Alternative titles; symbols
HGNC Approved Gene Symbol: LCLAT1
Cytogenetic location: 2p23.1 Genomic coordinates (GRCh38): 2:30,447,246-30,644,225 (from NCBI)
Phospholipids are remodeled through the Lands cycle to attain appropriate fatty acid composition for biologic activity. LCLAT1 functions as an acyltransferase in the endoplasmic reticulum (ER) and predominantly remodels anionic phospholipids, including phosphatidylinositol and phosphatidylglycerol (Zhao et al., 2009).
Cao et al. (2004) cloned mouse Lclat1, which they called Alcat1. The deduced 376-amino acid protein has a calculated molecular mass of 44.4 kD. Alcat1 has an N-terminal signal peptide, a C-terminal transmembrane domain, and an ER retention motif (KKxx) at its C terminus. Northern blot analysis detected a 4.3-kb Alcat1 transcript in most mouse tissues examined, with highest expression in heart and kidney. A slightly shorter Alcat1 variant was also detected in heart. Immunohistochemical analysis of transfected COS-7 cells showed that Alcat1 colocalized with ER marker proteins. EST database analysis revealed orthologs of Alcat1 from humans to fish.
By database analysis and PCR of a skeletal muscle cDNA library, Agarwal et al. (2006) cloned human LCLAT1, which they called AGPAT8. The deduced 376-amino acid protein has a calculated molecular mass of 44.4 kD. AGPAT8 has 2 conserved motifs seen in AGPATs, NHx4D and an EGTR-like motif (EGTD), which are involved in catalysis and substrate binding, respectively. AGPAT8 shares 89.1% amino acid identity with mouse Agpat8. Northern blot analysis detected a 5-kb AGPAT8 transcript in most tissues examined, with highest expression in heart and kidney. Quantitative real-time PCR detected AGPAT8 in all tissues examined, with highest expression in heart, skeletal muscle, kidney, ovary, small intestine, leukocytes, brain, and placenta. Database analysis revealed orthologs of AGPAT8 in plants, nematode worms, and cyanobacteria.
Using quantitative RT-PCR, Zhao et al. (2009) detected ALCAT1 expression in all tissues examined except skeletal muscle. Highest expression was detected in pancreas. Epitope-tagged ALCAT1 localized to the ER of transfected COS-7 cells.
Cao et al. (2004) showed that mouse Alcat1 expressed in insect or mammalian cells catalyzed acylation of lysocardiolipin and dilysocardiolipin and preferentially used the unsaturated C18 acyl donors linoleoyl-CoA and oleoyl-CoA as substrates. Similar activity was detected in rat liver and heart microsomes, with much lower activity in isolated liver and heart mitochondria.
Agarwal et al. (2006) showed that human AGPAT8 expressed in Chinese hamster ovary cells could acylate lysophosphatidic acids with C16 or C18 chains in either the sn-1 or sn-2 position, with variable tolerance for unsaturation. AGPAT8 did not appear to acylate lysocardiolipin. AGPAT8 used linoleoyl-CoA to synthesize phosphatidylethanolamine, phosphatidylcholine, and phosphatidic acid.
By assaying membrane preparations of HEK293 cells overexpressing human ALCAT1, Zhao et al. (2009) found that ALCAT1 possessed acyltransferase activity toward lysocardiolipin, dilysocardiolipin, lysophosphatidylinositol, and lysophosphatidylglycerol, but not lysophosphatidylcholine and lisophosphatidylethanolamine. ALCAT1 accepted these substrates with varying chain lengths in the sn-1 position. ALCAT1 transferred the acyl groups from several fatty acid-CoAs of long chain length, but not from fatty acid-CoAs with short chain length (8:0) or highly unsaturated arachidonyl-CoA. Knockdown of ALCAT1 in HeLa cells via small interfering RNA reduced in vitro synthesis of phosphatidylglycerol and phosphatidylinositol, but not cardiolipin. Mutation of asp168 to arg or cys completely abolished ALCAT1 activity, whereas mutation of thr169 to leu reduced synthesis of phosphatidylinositol, but not phosphatidylglycerol. Taking into account the localization of ALCAT1 in ER membranes, Zhao et al. (2009) concluded that ALCAT1 predominantly remodels phosphatidylinositol and phosphatidylglycerol in the ER, but that it is unlikely to remodel cardiolipin, a mitochondrial lipid.
Agarwal et al. (2006) determined that the LCLAT1 gene contains 6 exons and spans around 170 kb.
By genomic sequence analysis, Agarwal et al. (2006) mapped the LCLAT1 gene to chromosome 2p. Gross (2011) mapped the LCLAT1 gene to chromosome 2p23.1 based on an alignment of the LCLAT1 sequence (GenBank BC146817) and the genomic sequence (GRCh37).
Agarwal et al. (2006) mapped the mouse Lclat1 gene to chromosome 17.
Agarwal, A. K., Barnes, R. I., Garg, A. Functional characterization of human 1-acylglycerol-3-phosphate acyltransferase isoform 8: cloning, tissue distribution, gene structure, and enzymatic activity. Arch. Biochem. Biophys. 449: 64-76, 2006. [PubMed: 16620771] [Full Text: https://doi.org/10.1016/j.abb.2006.03.014]
Cao, J., Liu, Y., Lockwood, J., Burn, P., Shi, Y. A novel cardiolipin-remodeling pathway revealed by a gene encoding an endoplasmic reticulum-associated acyl-CoA:lysocardiolipin acyltransferase (ALCAT1) in mouse. J. Biol. Chem. 279: 31727-31734, 2004. [PubMed: 15152008] [Full Text: https://doi.org/10.1074/jbc.M402930200]
Gross, M. B. Personal Communication. Baltimore, Md. 9/22/2011.
Zhao, Y., Chen, Y.-Q., Li, S., Konrad, R. J., Cao, G. The microsomal cardiolipin remodeling enzyme acyl-CoA lysocardiolipin acyltransferase is an acyltransferase of multiple anionic lysophospholipids. J. Lipid Res. 50: 945-956, 2009. [PubMed: 19075029] [Full Text: https://doi.org/10.1194/jlr.M800567-JLR200]