Alkyl-dihydroxyacetone phosphate synthase

D-bifunctional protein deficiency [5], 2-methyl acyl-CoA racemase (AMACR) deficiency [3] and sterol carrier protein (SCP-x) deficiency [6], the disorders of etherphospholipid biosynthesis (dihydroxyacetone phosphate acyltransferase and alkyl- dihydroxyacetone phosphate synthase deficiency) [2], the disorders of phytanic acid alpha-oxidation (Refsum disease) [15], and the disorders of glyoxylate detoxification with hyperoxaluria type 1 as caused by alanine glyoxylate aminotransferase deficiency as a sole representative. 

Figure 5. Biosynthetic pathways for diacyl, plasmalogen and alkyl-ether molecular subclasses of phospholipids. Monoacyl dihydroxyacetone phosphate is the key branch-point intermediate whose utilization determines the phospholipid subclass distribution of newly synthesized phospholipids. Reduction of monoacyl dihydroxyacetone phosphate leads to the biosynthesis of diacyl phospholipids. Fatty alcohol exchange, catalyzed by alkyl dihydroxyacetone phosphate synthase, is the first committed step in the biosynthesis of alkyl-ether and plasmalogen subclasses of phospholipids.

Alkyl-dihydroxyacetone phosphate (DHAP) synthase Isolated alkyl-DHAP synthase deficiency... 

Fig. 4. Ether phospholipid synthesis from dihydroxyacetone-phosphate. (A) Dihydroxyacetone-P acyl transferase (DHAPAT). The first step of ether phospholipid synthesis is catalyzed by peroxisomal DHAPAT. This enzyme is a required component of complex ether lipid biosynthesis and its role cannot be assumed by a cytosolic enzyme that also forms acyldihydroxyacetone-P. (B) Ether bond formation by alkyl-DHAP synthase. The reaction that forms the 0-alkyl bond is catalyzed by alkyl-DHAP synthase and is thought to proceed via a ping-pong mechanism. Upon binding of acyl-DHAP to the enzyme alkyl-DHAP synthase, the pro-f hydrogen at carbon atom 1 is exchanged by enolization of the ketone, followed by release of the acyl moiety to form an activated enzyme-DHAP complex. The carbon atom at the 1-position of DHAP in the enzyme complex is thought to carry a positive charge that may be stabilized by an essential sulfhydryl group of the enzyme thus, the incoming alkox-ide ion reacts with carbon atom 1 to form the ether bond of alkyl-DHAP. It has been proposed that a nucleophilic cofactor at the active site covalently binds the DHAP portion of the substrate.

The biosynthesis of plasmalogens has been elegantly reviewed by several investigators (Paltauf, 1994 Lee, 1998 Nagan and Zoeller, 2001 Murphy, 2001). Briefly, the first three enzymes of plasmalogen biosynthesis (dihydroxyacetone phosphate acyltransferase, alkyldihydroxyacetone phosphate synthase, and acyl/alkyl dihydroxyacetone reductase) are located in peroxisomes. The other enzymes, namely l-alkyl- n-GroP acyltransferase, l-alkyl-2-acyl-5n-GroP phosphohydrolase, and l-alkyl-2-acyl-jn-Gro ... 

Figure 2. Biosynthesis of plasmalogens in mammalian tissues. Enzymes (1) dihydroxyacetone phosphate acyltransferase (2) 1-acyldihydroxyacetone phosphate synthase (3) 1-alkyldihydroxyacetone phosphate oxidoreductase (4) l-alkyl-5n-glycero-3-phosphate acyltransferase (5) 1-afkyl 2-acyl-5w-glycero-3-phosphohydrolase (6) CDP-ethanolamine transferase (7) l-alkyl-2-acyl-5w-glycero-3-phosphoethanolamine desaturase (8) methyltransferases and base-exchange enzymes. CDP-ethanolamine, cytidine diphosphoethanolamine. CMP, cytidine monophosphate. CoA, coenzyme A. DHAP, dihydroxyacetone phosphate. NADH, nicotinamide adenine dinucleotide, reduced form. NAD, nicotinamide adenine dinucleotide, oxidized form. Pi, phosphate.

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