Formation of a 2‐methyl‐branched fatty aldehyde during peroxisomal α‐oxidation

Abstract

In the final reaction of peroxisomal a-oxidation of 3-methyl-branched fatty acids a 2-hydroxy-3-methylacyl-CoA intermediate is cleaved to formyl-CoA and a hitherto unidentified product. The release of formyl-CoA suggests that the unidentified product may be a fatty aldehyde. When purified rat liver peroxisomes were incubated with 2-hydroxy-3-methylhexadecanoyl-CoA 2-methylpentadecanal was indeed formed. The production rates of formyl-CoA (measured as formate) and of the aldehyde were in the same range. While the production of formate remained unaltered in the presence of NAD+, the amount of 2-methylpentadecanal was decreased, which was accompanied by the formation of 2-methylpentadecanoic acid. These data indicate that (1) during a-oxidation the 2-hydroxy-3-methylacyl-CoA is cleaved to a 2-methyl-branched aldehyde and formyl-CoA and (2) liver peroxisomes are capable of converting this aldehyde to a 2-methyl-branched fatty acid. © 1997 Federation of European Biochemical Societies.

Breakdown of 2-Hydroxylated Straight Chain Fatty Acids via Peroxisomal 2-Hydroxyphytanoyl-CoA Lyase

“…tion mixture resulted in a further 20% increase of total oxidation (Table III) might be explained by a diminished product inhibition through NAD ϩ -dependent dehydrogenation of the generated aldehyde. Fatty aldehyde dehydrogenase activity is found in peroxisomes and endoplasmic reticula (13,46). It is currently unknown whether fatty aldehydes generated in the peroxisome are dehydrogenated exclusively by the peroxisomal dehydrogenase or also partially by the endoplasmic reticulum enzyme.…”

“…; n ϭ 4), but the lyase showed no activity toward [1-14 C]-labeled 3-methylhexadecanoyl-CoA, hexadecanoyl-CoA, 3-hydroxyhexadecanoyl-CoA, octadecanoyl-CoA, or toward 2-hydroxy-3-methylhexadecanoic acid, 3-methylhexadecanoic acid, hexadecanoic acid, and 2-hydroxyhexadecanoic acid. Furthermore, the production of [ 14 C]formyl-CoA/[ 14 C]formate from 2-hydroxy-3-methyl [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]hexadecanoyl-CoA was not reduced in the presence of 2-keto-octanoate, 2-hydroxyhexadecanoic acid, 2-methylhexadecanoyl-CoA, 2-methylhexadecanoic acid, 3-methylhexadecanoyl-CoA, 3-hydroxy-3-methylhexadecanoyl-CoA, or 3-hydroxy-2-methylhexadecanoyl-CoA (Fig. 6).…”

“…6). The addition of 50 M 2-hydroxyhexadecanoyl-CoA or 2-hydroxyoctadecanoyl-CoA to incubations with 10 M 2-hydroxy-3-methyl [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]hexadecanoylCoA, however, reduced the cleavage rates to a major extent (Fig. 6), indicating that 2-hydroxy straight chain acyl-CoA esters compete with 2-hydroxy-3-methyl-branched acyl-CoAs for cleavage by 2-HPCL.…”

“…The decarboxylation of 2-hydroxytetracosanoic acid was apparently independent of the preceding formation of an acyl-CoA and was supposed to be distinct from the ␣-oxidation of 3-methyl-branched fatty acids such as phytanic acid (11). The latter pathway is currently thought to proceed as follows; 1) activation to a CoA ester, 2) hydroxylation of carbon 2 by phytanoyl-CoA hydroxylase (PAHX), and 3) cleavage of the hydroxylated CoA-ester by 2-hydroxyphytanoyl-CoA lyase (2-HPCL) to formyl-CoA (12) and a 2-methyl-branched fatty aldehyde (13) in a TPP-dependent manner (14). Both PAHX and 2-HPCL are peroxisomal enzymes.…”

Molecular Mechanisms and Physiological Significance of Organelle Interactions and Cooperation

“…The mechanism would then be that succinate enters the mitochondrion via the mitochondrial dicarboxylate carrier and is converted back into 2-oxoglutarate via the concerted action of succinate dehydrogenase, fumarase, malate dehydrogenase, citrate synthase, and NAD-linked isocitrate dehydrogenase followed by export of 2-oxoglutarate via the mitochondrial carrier specific for 2-oxoglutarate (see Figure 9). With respect to one of the other products of alpha-oxidation, i.e., formyl-CoA, the current notion holds that formyl-CoA is rapidly hydrolyzed spontaneously to produce free CoASH and formic acid (Croes et al, 1997). Formic acid can be degraded via two pathways including: (1.)…”