Ether lipid biosynthesis

Glycosomes are membrane-bound microbody like intracellular organelles, which contain all the enzymes necessary for glycolysis, glycerol metabolism and fixation of CO2. The glycosomes also possess some enzymes associated with pyrimidine synthesis, purine salvage and ether-lipid biosynthesis [1,2]. 

This enzyme is an integral membrane protein exclusively localized to the lumenal side of peroxisomes (A. Poulos, 1993). Reports on the presence of this enzyme in other organelles are likely a result of peroxisomal contamination. This acyltransferase is important in ether lipid biosynthesis (Chapter 9). Once 1-acyldihydroxyacetone-P has been formed it can be used as a substrate for 1-alkyldihydroxyacetone-P synthesis (Chapter 9) or can be reduced to lyso-PA by a peroxisomal acyldihydroxyacetone-P reductase (Fig. 1) that also utilizes 1-alkyldihydroxyacetone-P as a substrate. 

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.

I. Rodemer, C., Thai, T.R, Brugger, B., Kaercher, T., Werner, H., Nave, K.A., Wieland, F., Gorgas, K., Just, W.W. 2003. Inactivation of ether lipid biosynthesis causes male infertility, defects in eye development and optic nerve hypoplasia in mice. Hum. Mol. Genet. 12 1881-1895. 

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.

Mangold, H. K., and Weber, N. 1987. Biosynthesis and biotransformation of ether lipids. Lipids, 22,789-799. 

The question then arises by what pathways are archaeal ether lipids biosynthesized and how were these pathways selected rather than those used by all other organisms for acyl ester lipid synthesis The available information on lipid biosynthesis in archaea is based largely, with a few exceptions, on labelling studies with whole cells (see previous reviews [4,5,9,10,13,15,85]). Biosynthetic pathways for archaeol, caldarchaeol and their complex lipid derivatives will now be discussed. 

Peroxisome proliferators are also involved in two other metabolic pathways of importance to lipid metabolism. Peroxisomes contain the most of di-hydroxyacetone phosphate acetyltransferase and alkyldihydroxyacetone phosphate synthetase activities. Therefore, they are responsible for initiating most ether glycerolipid biosynthesis. These enzymes are also moderately induced by peroxisome proliferators. Induction of cytochrome P450s by peroxisome proliferators will be addressed separately. 

ANTIPROTOZOAL EFFECTS Miltefosine is the first orally available therapy for leishmaniasis. It is safe and effective treatment for visceral leishmaniasis and has also shown >95% efficacy against cutaneous leishmaniasis. In Leishmania, the drug may alter ether-lipid metabohsm, ceU signaling, or glycosylphosphatidylinosital anchor biosynthesis. Mutations in a P-type ATPase of the aminophospholipid translocase subfamily apparently decrease drug uptake and thereby confer resistance. 

Peroxisomes are present in greater number in the liver than in other tissues. Liver peroxisomes contain the enzymes for the oxidation of very-long-chain fatty acids such as C24 0 and phytanic acid, for the cleavage of the cholesterol side chain necessary for the synthesis of bile salts, for a step in the biosynthesis of ether lipids, and for several steps in arachidonic acid metabohsm. Peroxisomes also contain catalase and are capable of detoxifying hydrogen peroxide. 

Koga Y, Nishihara M. Morii H, Akagawa-Maesushita M. Ether lipids of meihanogenic hac-teria Structures, comperative aspects, and biosynthesis. Microbiol Rev 1993 57 164-182. Englund PT. The structure and biosynthesis of glycosy phosphatidyiinositiol protein anchors. Annu Rev Biochem 1993 62 112-138. 

De Rosa, M., Gambacorta, A., and Nicolaus, B. (1980b) Regularity of isoprenoid biosynthesis in the ether lipids of archaebacteria. Phytochemistry, 19, 791-793. 

Gonthier, I., Rager, M.N., Metzget P., Guezennec, J., and Largeau, C. (2001) A di-O-dihydrogeranylgeranyl glycerol from Thermococcus S 557, a novel ether lipid, and hkely intermediate in the biosynthesis of diethers in Archaea. Tetrahedron Lett., 42,2795-2797. 

Koga Y., Nishihara M., Morii H., and Akagawa-MatsushitaM. (1993) Ether polar lipids of methanogenic bacteria structures, comparative aspects, and biosynthesis. Microbiol. Rev. 57, 164-182. 

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. 

Koga Y, Morii H Biosynthesis of ether-type polar lipids in archaea and evolutionary considerations. Microbiol Mol Biol Rev 2007, 71(1) 97-120. 

Figure 16.2 Pathways involved in the biosynthesis of ether-containing lipids. The enzymes that may be involved in nonselective utilization of acyl CoA pool are highlighted with broken-lined arrows. The formed ether-containing lipids are highlighted with light gray. The symbol of stands for CDP-ethanolamine l-0-alkyl-2-acyl-sn-glycerol ethanolamine phosphotransferase or CDP-choline 1 -O-alkyl-2-acyl-in-glycerol chohne phosphotransferase. DHAP denotes dihydroxyacetone phosphate. AU other abbreviations can be found in the list of abbreviations.

While hydrocarbons are usually the main components of B. braunii oil, the latter may contain not only the usual lipids commonly found in algal oils but also non-classical lipids which have been thoroughly studied in the case of the A race. In addition, the structural elements building up the outer walls of the different races of B. braunii were shown to consist of insoluble and chemically resistant biopolymers originating in extended cross linking of the lipids through ether bridges. The first part of this review will be therefore concerned with elucidation of the chemical structures and biosynthesis of the hydrocarbons, lipids and macromolecular lipids produced by B. braunii. 

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