Pahan K, Khan M, Singh I
Department of Pediatrics, Medical University of South Carolina, Charleston 29425, USA.
J Lipid Res. 1996 May;37(5):1137-43.
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.
在人类中，植烷酸的氧化是一种过氧化物酶体功能。为了了解在Refsum病（RD）和点状软骨发育不良（RCDP）患者的血浆和体液中植烷酸特征性蓄积的可能机制，我们研究了从对照、RD和RCDP受试者的培养皮肤成纤维细胞中分离出的过氧化物酶体中植烷酸代谢各个步骤（激活、转运和氧化）的活性。RD和RCDP的过氧化物酶体中植烷酸的激活均正常。在有无脂肪酸激活辅因子（ATP、MgCl2和CoASH）存在的情况下，植烷酸或植烷酰辅酶A转运至从RD和RCDP皮肤成纤维细胞分离出的过氧化物酶体中的情况，也与对照成纤维细胞的过氧化物酶体相似。[(2,3)-3H]-或[1-14C] -植烷酸，或[1-14C] -植烷酰辅酶A（α-氧化第一步的底物）在RD过氧化物酶体中的氧化缺陷，但[1-14C] -α-羟基植烷酸（α-氧化途径第二步的底物）的氧化正常，这清楚地表明RD患者血浆和体液中植烷酸的过度蓄积是由于过氧化物酶体中植烷酸α-羟化酶的缺乏。然而，在RCDP过氧化物酶体中，除了[1-14C] -植烷酸、植烷酰辅酶A或[(2,3)-3H] -植烷酸的氧化缺陷外，[1-14C] -α-羟基植烷酸的氧化也存在缺陷，这表明在RCDP中，植烷酸的α-羟化和α-羟基植烷酸的脱羧活性均存在缺陷。这些观察结果表明，植烷酸代谢中过氧化物酶体膜功能（植烷酸激活和转运）在RD和RCDP中均正常。RD的缺陷在于植烷酸的α-羟化；而在RCDP中，植烷酸的α-羟化以及α-羟基植烷酸的脱羧均存在缺陷。
