8.A.221. The Very Long Chain Fatty Acid Elongase (VLCFA-E) Family These integral membrane enzymes catalyze the first and rate-limiting reaction of the four reactions that constitute the long-chain fatty acid elongation cycle. This endoplasmic reticulum (ER)-bound enzymatic process allows the addition of 2 carbons to the chain of long- and very long-chain fatty acids (VLCFAs) per cycle (Leonard et al. 2000). The fatty acid elongase ELOVL5 is part of a protein family of multipass transmembrane proteins that reside in the endoplasmic reticulum (ER) where they catalyze long-chain fatty acid elongation. A missense variant (c.689G>T, p.Gly230Val) in ELOVL5 (of 299 aas and 7 TMSs) causes Spinocerebellar Ataxia subtype 38 (SCA38), a neurodegenerative disorder characterized by autosomal dominant inheritance, cerebellar Purkinje cell demise and adult-onset ataxia (Ferrero et al. 2023). This presumably alters the activities of several transporters in the ER and the plasma membrane.
References:
Ferrero, E., E. Di Gregorio, M. Ferrero, E. Ortolan, Y.A. Moon, A. Di Campli, L. Pavinato, C. Mancini, D. Tripathy, M. Manes, E. Hoxha, C. Costanzi, E. Pozzi, M. Rossi Sebastiano, N. Mitro, F. Tempia, D. Caruso, B. Borroni, M. Basso, M. Sallese, and A. Brusco. (2023). Spinocerebellar ataxia 38: structure-function analysis shows ELOVL5 G230V is proteotoxic, conformationally altered and a mutational hotspot. Hum Genet. [Epub: Ahead of Print]
Leonard, A.E., E.G. Bobik, J. Dorado, P.E. Kroeger, L.T. Chuang, J.M. Thurmond, J.M. Parker-Barnes, T. Das, Y.S. Huang, and P. Mukerji. (2000). Cloning of a human cDNA encoding a novel enzyme involved in the elongation of long-chain polyunsaturated fatty acids. Biochem. J. 350Pt3: 765-770.
Mueller, N., T. Sassa, S. Morales-Gonzalez, J. Schneider, D.J. Salchow, D. Seelow, E. Knierim, W. Stenzel, A. Kihara, and M. Schuelke. (2019). De novo mutation in causes ichthyosis, , hypomyelination, spastic paraplegia, high frequency deafness and optic atrophy. J Med Genet 56: 164-175.
Ohno, Y., S. Suto, M. Yamanaka, Y. Mizutani, S. Mitsutake, Y. Igarashi, T. Sassa, and A. Kihara. (2010). ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis. Proc. Natl. Acad. Sci. USA 107: 18439-18444.
Examples:
TC#	Name	Organismal Type	Example
8.A.221.1.1	*Elongation of very long chain fatty acids, protein 5 (ELOVL-5) of 299 aas and 7 TMSs. See family description for details (Ferrero et al.* 2023).**		ELOVL5 of Homo sapiens

8.A.221.1.2	Uncharacterized protein of 325 aas and 5 -7 TMSs possibly in a 2 + 3, or 2 + 5 TMS arrangement.		UP of Colletotrichum nupharicola

8.A.221.1.3	Uncharacterized protein of 275 aas and 7 TMSs.		UP of Gossypium mustelinum

8.A.221.1.4	Elongation of very long chain fatty acids protein 6 of 332 aas and 7 TMSs.		ELOVL6 of Holothuria leucospilota

8.A.221.1.5	Elongation of very long chain fatty acids protein 1, ELOV1 or ELOVL1 or SSC1 of 279 aas and 7 TMSs in a 2 + 5 TMS arrangement. Catalyzes the first and rate-limiting reaction of the four reactions that constitute the long-chain fatty acids elongation cycle (Mueller et al. 2019. This endoplasmic reticulum-bound enzymatic process allows the addition of 2 carbons to the chain of long- and very long-chain fatty acids (VLCFAs) per cycle. It is a condensing enzyme that exhibits activity toward saturated and monounsaturated acyl-CoA substrates, with the highest activity towards C22:0 acyl-CoA. It may participate in the production of both saturated and monounsaturated VLCFAs of different chain lengths that are involved in multiple biological processes as precursors of membrane lipids and lipid mediators. Important for saturated C24:0 and monounsaturated C24:1 sphingolipid synthesis (Ohno et al. 2010). It indirectly inhibits RPE65 via production of VLCFAs. The catalytic reaction catalyzed is: a very-long-chain acyl-CoA + H⁺ + malonyl-CoA → a very-long-chain 3-oxoacyl-CoA + CO₂ + CoA.		Elov1 of Homo sapiens

8.A.221.1.6	GNS1/SUR4 family domain-containing protein of 271 aas and 7 TMSs.		GNS1 protein of Ditylenchus destructor

8.A.221.1.7	Elongation of fatty acids protein-like protein of 352 aas and 7 or 8 TMSs.		*Elov protein of Hyaloscypha* sp. PMI_1271**

8.A.221.1.8	Fatty acid elongase, putative of 253 aas and 7 TMSs.		Elov of Trypanosoma cruzi

8.A.221.1.9	Uncharacterized protein of 304 aas and ~ 7 TMSs.		UP of Nannochloropsis salina