Ether lipid biosynthesis: alkyl-dihydroxyacetonephosphate synthase protein deficiency leads to reduced dihydroxyacetonephosphate acyltransferase activities.

Abstract

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).

• Authors: E C de Vet, L Ijlst, W Oostheim, C Dekker, H W Moser, H van Den Bosch, R J Wanders
• Journal: Journal of lipid research (J Lipid Res) Vol. 40 Issue 11 Pg. 1998-2003 (Nov 1999) ISSN: 0022-2275 [Print] United States
• PMID: 10553003 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Phospholipid Ethers
• Plasmalogens
• Acyltransferases
• glycerone-phosphate O-acyltransferase
• Alkyl and Aryl Transferases
• alkylglycerone-phosphate synthase

Topics

• Acyltransferases (metabolism)
• Adult
• Alkyl and Aryl Transferases (deficiency)
• Child, Preschool
• Chondrodysplasia Punctata, Rhizomelic (enzymology, pathology)
• Female
• Humans
• Male
• Phospholipid Ethers (metabolism)
• Plasmalogens (biosynthesis)