Alternative titles; symbols
HGNC Approved Gene Symbol: ACACA
Cytogenetic location: 17q12 Genomic coordinates (GRCh38): 17:37,084,992-37,406,836 (from NCBI)
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
---|---|---|---|---|
17q12 | Acetyl-CoA carboxylase deficiency | 613933 | Autosomal recessive | 3 |
The ACACA gene encodes the alpha form of acetyl-CoA carboxylase (ACC; EC 6.4.1.2), a human biotin-dependent enzyme that catalyzes the rate-limiting reaction in long-chain fatty acid biosynthesis (summary by Lopez-Casillas et al., 1988).
See also acetyl-CoA carboxylase-beta (ACACB; 601557).
In the rat, the ACC enzyme is a polymer of identical subunits (Tanabe et al., 1975). Lopez-Casillas et al. (1988) reported the structure of the coding sequence and the primary amino acid sequence of the rat acetyl-CoA carboxylase.
Abu-Elheiga et al. (1995) cloned and sequenced the cDNA coding for acetyl-CoA carboxylase of the human HepG2 cell line. The deduced protein contained 2,346 amino acids. The C-terminal 2.6-kb sequence was very different from that reported for human ACC by Ha et al. (1994). Northern blot analysis revealed that the ACC mRNA is approximately 10 kb long and that its expression level varies among the tissues tested.
By RNase protection assay, Travers et al. (2005) found Acaca expression in all mouse tissues examined. Expression from the PI promoter was abundant in brain and spinal column only. RT-PCR of human tissues showed highest expression of ACACA from the PI promoter in brain.
Abu-Elheiga et al. (2000) demonstrated that ACC-alpha is a cytosolic protein, whereas ACC-beta (ACACB; 601557) is associated with the mitochondria. Consistent with the practice of referring to the cytosolic and mitochondrial isoforms of enzymes as 1 and 2, respectively, they symbolized the cytosolic form ACC1 and the mitochondrial form ACC2.
During fasting, increased concentrations of circulating catecholamines promote the mobilization of lipid stores from adipose tissue in part by phosphorylating and inactivating ACC, the rate-limiting enzyme in fatty acid synthesis. Qi et al. (2006) described a parallel pathway, in which the pseudokinase TRB3 (TRIB3; 607898), whose abundance is increased during fasting, stimulates lipolysis by triggering the degradation of ACC in adipose tissue. TRB3 promoted ACC ubiquitination through an association with the E3 ubiquitin ligase constitutive photomorphogenic protein-1 (COP1; 608067). Indeed, Qi et al. (2006) found that adipocytes deficient in TRB3 accumulated larger amounts of ACC protein than did wildtype cells. Because transgenic mice expressing TRB3 in adipose tissue are protected from diet-induced obesity due to enhanced fatty acid oxidation, Qi et al. (2006) concluded that their results demonstrated how phosphorylation and ubiquitination pathways converge on a key regulator of lipid metabolism to maintain energy homeostasis.
In studies in rats, Gao et al. (2007) observed that intracerebroventricular (ICV) injection of leptin (164160) inhibited AMPK (see 600497) while concomitantly activating ACC in the arcuate and paraventricular nuclei of the hypothalamus. In the arcuate nucleus, overexpression of constitutively active AMPK prevented arcuate ACC activation in response to ICV leptin, and inhibition of hypothalamic ACC with 5-tetradecyloxy-2-furoic acid (TOFA) blocked leptin-mediated decreases in food intake, body weight, and mRNA level of the orexigenic neuropeptide NPY (162640), demonstrating that hypothalamic ACC makes an important contribution to leptin's anorectic effects. ICV leptin also upregulated arcuate nucleus levels of malonyl-CoA and periventricular nucleus levels of palmitoyl-CoA, and the increase in both was blocked by TOFA, which also blocked leptin-mediated hypophagia. Gao et al. (2007) suggested that whereas malonyl-CoA is a downstream mediator of ACC in the leptin signaling pathway in the arcuate nucleus, palmitoyl-CoA might be an effector in relaying ACC signaling in the periventricular nucleus, thus highlighting site-specific impacts of hypothalamic ACC activation in the leptin anorectic signaling cascade.
ACC activity is regulated by phosphorylation status, transcription, and polymerization. Citrate, the acetyl-CoA precursor, induces ACC tetramerization and activation. By coimmunoprecipitation analysis of mouse liver, Kim et al. (2010) detected binding between ACC and Mig12 (MID1IP1; 300961). Interaction of Mig12 with Acc1 induced Acc1 polymerization in the presence or absence of citrate and lowered the concentration of citrate required for Acc1 half-maximal activity. With Acc2, Mig12 also induced polymerization and increased enzyme activity, but only in the presence of citrate. Gel filtration, followed by mass spectrometric analysis, revealed that Mig12 was incorporated into Acc1 polymers with a 1:1 stoichiometry and into Acc2 polymers with an approximately 2:1 stoichiometry.
Jeon et al. (2012) demonstrated that AMPK (see 602739) activation, during energy stress, prolongs cell survival by redox regulation. Under these conditions, NADPH generation by the pentose phosphate pathway is impaired, but AMPK induces alternative routes to maintain NADPH and inhibit cell death. The inhibition of the acetyl-CoA carboxylases ACC1 and ACC2 (601557) by AMPK maintains NADPH levels by decreasing NADPH consumption in fatty acid synthesis and increasing NADPH generation by means of fatty acid oxidation. Knockdown of either ACC1 or ACC2 compensates for AMPK activation and facilitates anchorage-independent growth and solid tumor formation in vivo, whereas the activation of ACC1 or ACC2 attenuates these processes. Thus AMPK, in addition to its function in ATP homeostasis, has a key function in NADPH maintenance, which is critical for cancer cell survival under energy stress conditions, such as glucose limitations, anchorage-independent growth, and solid tumor formation in vivo.
Crystal Structure
Zhang et al. (2003) determined the crystal structure of the free enzyme and the coenzyme A complex of yeast carboxyltransferase at 2.7-angstrom resolution and found that it comprises 2 domains, both belonging to the crotonase/ClpP superfamily. The active site is at the interface of a dimer. Mutagenesis and kinetic studies revealed the functional roles of conserved residues here.
Cryoelectron Microscopy
Hunkeler et al. (2018) identified distinct activated and inhibited ACC1 filament forms and obtained cryoelectron microscopy structures of an activated filament that is allosterically induced by citrate (ACC-citrate), and an inactivated filament form that results from binding of the BRCA1 (113705) protein. While nonpolymeric ACC1 is highly dynamic, filament formation locks ACC1 into different catalytically competent or incompetent conformational states. Hunkeler et al. (2018) concluded that this unique mechanism of enzyme regulation via large-scale conformational changes observed in ACC1 has potential uses in engineering of switchable biosynthetic systems.
Abu-Elheiga et al. (1995) presented evidence that the human ACC gene spans 200 to 480 kb.
Mao et al. (2003) identified 64 exons, including 7 alternatively spliced minor exons, in the human ACC1 gene (approximately 330 kb). The gene was found to be regulated by 3 promoters (PI, PII, and PIII), which are located upstream of exons 1, 2, and 5A, respectively. PI is a constitutive promoter and has no homology with the PI sequences of other mammalian ACC1 genes. PII is regulated by various hormones. PIII is expressed in a tissue-specific manner. The presence of several alternatively spliced exons does not alter the translation of the 265-kD ACC1 protein starting from an ATG present in exon 5. Translation of PIII transcripts from exon 5A generated a 259-kD isoform in which the N-terminal 75 amino acids of the 265-kD ACC1 were replaced with a new sequence of 17 amino acids. The inclusion of exon 5B between 5A and 6 in PIII transcripts would yield a third 257-kD isoform, which is translated from an ATG in exon 6. However, the presence of exon 5B in PI and PII transcripts leads to an in-frame stop codon that results in an ACC1-related 77-amino acid peptide.
Travers et al. (2005) determined that the ACACA and TADA2L (602276) genes are oriented in a head-to-head fashion. The intergenic region, which is embedded within a CpG island, contains 2 promoters and exon 1 of the TADA2L gene and the first promoter and exon 1 of the ACACA gene. The shared promoter contains an AP2 (107580) motif, but no TATA or CCAAT boxes. Travers et al. (2005) showed that the bidirectional promoter was functional, and it regulated transcription of the 2 genes in an asymmetric fashion in mouse and human tissues. Regulation occurred in the recruitment of RNA polymerase II (see 180660) to the promoter and possibly in the clearance of elongating complexes. Travers et al. (2005) found that activity of the ACACA PII promoter could also coordinate expression of TADA2L mRNA in human tissues.
By in situ hybridization, Milatovich et al. (1988) assigned the ACC locus to chromosome 17q21, proximal to 17q21.33.
By fluorescence in situ hybridization, Abu-Elheiga et al. (1995) mapped the ACC gene to 17q12. They also provided evidence for the presence of another ACC-like gene with similarly sized mRNA but with different tissue-specific expression. The gene they reported had a relative molecular mass of approximately 265 kD. Others had reported a 280-kD form of ACC, and indeed, had assigned the ACC gene to a more distal site, 17q21 (Milatovich et al., 1988).
In a Chinese girl, born to nonconsanguineous parents, with acetyl-CoA carboxylase-alpha deficiency (ACACAD; 613933), Lou et al. (2021) identified compound heterozygous mutations in the ACACA gene (A1680T, 200350.0001 and R2161W, 200350.0002). Each parent was heterozygous for one of the mutations, which were identified by whole-exome sequencing and confirmed by Sanger sequencing. In patient lymphoblasts, ACACA gene expression was similar to that in controls, but protein levels and enzyme activity levels were decreased. From a functional standpoint, apoptosis and cell proliferation in patient lymphoblasts were unchanged from control cells, but cell motility capacity was impaired.
In an Iranian boy, born to consanguineous parents, with acetyl-CoA carboxylase-alpha deficiency, Shafieipour et al. (2023) identified a homozygous mutation (P2214H; 200350.0003) in the ACACA gene. The parents were heterozygous for the mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing.
Abu-Elheiga et al. (2005) found that deletion of Acc1 in mice was embryonic lethal. Knockout embryos were undeveloped at embryonic day 7.5 and died by embryonic day 8.5. In contrast, heterozygous mutants (Acc1 +/-) had normal fertility and life spans and maintained a body weight similar to that of their wildtype cohorts. The mRNA level of Acc1 in tissues of Acc1 +/- mice was half that of wildtype mice; however, the protein level of Acc1 and the total malonyl-CoA level were similar. In addition, there was no difference in acetate incorporation into fatty acids or in fatty acid oxidation between hepatocytes of Acc1 +/- mice and those of wildtype mice.
Mao et al. (2006) generated mice with a targeted deletion of liver Acc1. The mutant mice had no obvious health problems under normal feeding conditions, but their livers had 70 to 75% lower total Acc and malonyl-CoA levels and accumulated 40 to 70% less triglycerides than wildtype. On a fat-free diet, there was significant upregulation of Pparg (601487) and other lipogenic enzymes in the livers of mutant mice compared to wildtype, including a 2-fold increase in fatty acid synthase (FASN; 600212) mRNA, protein, and activity. Despite this upregulation, there was significant decrease in de novo fatty acid synthesis and triglyceride accumulation in the liver; however, there were no significant changes in blood glucose and fasting ketone body levels. Mao et al. (2006) concluded that reducing cytosolic malonyl-CoA and, therefore, de novo fatty acid synthesis in the liver, does not affect fatty acid oxidation and glucose homeostasis under lipogenic conditions.
In a Chinese girl with acetyl-CoA carboxylase-alpha deficiency (ACACAD; 613933), who had developmental delay, hypotonia, and dysmorphic facial features, Lou et al. (2021) identified compound heterozygous mutations in the ACACA gene, a c.4858G-A transition (c.4858G-A, NM_198839), resulting in an ala1680-to-thr (A1680T) substitution, and a c.6481C-T transition, resulting in an arg2161-to-trp (R2161W; 200350.0002) substitution. The mutations, which were identified by whole-exome sequencing and confirmed by Sanger sequencing, were identified in the carrier state in the parents. The mutations were not present in the dbSNP, 1000 Genomes Project, and gnomAD databases. In patient lymphoblasts, ACACA gene expression was similar to that in controls, but protein levels and enzyme activity levels were decreased. From a functional standpoint, apoptosis and cell proliferation in patient lymphoblasts were unchanged from control cells, but cell motility capacity was impaired. Lipid analysis in patient cells demonstrated comparable levels of palmitic acid, phosphatidylinositol, and phosphatidylserine in patient lymphoblasts to those in controls, but decreased levels of phosphatidylglycerol, phosphatidylcholine, and phosphatidylethanolamine.
For discussion of the c.6481C-T transition (c.6481C-T, NM_198839) in the ACACA gene, resulting in an arg2161-to-trp (R2161W) substitution, that was identified in compound heterozygous state in a patient with acetyl-CoA carboxylase-alpha deficiency (ACACAD; 613933) by Lou et al. (2021), see 200350.0001.
In an Iranian boy, born to consanguineous parents, with acetyl-CoA carboxylase-alpha deficiency (ACACAD; 613933), Shafieipour et al. (2023) identified homozygosity for a c.6641C-A transversion (c.6641C-A, NM_198834.3) in the ACACA gene, resulting in a pro2214-to-his (P2214H) substitution. The parents were heterozygous for the mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies in patient cells were not performed.
Abu-Elheiga, L., Brinkley, W. R., Zhong, L., Chirala, S. S., Woldegiorgis, G., Wakil, S. J. The subcellular localization of acetyl-CoA carboxylase 2. Proc. Nat. Acad. Sci. 97: 1444-1449, 2000. [PubMed: 10677481] [Full Text: https://doi.org/10.1073/pnas.97.4.1444]
Abu-Elheiga, L., Jayakumar, A., Baldini, A., Chirala, S. S., Wakil, S. J. Human acetyl-CoA carboxylase: characterization, molecular cloning, and evidence for two isoforms. Proc. Nat. Acad. Sci. 92: 4011-4015, 1995. [PubMed: 7732023] [Full Text: https://doi.org/10.1073/pnas.92.9.4011]
Abu-Elheiga, L., Matzuk, M. M., Kordari, P., Oh, W., Shaikenov, T., Gu, Z., Wakil, S. J. Mutant mice lacking acetyl-CoA carboxylase 1 are embryonically lethal. Proc. Nat. Acad. Sci. 102: 12011-12016, 2005. [PubMed: 16103361] [Full Text: https://doi.org/10.1073/pnas.0505714102]
Gao, S., Kinzig, K. P., Aja, S., Scott, K. A., Keung, W., Kelly, S., Strynadka, K., Chohnan, S., Smith, W. W., Tamashiro, K. L. K., Ladenheim, E. E., Ronnett, G. V., Tu, Y., Birnbaum, M. J., Lopaschuk, G. D., Moran, T. H. Leptin activates hypothalamic acetyl-CoA carboxylase to inhibit food intake. Proc. Nat. Acad. Sci. 104: 17358-17363, 2007. [PubMed: 17956983] [Full Text: https://doi.org/10.1073/pnas.0708385104]
Ha, J., Daniel, S., Kong, I.-S., Park, C.-K., Tae, H.-J., Kim, K.-H. Cloning of human acetyl-CoA carboxylase cDNA. Europ. J. Biochem. 219: 297-306, 1994. [PubMed: 7905825] [Full Text: https://doi.org/10.1111/j.1432-1033.1994.tb19941.x]
Ha, J., Lee, J.-K., Kim, K.-S., Witters, L. A., Kim, K.-H. Cloning of human acetyl-CoA carboxylase-beta and its unique features. Proc. Nat. Acad. Sci. 93: 11466-11470, 1996. [PubMed: 8876158] [Full Text: https://doi.org/10.1073/pnas.93.21.11466]
Hunkeler, M., Hagmann, A., Stuttfeld, E., Chami, M., Guri, Y., Stahlberg, H., Maier, T. Structural basis for regulation of human acetyl-CoA carboxylase. Nature. 558: 470-474, 2018. [PubMed: 29899443] [Full Text: https://doi.org/10.1038/s41586-018-0201-4]
Jeon, S.-M., Chandel, N. S., Hay, N. AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature 485: 661-665, 2012. [PubMed: 22660331] [Full Text: https://doi.org/10.1038/nature11066]
Kim, C.-W., Moon, Y.-A., Park, S. W., Cheng, D., Kwon, H. J., Horton, J. D. Induced polymerization of mammalian acetyl-CoA carboxylase by MIG12 provides a tertiary level of regulation of fatty acid synthesis. Proc. Nat. Acad. Sci. 107: 9626-9631, 2010. [PubMed: 20457939] [Full Text: https://doi.org/10.1073/pnas.1001292107]
Lopez-Casillas, F., Bai, D.-H., Luo, X., Kong, I.-S., Hermodson, M. A., Kim, K.-H. Structure of the coding sequence and primary amino acid sequence of acetyl-coenzyme A carboxylase. Proc. Nat. Acad. Sci. 85: 5784-5788, 1988. [PubMed: 2901088] [Full Text: https://doi.org/10.1073/pnas.85.16.5784]
Lou, X., Zhou, X., Li, H., Lu, X., Bao, X., Yang, K., Liao, X., Chen, H., Fang, H., Yang, Y., Lyu, J., Zheng, H. Biallelic mutations in ACACA cause a disruption in lipid homeostasis that is associated with global developmental delay, microcephaly, and dysmorphic facial features. Front. Cell Dev. Biol. 9: 618492, 2021. [PubMed: 34552920] [Full Text: https://doi.org/10.3389/fcell.2021.618492]
Mao, J., Chirala, S. S., Wakil, S. J. Human acetyl-CoA carboxylase 1 gene: presence of three promoters and heterogeneity at the 5-prime-untranslated mRNA region. Proc. Nat. Acad. Sci. 100: 7515-7520, 2003. [PubMed: 12810950] [Full Text: https://doi.org/10.1073/pnas.1332670100]
Mao, J., DeMayo, F. J., Li, H., Abu-Elheiga, L., Gu, Z., Shaikenov, T. E., Kordari, P., Chirala, S. S., Heird, W. C., Wakil, S. J. Liver-specific deletion of acetyl-CoA carboxylase 1 reduces hepatic triglyceride accumulation without affecting glucose homeostasis. Proc. Nat. Acad. Sci. 103: 8552-8557, 2006. [PubMed: 16717184] [Full Text: https://doi.org/10.1073/pnas.0603115103]
Milatovich, A., Plattner, R., Heerema, N. A., Palmer, C. G., Lopez-Casillas, F., Kim, K.-H. Localization of the gene for acetyl-CoA carboxylase to human chromosome 17. Cytogenet. Cell Genet. 48: 190-192, 1988. [PubMed: 2906852] [Full Text: https://doi.org/10.1159/000132623]
Qi, L., Heredia, J. E., Altarejos, J. Y., Screaton, R., Goebel, N., Niessen, S., MacLeod, I. X., Liew, C. W., Kulkarni, R. N., Bain, J., Newgard, C., Nelson, M., Evans, R. M., Yates, J., Montminy, M. TRB3 links the E3 ubiquitin ligase COP1 to lipid metabolism. Science 312: 1763-1766, 2006. [PubMed: 16794074] [Full Text: https://doi.org/10.1126/science.1123374]
Shafieipour, N., Jafari Khamirani, H., Kamal, N., Tabei, S. M. B., Dianatpour, M., Dastgheib, S. A. The third patient of ACACA-related acetyl-CoA carboxylase deficiency with seizure and literature review. Europ. J. Med. Genet. 66: 104707, 2023. [PubMed: 36709796] [Full Text: https://doi.org/10.1016/j.ejmg.2023.104707]
Tanabe, T., Wada, K., Azaki, T., Numa, S. Acetyl-coenzyme-A carboxylase from rat liver. Europ. J. Biochem. 57: 15-24, 1975. [PubMed: 240717] [Full Text: https://doi.org/10.1111/j.1432-1033.1975.tb02272.x]
Travers, M. T., Cambot, M., Kennedy, H. T., Lenoir, G. M., Barber, M. C., Joulin, V. Asymmetric expression of transcripts derived from the shared promoter between the divergently oriented ACACA and TADA2L genes. Genomics 85: 71-84, 2005. [PubMed: 15607423] [Full Text: https://doi.org/10.1016/j.ygeno.2004.10.001]
Zhang, H., Yang, Z., Shen, Y., Tong, L. Crystal structure of the carboxyltransferase domain of acetyl-coenzyme A carboxylase. Science 299: 2064-2067, 2003. [PubMed: 12663926] [Full Text: https://doi.org/10.1126/science.1081366]