Plasmalogen, biosynthesis

Nagan N, Zoeller RA. Plasmalogens biosynthesis and functions. Prog. Lipid Res. 2001 40 199-229. 

Nagan, N., Zoeller, R.A. 2001. Plasmalogens biosynthesis and functions. Prog. Lipid Res. 40 199-229. Brites, P., Waterham, H.R., Wanders, R.J. 2004. Functions and biosynthesis of plasmalogens in health and disease. Biochim. Biophys. Acta 1636 219-231. 

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 24-4. Biosynthesis of ether lipids, including plasmalogens, and platelet-activating factor (PAF). In the de novo pathway for PAF synthesis, acetyl-CoA is incorporated at stage, avoiding the last two steps in the pathway shown here.

Although the mitochondria are the primary site of oxidation for dietary and storage fats, the peroxisomal oxidation pathway is responsible for the oxidation of very long-chain fatty acids, jS-methyl branched fatty acids, and bile acid precursors. The peroxisomal pathway also plays a role in the oxidation of dicarboxylic acids. In addition, it plays a role in isoprenoid biosynthesis and amino acid metabolism. Peroxisomes are also involved in bile acid biosynthesis, a part of plasmalogen synthesis and glyoxylate transamination. Furthermore, the literature indicates that peroxisomes participate in cholesterol biosynthesis, hydrogen peroxide-based cellular respiration, purine, fatty acid, long-chain... 

Peroxisomes contain dihydroxyacetone phosphate acyl-transferase and alkyldihydroxyacetone phosphate synthase, which are involved in synthesis of the plasmalogens (Chapter 19). Peroxisomes may also participate in the biosynthesis of bile acids. The conversion of trihydrox-ycholestanoic acid to cholic acid (Chapter 19) has been localized to peroxisomes. 

The a,jS-unsaturated fatty ether is an aldehydogenie group because its hydrolysis releases an a -unsaturated primary alcohol that readily tautomerizes to an aldehyde. Choline, ethanolamine, and serine plasmalogens are found in cardiac and skeletal muscle, brain, and liver. The biosynthesis of phosphatidylethanolamine is shown in Figure 19-5. 

Biosynthesis of ethanolamine plasmalogen. Enzymes (1) acyltransferase (2) synthase (3) oxidoreductase (4) acyltransferase (5) phosphatase (6) transferase (7) A -alkyl desaturase. 

Very little is known about the biosynthesis of the three most recently proposed endocannabinoids, 2-AGE, virodhamine and NADA. Regarding 2-AGE (noladin ether), this compound was previously identified in pig brain (Hanus et al. 2001) and in some rat tissues and brain areas (Fezza et al. 2002) by using mass-spectrometric (MS) methods coupled to chromatographic separations. However, a recent study cast some doubt on the actual existence of 2-AGE in mammalian brain tissue (Oka et al. 2003). At the time of this study it was already known that (1) the only acyl ethers to have been detected in animals before the discovery of 2-AGE were 2-acyl ethers (e.g. alkenyl ethers such as platelet activating factor and plasmalogens) (2) there was no evidence for the existence of any enzyme catalysing the formation... 

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.

The r-alkyl desaturase system, a microsomal mixed-function oxidase responsible for the biosynthesis of ethanolamine plasmalogens from alkyl lipids (Fig. 6), was initially characterized in the early 1970s (F. Snyder, 1971 A. Paltauf, 1973). The reverse of this reaction (i.e., conversion of an alk-l -enyl moiety to an alkyl chain via a reductase) has not been observed. The alkyl desaturase is a unique activity since it can specifically and stereospecifically abstract hydrogen atoms from C-1 and C-2 of the 0-alkyl chain of an intact phospholipid molecule to form the cis double bond of the O-alk-l -enyl moiety. Only intact l-alkyl-2-acyl-in-glycero-3-phosphoethanolamine is known to serve as a substrate for the alkyl desaturase. As with other reactions in complex ether phospholipid synthesis, the molecular identity of the responsible enzyme is unknown. 

Like the acyl-CoA desaturases (Chapter 7), the 1 -alkyl desaturase exhibits the typical requirements of a microsomal mixed-function oxidase. Molecular oxygen, a reduced pyridine nucleotide, cytochrome b, cytochrome reductase, and a terminal desaturase protein that is sensitive to cyanide are all required. The precise reaction mechanism responsible for the biosynthesis of ethanolamine plasmalogens is unknown, but it is clear from an investigation with a tritiated fatty alcohol that only the 15 and 25 (erythro)-labeled hydrogens are lost during the formation of the alk-l -enyl moiety of ethanolamine plasmalogens. 

Fig. 6. Biosynthesis of ethanolamine plasmalogens by I -alkyl desaturase. Components of the enzyme complex responsible for this unusual desaturation between carbons 1 and 2 of the 0-alkyl chain are (I) NADH cytochrome h, reductase, (II) cytochrome b, and (III) Al -alkyl desaturase, which is cyanide-sensitive. GPE, jn-glycero-3-phosphoethanolamine.

Fig. 7. Biosynthesis of choline plasmalogens (plasmenylcholines) via modification of the sn-3 polar head group of ethanolamine plasmalogens (plasmenylethanolamines). These reactions are proposed to be catalyzed directly by (1) a base exchange enzyme or (II) At-methyltransferase. A combination of other enzymatic reactions could also result in replacement of the ethanolamine moiety of plasmenylethanolamine to produce plasmenylcholines the enzymes responsible include (IB) phospholipase C, (IV) the reverse reaction of ethanolamine phosphotransferase, (V) phospholipase D, (VI) phosphohydtolase, and (VII) cholinephosphotransferase. AdoMet, 5-adenosyl-L-methionine AdoHcy, 5-adenosyl-L-homocysteine Etn, ethanolamine GPE, sn-glycero-...

Lee, T.C. 1998. Biosynthesis and possible biological functions of plasmalogens. Biochim. Biophys. Acta 1394 129-145. 

P ADP -I- l-alkyl-sn-glycero-3-phosphate <1> (<1> the product l-alkyl-2-lyso-sn-glycero-3-phosphate is the branch point intermediate in the de novo biosynthesis of ether-linked glycerolipids, plasmanylcholine, i.e. ethanolamine, and corresponding plasmalogenic analogs in membranes or platelet-activating factor PAF [2]) [1, 2]... 

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