Structural Research of Very Long Chain Fatty Acid Elongases

The very long-chain fatty acid elongase (ELOVL) family plays an essential role in lipid metabolism and cellular function, catalyzing the first step in the fatty acid elongation cycle. ELOVL synthesizes very long-chain fatty acids (VLCFA) by promoting the elongation of fatty acids beyond typical chain lengths. VLCFA is an essential component of a variety of cellular processes, including lipid metabolism, membrane structure, and cellular signaling. Research has linked the dysregulation of ELOVL expression to a variety of diseases, including metabolic disorders, neurodegenerative diseases, skin diseases, and cancer. The identification of ELOVL-based biomarkers may advance diagnostics and personalized medicine.

Structural and functional overview of ELOVL

Members of the ELOVL family share common structural and functional characteristics. These enzymes are integral membrane proteins present in the endoplasmic reticulum (ER) that act as catalysts in the fatty acid elongation process. In structure, ELOVL consists of a transmembrane structural domain that anchors it to the endoplasmic reticulum membrane and a catalytic structural domain that facilitates the enzymatic reaction. The catalytic structural domain typically contains conserved motifs and residues essential for substrate binding and enzymatic activity. Functionally, ELOVL works by adding two carbon units to the acyl chain, allowing for the gradual addition of carbon atoms to the growing fatty acid chain, ultimately producing VLCFA.

Structural analysis of human ELOVL7

There are seven mammalian ELOVLs (ELOVL1-7), and each elongase has different preferences for acyl chain length and unsaturation. To understand the molecular basis of acyl chain lengthening by ELOVL, researchers have resolved the structure of human ELOVL7 by X-ray crystallography. Overall, ELOVL7 has seven transmembrane helices (TM1-TM7), with TM2-7 forming six TM inverted barrels around a narrow tunnel. The two 3-helix units are assembled in an inverted repeating fashion around the central tunnel, with TM1 located outside the barrel against TM3/4. The central tunnel has a narrow opening in the cytoplasmic plane, which is sealed at the end of its ER lumen by a short-buried loop between TMs4-5, which connects the two halves of the barrel.

Figure 1. The overall structure of ELOVL7. (Nie L, et al., 2021)

Table 1. Structural research of the very long chain fatty acid elongases.

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References

1. Nie L, et al. The structural basis of fatty acid elongation by the ELOVL elongases. Nat Struct Mol Biol. 2021. 28(6): 512-520.
2. Wang X, et al. A comprehensive review of the family of very-long-chain fatty acid elongases: structure, function, and implications in physiology and pathology. Eur J Med Res. 2023. 28(1): 532.