Alternative titles; symbols
HGNC Approved Gene Symbol: ACLY
Cytogenetic location: 17q21.2 Genomic coordinates (GRCh38): 17:41,866,917-41,930,545 (from NCBI)
ATP citrate lyase is the primary enzyme responsible for the synthesis of cytosolic acetyl-CoA in many tissues. The enzyme is a tetramer (relative molecular weight approximately 440,000) of apparently identical subunits. It catalyzes the formation of acetyl-CoA and oxaloacetate from citrate and CoA with a concomitant hydrolysis of ATP to ADP and phosphate. The product, acetyl-CoA, serves several important biosynthetic pathways, including lipogenesis and cholesterogenesis. In nervous tissue, ATP citrate-lyase may be involved in the biosynthesis of acetylcholine.
Cloning of cDNAs has been reported for murine (Sul et al., 1984), rat (Elshourbagy et al., 1990), and human (Elshourbagy et al., 1992) ATP citrate lyase. Elshourbagy et al. (1992) found that the subunits of the enzyme have 1,105 amino acids and a calculated molecular mass of 121,419 Da. The human and rat ATPCL cDNAs showed 96.3% amino acid identity.
Wellen et al. (2009) showed that histone acetylation in mammalian cells is dependent on ATP-citrate lyase (ACL), the enzyme that converts glucose-derived citrate into acetyl-CoA. They found that ACL is required for increases in histone acetylation in response to growth factor stimulation and during differentiation, and that glucose availability can affect histone acetylation in an ACL-dependent manner. Wellen et al. (2009) concluded that ACL activity is required to link growth factor-induced increases in nutrient metabolism to the regulation of histone acetylation and gene expression.
By immunoprecipitation analysis followed by mass spectrometry, Sanchez-Solana et al. (2014) found that the zinc finger protein MORC2 bound ACLY in HeLa cells. Protein pull-down assays confirmed the MORC2-ACLY interaction, and immunoprecipitation showed that endogenous MORC2 and ACLY interacted specifically in cytosol of MCF-7 lipogenic human breast cancer cells. Induced expression of MORC2 in MCF-7 cells and another lipogenic human breast cancer cell line increased phosphorylation and activity of ACLY. Conversely, depletion of endogenous MORC2 via small interfering RNA significantly reduced ACLY phosphorylation and activity. Depletion of MORC2 in human breast cancer cells downregulated expression of genes encoding enzymes dependent on acetyl-CoA, such as HMGCR (142910), the first and rate-limiting enzyme in the mevalonate pathway. Morc2 expression increased with differentiation in mouse mammary gland and in 3T3-L1 mouse preadipocytes. Knockdown of Morc2 in 3T3-L1 cells interfered with adipogenic marker gene expression, lipid accumulation, and adipogenic differentiation. Sanchez-Solana et al. (2014) concluded that cytosolic MORC2 has a role in lipogenesis, adipogenic differentiation, and lipid homeostasis.
By coimmunoprecipitation and mass spectrometric analyses, Zhang et al. (2016) showed that ACLY interacted indirectly with CUL3 (603136) through KLHL25 (619893) to form a complex in human lung cancer H1299 cells. KLHL25 interacted directly with ACLY and functioned as a substrate adaptor to bridge ACLY to CUL3. CUL3-KLHL25 negatively regulated ACLY protein levels in cells through protein ubiquitination and degradation, and low CUL3 expression was associated with high ACLY expression in human lung cancer. Through negative regulation of ACLY, CUL3-KLHL25 reduced acetyl-CoA levels and inhibited lipid synthesis, which in turn contributed to the inhibitory effect of CUL3-KLHL25 on proliferation and anchorage-independent growth of lung cancer cells. In vivo analysis revealed that CUL3-KLHL25 inhibited growth of xenograft lung tumors in mice through negative regulation of ACLY.
Tian et al. (2021) found that Acly regulated differentiation of mouse inducible regulatory T cells (iTregs). Tgfb1 (190180) induced Acly downregulation through Cul3-Klhl25-mediated ubiquitination and degradation, which in turn facilitated iTreg differentiation. Analysis with human iTregs confirmed the conserved role of CUL3-KLHL25-mediated ACLY ubiquitination in iTreg differentiation. Analysis with a mouse inflammatory bowel disease (IBD; see 266600) model revealed an important role of Cul3-Klhl25-mediated Acly ubiquitination in colitis alleviation and in regulation of diarrhea.
Using in vivo isotope tracing, Zhao et al. (2020) showed that liver-specific deletion of Acly in mice is unable to suppress fructose-induced lipogenesis. Dietary fructose is converted to acetate by the gut microbiota, and this supplies lipogenic acetyl-CoA independently of Acly. Depletion of the microbiota or silencing of hepatic Acss2 (605832), which generates acetyl-CoA from acetate, potently suppresses the conversion of bolus fructose into hepatic acetyl-CoA and fatty acids. When fructose is consumed more gradually to facilitate its absorption in the small intestine, both citrate cleavage in hepatocytes and microorganism-derived acetate contribute to lipogenesis. By contrast, the lipogenic transcriptional program is activated in response to fructose in a manner that is independent of acetyl-CoA metabolism. Zhao et al. (2020) concluded that their data revealed a 2-pronged mechanism that regulates hepatic lipogenesis, in which fructolysis within hepatocytes provides a signal to promote the expression of lipogenic genes, and the generation of microbial acetate feeds lipogenic pools of acetyl-CoA.
Cryoelectron Microscopy
Wei et al. (2019) developed a series of low-nanomolar small-molecule inhibitors of human ACLY, and determined the structure of the full-length human ACLY homotetramer in complex with one of these inhibitors (NDI-091143) by cryoelectron microscopy. The structure revealed that the compound is located in an allosteric, mostly hydrophobic cavity next to the citrate-binding site, and requires extensive conformational changes in the enzyme that indirectly disrupt citrate binding. The observed binding mode was supported by and explained the structure-activity relationships of these compounds.
Crystal Structure
Verschueren et al. (2019) reported high-resolution crystal structures of bacterial, archaeal, and human ACLY, and used distinct substrate-bound states to link the conformational plasticity of ACLY to its multistep catalytic itinerary. The authors concluded that such detailed insights will provide the framework for targeting human ACLY in cancer and hyperlipidemia. Their structural studies also unmasked a fundamental evolutionary relationship that links citrate synthase, the first enzyme of the oxidative Krebs cycle, to an ancestral tetrameric citryl-CoA lyase module that operates in the reverse Krebs cycle. Verschueren et al. (2019) concluded that this molecular transition marked a key step in the evolution of metabolism on Earth.
Remmers et al. (1992) found that the genes for growth hormone (139250), pancreatic polypeptide (167780), ERBB2 (164870), sex hormone binding globulin (182205), embryonic skeletal myosin heavy chain (160720), and asialoglycoprotein receptor (108360) map to human chromosome 17 and rat chromosome 10. Many of the same genes are known to be located on mouse chromosome 11. Furthermore, Remmers et al. (1992) showed that in the rat the gene for ATP citrate lyase is closely linked to the gene for PPY, which in turn is close to the GH gene, on chromosome 10. They predicted, therefore, that the homologous gene in the human would be located on chromosome 17, probably close to PPY which is situated at 17q22-q24. Couch et al. (1994) mapped the ACLY gene to 17q12-q21 by PCR analysis of a panel of human/rodent somatic cell hybrids and localized it to 17q21.1 by PCR on a panel of radiation hybrids. The radiation hybrid panel indicated that the most likely position of ACLY on 17q21.1 is between gastrin (137250) and D17S856 at a distance of 170 to 290 kb from the GAS locus.
Couch, F. J., Abel, K. J., Brody, L. C., Boehnke, M., Collins, F. S., Weber, B. L. Localization of the gene for ATP citrate lyase (ACLY) distal to gastrin (GAS) and proximal to D17S856 on chromosome 17q12-q21. Genomics 21: 444-446, 1994. [PubMed: 8088842] [Full Text: https://doi.org/10.1006/geno.1994.1293]
Elshourbagy, N. A., Near, J. C., Kmetz, P. J., Sathe, G. M., Southan, C., Strickler, J. E., Gross, M., Young, J. F., Wells, T. N. C., Groot, P. H. E. Rat ATP citrate-lyase: molecular cloning and sequence analysis of a full-length cDNA and mRNA abundance as a function of diet, organ, and age. J. Biol. Chem. 265: 1430-1435, 1990. [PubMed: 2295639]
Elshourbagy, N. A., Near, J. C., Kmetz, P. J., Wells, T. N. C., Groot, P. H. E., Saxty, B. A., Hughes, S. A., Franklin, M., Gloger, I. S. Cloning and expression of a human ATP-citrate lyase cDNA. Europ. J. Biochem. 204: 491-499, 1992. [PubMed: 1371749] [Full Text: https://doi.org/10.1111/j.1432-1033.1992.tb16659.x]
Remmers, E. F., Goldmuntz, E. A., Cash, J. M., Crofford, L. J., Misiewicz-Poltorak, B., Zha, H., Wilder, R. L. Genetic map of nine polymorphic loci comprising a single linkage group on rat chromosome 10: evidence for linkage conservation with human chromosome 17 and mouse chromosome 11. Genomics 14: 618-623, 1992. [PubMed: 1358809] [Full Text: https://doi.org/10.1016/s0888-7543(05)80160-0]
Sanchez-Solana, B., Li, D.-Q., Kumar, R. Cytosolic functions of MORC2 in lipogenesis and adipogenesis. Biochim. Biophys. Acta 1843: 316-326, 2014. [PubMed: 24286864] [Full Text: https://doi.org/10.1016/j.bbamcr.2013.11.012]
Sul, H. S., Wise, L. S., Brown, M. L., Rubin, C. S. Cloning of cDNA sequences for murine ATP-citrate lyase: construction of recombinant plasmids using an immunopurified mRNA template and evidence for the nutritional regulation of ATP-citrate lyase mRNA content in mouse liver. J. Biol. Chem. 259: 1201-1205, 1984. [PubMed: 6546379]
Tian, M., Hao, F., Jin, X., Sun, X., Jiang, Y., Wang, Y., Li, D., Chang, T., Zou, Y., Peng, P., Xia, C., Liu, J., Li, Y., Wang, P., Feng, Y., Wei, M. ACLY ubiquitination by CUL3-KLHL25 induces the reprogramming of fatty acid metabolism to facilitate iTreg differentiation. eLife 10: e62394, 2021. [PubMed: 34491895] [Full Text: https://doi.org/10.7554/eLife.62394]
Verschueren, K. H. G., Blanchet, C., Felix, J., Dansercoer, A., De Vos, D., Bloch, Y., Van Beeumen, J., Svergun, D., Gutsche, I., Savvides, S. N., Verstraete, K. Structure of ATP citrate lyase and the origin of citrate synthase in the Krebs cycle. Nature 568: 571-575, 2019. [PubMed: 30944476] [Full Text: https://doi.org/10.1038/s41586-019-1095-5]
Wei, J., Leit, S., Kuai, J., Therrien, E., Rafi, S., Harwood, H. J., Jr., DeLaBarre, B., Tong, L. An allosteric mechanism for potent inhibition of human ATP-citrate lyase. Nature 568: 566-570, 2019. [PubMed: 30944472] [Full Text: https://doi.org/10.1038/s41586-019-1094-6]
Wellen, K. E., Hatzivassiliou, G., Sachdeva, U. M., Bui, T. V., Cross, J. R., Thompson, C. B. ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324: 1076-1080, 2009. [PubMed: 19461003] [Full Text: https://doi.org/10.1126/science.1164097]
Zhang, C., Liu, J., Huang, G., Zhao, Y., Yue, X., Wu, H., Li, J., Zhu, J., Shen, Z., Haffty, B. G., Hu, W., Feng, Z. Cullin3-KLHL25 ubiquitin ligase targets ACLY for degradation to inhibit lipid synthesis and tumor progression. Genes Dev. 30: 1956-1970, 2016. [PubMed: 27664236] [Full Text: https://doi.org/10.1101/gad.283283.116]
Zhao, S., Jang, C., Liu, J., Uehara, K., Gilbert, M., Izzo, L., Zeng, X., Trefely, S., Fernandez, S., Carrer, A., Miller, K. D., Schug, Z. T., Snyder, N. W., Gade, T. P., Titchenell, P. M., Rabinowitz, J. D., Wellen, K. E. Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate. Nature 579: 586-591, 2020. [PubMed: 32214246] [Full Text: https://doi.org/10.1038/s41586-020-2101-7]