two apparently unrelated pathways (i.e., phytanic acid oxidation and ether lipid biosynthesis [15].

Biological context of PHYTANIC ACID

• Peroxisomal functions, including the breakdown of very long-chain (>20 carbons) fatty acids, phytanic acid oxidation, and the acylation of DHAP, were normal [16].
• In accordance with these findings, a stimulating effect on acyl-CoA oxidase gene expression was also observed after incubation of the rat hepatoma cell line MH1C1 with phytanic acid [5].
• Second, L-FABP gene ablation inhibited phytanic acid peroxisomal oxidation and microsomal esterification [17].
• Initial uptake of phytanic acid uptake was unaltered apparently due to concomitant 5.3-, 1.6-, and 1.4-fold up-regulation of plasma membrane fatty acid transporter/translocase proteins (glutamic-oxaloacetic transaminase, fatty acid transport protein, and fatty acid translocase, respectively) [17].
• Rotenone-like action of the branched-chain phytanic acid induces oxidative stress in mitochondria [18].

Anatomical context of PHYTANIC ACID

• The dialysis of endoplasmic reticulum, mitochondrial, and peroxisomal fractions from human liver and cultured skin fibroblasts for 2 h against isotonic solution increased the specific activity of phytanic acid oxidation by 1.3-, 1.3-, and 5-21-fold, respectively, after removal of Nycodenz as compared with nondialyzed samples [19].
• The results reported indicate that phytanic acid, the fatty acid which can be initially degraded by alpha-oxidation due to the presence of a beta-methyl group in the molecule, cannot be transported across the mitochondrial membranes [20].
• We also observed that Nycodenz (commonly used gradient material for isolation of subcellular organelles) has a strong inhibitory effect on the alpha-oxidation of phytanic acid [19].
• Therefore, phytanic acid (most common dietary branched-chain fatty acid) was chosen to address these issues in cultured primary hepatocytes isolated from livers of L-FABP gene-ablated (-/-) and wild type (+/+) mice [17].
• To elucidate the pathogenic mechanism, we investigated the influence of phytanic acid on cellular physiology of rat hippocampal astrocytes [21].

Associations of PHYTANIC ACID with other chemical compounds

• Plasma levels of di- and trihydroxy-coprostanoic acid, phytanic acid, and pipecolic acid were normal; furthermore, acyl-CoA:dihydroxyacetone phosphate acyltransferase activity in cultured fibroblasts was also found to be normal [22].
• After dialysis, the rate of oxidation of phytanic acid in peroxisomes from human liver and cultured skin fibroblasts was 4-26 times higher than that in mitochondria and 43-130 times than that in the endoplasmic reticulum, suggesting that, in human tissues, phytanic acid is oxidized to pristanic acid in peroxisomes [19].
• Dietary phytol supplementation was used to modulate the concentration of phytanic acid in C57Bl/6 and Scp2 (-/-) mice [5].
• Furthermore, MFP-2-deficient mice accumulated VLCFA in brain and liver phospholipids, immature C(27) bile acids in bile, and, after supplementation with phytol, pristanic and phytanic acid in liver triacylglycerols [23].
• The presence of PICD in mammalian peroxisomes suggests roles in the regeneration of NADPH for intraperoxisomal reductions, such as the conversion of 2, 4-dienoyl-CoAs to 3-enoyl-CoAs, as well as in peroxisomal reactions that consume 2-oxoglutarate, namely the alpha-hydroxylation of phytanic acid [24].

Gene context of PHYTANIC ACID

• Biochemically Pex7(-/-) mice display the abnormalities related to a Pex7 deficiency, i.e. a severe depletion of plasmalogens, impaired alpha-oxidation of phytanic acid and impaired beta-oxidation of very-long-chain fatty acids [25].
• We conclude that phytanic acid can be considered as a bona fide physiological ligand of murine PPARalpha [5].
• In addition, diminished peroxisomal alpha-oxidation of phytanic acid (3,7,11, 15-tetramethylhexadecanoic acid) in these null mice was attributed to the absence of SCP2 which has a number of properties supporting a function as carrier for fatty acyl-CoAs rather than for sterols [26].
• Here we show first that phytanic acid binds to recombinant L-FABP with high affinity [27].
• 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 [28].

Analytical, diagnostic and therapeutic context of PHYTANIC ACID

• The impaired renal hemodynamic function and various tubular functions improved following plasmaphereses associated with reduction of plasma phytanic acid [29].
• The HPLC method also measures phytanate concentrations in plasma [30].
• Pristanic acid/phytanic acid ratios were markedly increased in bifunctional protein and/or 3-oxoacyl-CoA thiolase deficiency, indicating their role in the (differential) diagnosis of disorders of peroxisomal beta-oxidation [31].
• METHODS: One hundred and four prostate cancer patients and controls were recruited in North Carolina. Serum levels of phytanic acid were measured using a gas liquid chromatography/mass spectroscopy analysis, and a food frequency questionnaire was administered to each individual to assess dietary intake [32].
• Lowering the plasma phytanic acid by plasma exchange produced a rapid clinical improvement [33].

References