Ether lipid biosynthesis: alkyl-dihydroxyacetonephosphate synthase protein deficiency leads to reduced dihydroxyacetonephosphate acyltransferase activities.
Recent studies have indicated that two peroxisomal enzymes involved in ether lipid synthesis, i.e., dihydroxyacetonephosphate acyltransferase and alkyl-dihydroxyacetonephosphate synthase, are directed to peroxisomes by different targeting signals, i.e., peroxisomal targeting signal type 1 and type 2, respectively. In this study, we describe a new human fibroblast cell line in which alkyl-dihydroxyacetonephosphate synthase was found to be deficient both at the level of enzyme activity and enzyme protein. At the cDNA level, a 128 base pair deletion was found leading to a premature stop. Remarkably, dihydroxyacetonephosphate acyltransferase activity was strongly reduced to a level comparable to the activities measured in fibroblasts from patients affected by the classical form of rhizomelic chondrodysplasia punctata (caused by a defect in peroxisomal targeting signal type 2 import). Dihydroxyacetonephosphate acyltransferase activity was completely normal in another alkyl-dihydroxyacetonephosphate synthase activity-deficient patient. Fibroblasts from this patient showed normal levels of the synthase protein and inactivity results from a point mutation leading to an amino acid substitution. These results strongly suggest that the activity of dihydroxyacetonephosphate acyltransferase is dependent on the presence of alkyl-dihydroxyacetonephosphate synthase protein. This interpretation implies that the deficiency of dihydroxyacetonephosphate acyltransferase (targeted by a peroxisomal targeting signal type 1) in the classic form of rhizomelic chondrodysplasia punctata is a consequence of the absence of the alkyl-dihydroxyacetonephosphate synthase protein (targeted by a peroxisomal targeting signal type 2).
de Vet
E C
EC
Centre for Biomembranes and Lipid Enzymology, Institute for Biomembranes, Utrecht University, Utrecht, The Netherlands.
Ijlst
L
L
Oostheim
W
W
Dekker
C
C
Moser
H W
HW
van Den Bosch
H
H
Wanders
R J
RJ
D000217:Acyltransferases / Q000378:metabolism; D000328:Adult; D019883:Alkyl and Aryl Transferases / Q000172:deficiency; D002675:Child, Preschool; D018902:Chondrodysplasia Punctata, Rhizomelic / Q000201:enzymology / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D010742:Phospholipid Ethers / Q000378:metabolism*; D010955:Plasmalogens / Q000096:biosynthesis*
D010742:Phospholipid Ethers; D010955:Plasmalogens; D000217:Acyltransferases; C020051:glycerone-phosphate O-acyltransferase; D019883:Alkyl and Aryl Transferases; C019654:alkylglycerone-phosphate synthase