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Among glycerophospholipids, plasmalogens represent a special class that is characterized by the presence of a long-chain enol ether (vinyl ether) bond at the sn-l position of the glycerol moiety. The levels of ethanolamine plasmalogen in brain tissue depend on the degree of myelination (Horrocks and Sharma, 1982). Thus the concentration of plasmalogens increases rapidly during the intense period of myelination and the ethanolamine glycerophospholipids in myelin include up to 70% plasmalogens. The enol ether-linked aliphatic moieties at the sn-l position in plasmalogens are almost exclusively 16:0, 18:0, and 18:1 and form the corresponding fatty aldehyde upon acid hydrolysis. The sn-2 position in the glycerol moiety of plasmalogens is enriched in arachidonic acid, AA, 20:4 n-6, or docosahexaenoic acid, DHA, 22:6 n-3.

Synthetic 3-methyl-branched chain fatty acids were used to decipher the breakdown of phytanic acid. Based on results obtained in intact or permeabilized rat hepatocytes, rat liver homogenates or subcellular fractions, a revised α-oxidation pathway is proposed which appears to be functioning in man as well. In a first step, the 3-methyl-branched chain fatty acid is activated by an acyl-CoA synthetase. This reaction requires CoA, ATP and Mg2+. Subsequently, the acyl-CoA ester is hydroxylated at position 2 by a peroxisomal dioxygenase. This step is dependent on α-oxoglutarate, ascorbate (or glutathione), Fe2+ and O2. The 2-hydroxy-3-methylacyl-CoA intermediate is cleaved by a peroxisomal lyase to formyl-CoA and a 2-methyl-branchedfatty aldehyde. Formyl-CoA is (partly enzymically) hydrolyzed to formate, which is then converted, most likely in the cytosol, to CO2. In the presence of NAD+, the aldehyde is dehydrogenated to a 2-methyl-branched fatty acid, presumably by a peroxisomal aldehyde dehydrogenase. This acid can—after activation—be degraded via a D-specific peroxisomal β-oxidation system.

Aldehyde dehydrogenase, isolated from the luminescent bacterium, Vibrio harveyi, catalyzes the oxidation of fatty aldehydes (Meighen et al.,1976). This enzyme has a preference for long chain aldehydes as reflected by a large decrease in the Km for aldehydes on increasing the chain length from acetaldehyde to tetradecanal (Bognar & Meighen, 1978; Vedadi et al., 1995). As one of the substrates for luciferase is tetradecanal, the potential involvement of aldehyde dehydrogenase in the luminescent system has been proposed. Tetradecanal is produced in luminescent bacteria by a lux-specific fatty acid reductase complex which activates (plus ATP) tetradecanoic acid to fatty acyl-AMP; the acyl group is then transferred between the fatty acid reductase subunits before being reduced with NADPH (Riendeau et al., 1982; Rodriguez et al., 1983a, 1983b). The V. harveyi aldehyde dehydrogenase(Vh ALDH) may be present so as to maintain aldehyde at nontoxic levels under conditions where excess levels of aldehyde are produced by the fatty acid reductase complex. However, the possibility that the function of aldehyde dehydrogenase is unrelated to luminescence can certainly not be excluded as Vh ALDH is under different regulation than the lux-specific proteins and has not been detected in other luminescent bacteria (Byers et al., 1988; Vedadi, M. unpublished data).

Class 3 ALDHs prefer NAD as coenzyme, but can use NADP effectively in vitro. They function as dimers of identical ~50kDa monomers, and share about 30% sequence identity with either of the tetrameric class 1 or 2 enzymes. Interest in the Class 3 ALDH (ALDH-3) has focused on its diversity of expression (Lindahl, 1992). No ALDH-3 activity is detectable in normal mammalian liver, but high levels are obtained after exposure to certain xenobiotics. Many neoplasms possess elevated ALDH-3 activities, while many normal tissues, such as cornea and stomach constitutively express ALDH-3. ALDH-3 enzymes prefer aromatic aldehydes and medium chain-length (C-6 to C-10) aliphatic aldehydes as substrate. Known substrates include benzaldehyde and hexenal as well as 4-hydroxynonenal derived from membrane lipid peroxidation (Lindahl and Peterson, 1991). The microsomal ALDH-3 has also received clinical attention from the recent demonstration that Sjogren-Larsson Syndrome is the result of mutations inactivating this “fatty aldehyde dehydrogenase” (DeLaurenzi, et al, 1996).

Glyceryl ether monooxygenase is a microsomal enzyme which hydroxylates the α-carbon atom of the fatty side-chain of glyceryl ethers of long-chain fatty alcohols. The reaction requires oxygen and a tetrahydropterin cofactor. It is a mixed-function oxidase and by analogy with phenylalanine hydroxylase the reaction shown in Scheme 1 was postulated.1 We investigated aspects of the stoichiometry of the oxygenase because two earlier reports were not entirely satisfactory. Tietz, Lindberg and Kennedy1 had shown that the amount of fatty aldehyde produced, in a non regenerating system, was 40-50% of tetrahydropterin oxidised and attributed this to the fact that the pterin was a DL mixture. This statement is incorrect in view of later work2 and because we have found that the monooxygenase activity with the two separate enantiomers S(-) and R(+) 6-methyl-5,6,7,8-tetrahydropterin as cofactors is the same. The second report was by Kotting, Unger and Eibl3 who determined the stoichiometry of the reaction in a coupled reaction with DHPR and NADH, and showed that the amount of NADH oxidised after one minute was equivalent to the total amount of fatty aldehyde, alcohol and acid produced.3 Since the fatty aldehyde, alcohol and acid are produced by several reactions following enzymic hydroxylation of the ether substrate the conclusion was dubious.