Biosynthesis, degradation and pharmacological importance of the fatty acid amides

Abstract

The identification of two biologically active fatty acid amides, N-arachidonoylethanolamine (anandamide) and oleamide, has generated a great deal of excitement and stimulated considerable research. However, anandamide and oleamide are merely the best-known and best-understood members of a much larger family of biologically occurring fatty acid amides. In this review, we will outline which fatty acid amides have been isolated from mammalian sources, detail what is known about how these molecules are made and degraded in vivo, and highlight their potential for the development of novel therapeutics.

Figure 1

The Structures of the Fatty Acid Amides ^aR₂ represents the functional groups that define the different amino acids The arrow points to carbon-2 in the fatty acid chain. R₁ is an acyl group, making these structures fatty acids. R₂ and R₃ are also acyl groups.

Figure 2

Biosynthetic Pathways for N-Acylethanolamines (NAEs) The enzymes catalyzing the individual reactions are in the shaded boxes and the numbers that refer to reactions in the text are in bold blue. The reader is referred to Simon and Cravatt [23] and Liu et al. [31] for greater details on NAE biosynthesis. Abdh4, α,β-hydrolase 4, G3P, glyercol-3-phosphate, LPA, lysophosphatic acid, LysoPLD, lysophospholipase D, NAPE-PLD, NAPE-specific phospholipase D, PA, phosphatidic acid, PDEase, phosphodiesterase, PLA₂, phopholipase A₂, PLC, phopholipase C, PTase, phosphatase (most likely tyrosine phosphatase, PTPN22, or inositol-5′-phosphatase, SHIP1, in vivo)

Figure 3

Biosynthesis of the N-Acylphosphatidylethanolamine (NAPE)

Figure 4

Proposed Biosynthetic Pathways for the Primary Fatty Acid Amides (PFAMs) The enzymes catalyzing the individual reactions are in the shaded boxes and the fatty acyl group are represent by the bold blue “R”. The fatty acid amides discussed in this review are highlighted in red. The reader is referred to Mueller and Driscoll [73] and Merkler et al.[74] for greater details on PFAM biosynthesis. ASC, ascorbic acid, Cyto c, cytochrome c, fADH, fatty alcohol dehydrogenase, fAldDH, fatty aldehyde dehydrogenase, NAcylT, a novel acyl-CoA:N-amino acid transferase, PAM, peptidyglycine α-amidating monooxygenase, SDA, semidehydroascorbic acid