Reactome: A Curated Pathway Database

Synthesis of very long-chain fatty acyl-CoAs

Stable Identifier
R-HSA-75876
Type
Pathway
Species
Homo sapiens
Compartment
Synonyms
Conversion of palmitic acid to very long chain fatty acyl-CoAs
Locations in the PathwayBrowser
Summation

Very long-chain fatty acids (VLCFA), ones with more than 20 carbon atoms, have diverse physiological roles, notably as components of ceramides in membrane lipids and as precursors of the eicosanoid hormones that play central roles in the generation and resolution of inflammatory responses. Saturated and monounsaturated VLCFAs can be synthesized by elongation od palmitic acid synthesized de novo or derived from the diet. Polyunsaturated VLCFAs are synthesized from dietary linoleic and linolenic acids - humans lack the desaturase enzymes to synthesize these molecules from stearate.

Chemically, the elongation process that yields VLCFA parallels the one by which palmitate (16 carbones) or stearate (18 carbons) are synthesized de novo from acetate. The starting fatty acid is activated by conjugation with coenzyme A (CoA-SH), condensed with malonyl-CoA to form a 3-oxoacyl CoA containing two more carbon atoms than the starting long chain fatty acyl CoA and CO2, reduced with NADPH to a 3-hydroxyacyl CoA, dehydrated to a trans 2,3-enoyl-CoA, and reduced with NADPH to yield a fatty acyl-CoA two carbons longer than the starting one.

The process differs from the de novo one in that the enzymatic activities resposible for each step are expressed by different proteins associated with the endoplasmic reticulum membrane, not by separate domains of a single multifunctional cytosolic protein. In humans, activation is catalyzed by one of five acyl-CoA synthetase long-chain (ACSL) enzymes, conjugation by one of seven elongation of very long chain fatty acids (ELOVL) proteins, reduction by one of two HSB17B estradiol dehydrogenases, dehydration by one of four protein tyrosine phosphatase-like / 3-hydroxyacyl-CoA dehydratase (PTPL / HACD) proteins, and reduction by one of two trans-2,3-enoyl-CoA reductase (TECR) proteins. Members of the four enzyme families differ in their tissue-specific expression patterns and in their substrate preferences (chain length, degree of saturation), leading to tissue-specific complements of VLCA (Jakobsson et al. 2006; Kihara 2012; Nugteren 1965).

Here the full two-carbon elongation cycle to form stearate from palmitate is annotated, as well as the activation and condensation steps for elongation of arachidonate, the 20-carbon unsaturated fatty acid that plays a central role in the synthesis of prostaglandins and related hormones.

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