Alkyl-Dihydroxyacetonephosphate Synthase

Abstract

Peroxisomes play an indispensible role in ether lipid biosynthesis as evidenced by the deficiency of ether phospholipids in fibroblasts and tissues from patients suffering from a number of peroxisomal disorders. Alkyl-dihydroxyacetonephosphate synthase, a peroxisomal enzyme playing a key role in the biosynthesis of ether phospholipids, contains the peroxisomal targeting signal type 2 in a N-terminal cleavable presequence. Using a polyclonal antiserum raised against alkyl-dihydroxyacetonephosphate synthase, levels of this enzyme were examined in fibroblast cell lines from patients affected by peroxisomal disorders. Strongly reduced levels were found in fibroblasts of Zellweger syndrome and rhizomelic chondrodysplasia punctata patients, indicating that the enzyme is not stable in the cytoplasm as a result of defective import into peroxisomes. In a neonatal adrenoleukodystrophy patient with an isolated import deficiency of proteins carrying the peroxisomal targeting signal type 1, the precursor form of alkyl-dihydroxyacetonephosphate synthase was detected at a level comparable to that of the mature form in control fibroblasts, in line with an intraperoxisomal localization. A patient with an isolated deficiency in alkyl-dihydroxyacetonephosphate (DHAP) synthase activity had normal levels of this protein. Analysis at the cDNA level revealed a missense mutation leading to a R419H substitution in the enzyme of this patient. Expression of a recombinant protein carrying this mutation in Escherichia coli yielded an inactive enzyme, whereas a comparable control recombinant enzyme was active, providing further proof that this substitution is responsible for the inactivity of the enzyme and the phenotype. In line with this result is the observation that wild-type alkyl-DHAP synthase activity can be inactivated by the arginine-modifying agent phenylglyoxal. The enzyme is efficiently protected against this inactivation when the substrate palmitoyl-DHAP is present at a saturating concentration. The gene encoding human alkyl-dihydroxyacetonephosphate synthase was mapped on chromosome 2q31.

Tysnd1 Deficiency in Mice Interferes with the Peroxisomal Localization of PTS2 Enzymes, Causing Lipid Metabolic Abnormalities and Male Infertility

“…Developing gametes mature in the epididymis where the remodelling of ether lipids that constitute the sperm cell membrane occurs [39]. In Tysnd1 −/− hepatocytes Agps, a rate-limiting enzyme [40] in the peroxisomal steps of plasmalogen synthesis showed almost no peroxisomal co-localization with DsRed2-Peroxi when transfected as GFP construct (Figure 6C). The changes in the composition of choline- and ethanolamine-type components of epididymal plasmalogens (Figure 3) most likely result in fragile sperm cell membranes and missing or defect acrosomes.…”

Alkylglycerone phosphate synthase (AGPS) deficient mice: Models for rhizomelic chondrodysplasia punctata type 3 (RCDP3) malformation syndrome

“…Genetic studies have determined that RCDP is a heterogeneous disorder with three distinct forms: RCDP type 1 (RCDP1) [OMIM 215100], RCDP type 2 (RCDP2) [OMIM 222765], and RCDP type 3 (RCDP3) [OMIM 600121] 1, 4, 5 . RCDP1 is caused by mutations in PEX7 6-8 , RCDP2 is caused by mutations in glyceronephosphate O-acyltransferase ( GNPAT ) 9, 10 , and RCDP3 is caused by mutations in alkylglycerone phosphate synthase ( AGPS ) 11, 12 . Although genetically distinct, biochemical studies have determined that the depletion of plasmalogens cause all three forms of RCDP 13 and as such all three RCDP forms are clinically indistinguishable.…”

Alkyl-Glycerol Rescues Plasmalogen Levels and Pathology of Ether-Phospholipid Deficient Mice

“…Despite this triple deficiency, the main pathophysiological factor in RCDP type 1 patients is the severe deficiency in the biosynthesis of plasmalogens, due to the absence of Agps from peroxisomes [23]–[25]. Indeed, strikingly similar clinical features are seen in two other forms of RCDP, namely type 2 and type 3, as caused by mutations in GNPAT and AGPS , respectively [5], [26]. All types of RCDP share the same clinical presentations which demonstrate that the deficiency in ether-phospholipids is the major cause of tissue pathology and disease state, and highlight the importance of plasmalogens for human health.…”