Stability of Alkyl-Dihydroxyacetonephosphate Synthase in Human Control and Peroxisomal Disorder Fibroblasts

Abstract

Alkyl-dihydroxyacetonephosphate synthase (alkyl-DHAP synthase) is a peroxisomal enzyme that plays a key role in ether phospholipid biosynthesis. To determine the turnover of alkyl-DHAP synthase in several peroxisomal disorders, pulse-chase experiments were performed. In control fibroblasts, mature alkyl-DHAP synthase displayed a half-life of 23 +/- 12 h. In Zellweger syndrome and rhizomelic chondrodysplasia punctata fibroblast cell lines, in which alkyl-DHAP synthase cannot be imported into peroxisomes, the enzyme was mainly detected in its precursor form. This precursor form showed a much shorter half-life, 5 +/- 2 h. In contrast, when the precursor protein accumulated inside the peroxisome of a particular neonatal adrenoleukodystrophy cell line in which processing does not take place, a half-life of 18 +/- 8 h, resembling that of the mature protein in controls, was observed. In a cell line from a patient with a single deficiency in the activity of alkyl-DHAP synthase, the mature form was detected and its radioactivity decreased with a half-life of 16 +/- 7 h. Collectively, these results provide an explanation for the instability of alkyl-DHAP synthase outside its target organelle. Additionally, they indicate that both the precursor and mature form of alkyl-DHAP synthase exhibit considerable intraperoxisomal turnover.

Caenorhabditis elegans has a single pathway to target matrix proteins to peroxisomes

“…In humans, loss of the PTS2 receptor, Pex7p, causes multiple enzyme deficiencies due to missorting of (at least) three (PTS2‐containing) proteins, and results in the severe developmental disorder RCDP (Braverman et al ., 1997; Motley et al ., 1997; Purdue et al ., 1997). It is the mislocalization and resulting loss of activity (Biermann et al ., 1999) of one of these PTS2‐containing enzymes, ADHAPS, that gives rise to the disease; in some RCDP patients, the only deficient activity is that of ADHAPS (Wanders et al ., 1994) as a result of mutations in the gene encoding this enzyme (de Vet et al ., 1998a).…”

Plasmalogen synthesis is regulated via alkyl‐dihydroxyacetonephosphate‐synthase by amyloid precursor protein processing and is affected in Alzheimer’s disease

“…Furthermore, Ab and ROS have been shown to induce peroxisomal dysfunction (Schrader and Fahimi 2004;Cimini et al 2009). Interestingly, the transport of AGPS, which plays a key role in plasmalogen synthesis, to peroxisomes is impaired in peroxisomal disorder fibroblasts and displays a much shorter half-life compared to AGPS localized in peroxisomes (Biermann et al 1999). Because Ab and ROS impair peroxisomal function and AGPS halflife critically depends on peroxisomal function, one would expect to detect decreased AGPS protein level in samples with high amount of Ab.…”

“…2009). Interestingly, the transport of AGPS, which plays a key role in plasmalogen synthesis, to peroxisomes is impaired in peroxisomal disorder fibroblasts and displays a much shorter half‐life compared to AGPS localized in peroxisomes (Biermann et al. 1999).…”