Abstract
In humans the oxidation of phytanic acid is a peroxisomal function. To understand the possible mechanisms for the pathognomic accumulation of phytanic acid in plasma and body fluids of Refsum disease (RD) and rhizomelic chondrodysplasia 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 subjects. 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 activating cofactors (ATP, MgCl2, 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)-3H]- or [1-14C]phytanic acid, or [1-14C]phytanoyl-CoA (substrate for the first step of alpha-oxidation) but normal oxidation of [1-14C] alpha-hydroxyphytanic acid (substrate for the second step of the alpha-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 alpha-hydroxylase in peroxisomes. However, in RCDP peroxisomes, in addition to deficient oxidation of [1-14C]phytanic acid or phytanoyl-CoA or [(2,3)-3H]phytanic acid, the oxidation of [1-14C] alpha-hydroxyphytanic acid was also deficient, indicating that in RCDP the activities both of alpha-hydroxylation of phytanic acid and decarboxylation of alpha-hydroxyphytanic acid are deficient. 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 alpha-hydroxylation of phytanic acid; whereas in RCDP both alpha-hydroxylation of phytanic acid as well as decarboxylation of alpha-hydroxyphytanic acid are deficient.
Highlights
In humans the oxidation of phytanic acid is a peroxisomal function
The peroxisomes isolated from cultured skin fibroblasts from control, Refsum disease (RD), and rhizomelicchondrodysplasia punctata (RCDP) were of approximately 90% percent purity with only relatively minor contamination by mitochondria (5.5-6.2%) and microsomes (3.2-3.5%) as protein
The deficient oxidation of phytanic acid as compared to normal oxidation of a-hydroxyphytanic acid in cultured skin fibroblast monolayers of RD patients suggests a defect in the conversion of phytanic acid to a-hydroxyphytanicacid (1,8);the subcellular organelle responsible for this function was not identified
Summary
In humans the oxidation of phytanic acid is a peroxisomal function. To understand the possible mechanisms for the pathognomicaccumulationof phytanic acid in plasma and body fluidsof Refsum disease (RD) and rhizomelicchondrodysplasia 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 subjects. We have demonstrated that in humans, a-oxidation of phytanic acid to pristanic acid takes place in peroxisomes (3-7)but peroxisomes from RD and RCDP are deficient in this activity (4,5).Phytanoyl-CoA
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