Alternative titles; symbols
HGNC Approved Gene Symbol: CES1
Cytogenetic location: 16q12.2 Genomic coordinates (GRCh38): 16:55,802,851-55,833,096 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16q12.2 | Drug metabolism, altered, CES1-related | 618057 | Autosomal dominant | 3 |
Mammalian liver carboxylesterases (CESs; EC 3.1.1.1) hydrolyze various xenobiotics and endogenous substrates with ester, thioester, or amide bonds and are thought to function mainly in drug metabolism and detoxication of harmful chemicals (Satoh, 1987). CES1 is also responsible for hydrolysis of stored cholesterol esters in macrophage foam cells and release of free cholesterol for high density lipoprotein-mediated cholesterol efflux (Ghosh and Natarajan, 2001).
Riddles et al. (1991) cloned a human liver carboxylesterase-encoding cDNA using synthetic oligodeoxyribonucleotides based on the known amino acid sequences of rabbit and rat liver CESs. Shibata et al. (1993) isolated a cDNA encoding a human liver carboxylesterase and its corresponding gene, CES1. The deduced 567-amino acid protein contains a putative 18-amino acid signal peptide and a characteristic C-terminal endoplasmic reticulum retention signal (HXEL).
Ketterman et al. (1989) presented evidence for 2 CESs from human liver by kinetic analysis of purified enzyme (see CES2, 605278).
In mammalian cells, the level of free cholesterol is regulated by control of de novo synthesis, receptor-mediated cholesterol uptake, and esterification of free cholesterol with long-chain fatty acids. Cholesterol esterification is catalyzed by acyl coenzyme A:cholesterol acyltransferase (ACAT2; 601311), a microsomal enzyme that preferentially uses oleoyl-CoA and cholesterol as substrates. Becker et al. (1994) purified an enzyme with ACAT activity from porcine liver and determined that it was identical to porcine liver carboxylesterase. These authors found that the homologous human gene was identical to human liver carboxylesterase, but shared no similarity with SOAT1 (102642), a gene encoding another human enzyme with ACAT activity. The predicted 561-amino acid ACAT/carboxylesterase protein contains a leader sequence, a putative membrane-spanning domain, an endoplasmic reticulum retention signal, and the consensus active site sequence of serine esterases. Northern blot analysis indicated that the 1.8-kb ACAT/carboxylesterase mRNA is induced by cholesterol loading.
Becker-Follmann et al. (1991) cloned one of the monocyte serine esterase variants, which they designated SES1 but which was later designated CES1 by HGM11. The deduced amino acid sequence of 503 residues showed up to 78% identity with other serine esterases of different species.
Ghosh (2000) cloned CEH from a human macrophage cDNA library. The deduced 567-amino acid protein contains the conserved catalytic triad (ser221, his468, and glu354) and SEDCLY motif of carboxylesterases. Northern blot analysis detected a 2.2-kb CEH transcript in primary human monocytes and in a macrophage cell line.
Shibata et al. (1993) determined that the CES1 gene contains 14 small exons and spans approximately 30 kb. The organization of the gene supported the conclusion that the multiple carboxylesterases evolved from a common ancestral gene.
Ghosh and Natarajan (2001) identified a CAAT box, a GC-rich sequence, several SP1 (189906)-binding sites, and 3 putative peroxisome proliferator response elements (PPREs) in the promoter region of the CES1 gene.
Stage et al. (2017) stated that 4 major haplotypes have been reported in the CES1 gene. Various combinations of the haplotypes give rise to 3 different diplotypes with 2, 3, or 4 copies of CES1. Two of the haplotypes contain a CES1-related pseudogene (CES1P1, also known as CES1A3, which has 6 exons). CES1 is subject to duplication, and the duplicated CES1 variant is called CES1A2, while the original CES1 copy is called CES1A1. The promoter region, exon 1 and the first part of intron 1 in CES1A2 are homologous to CES1P1, but apart from these regions, CES1A1 and CES1A2 are identical. A number of CES1A2 haplotypes exist, but the most common is the variant with the CES1P1 promoter, which is transcribed to a lesser extent than CES1A1. There are also isoforms of CES1A1, including a variant designated CES1A1c by Tanimoto et al. (2007), in which exon 1 with flanking sequences is replaced by the corresponding sequences of CES1P1; the CES1P1 segment may affect initiation of translation.
By Southern blot analysis of DNA from mouse/human somatic cell hybrids representing various breakpoints on human chromosome 16, Becker-Follmann et al. (1991) assigned the CES1 gene to 16q13-q22.1. Leukocyte esterase B3 (ESB3; 133290) had previously been mapped to chromosome 16. Both CES1 and ESB3 accept alpha-naphthylbutyrate or acetate as substrates; however, it was not clear whether these were identical esterases. The homologous gene was mapped to mouse chromosome 8.
Lehner and Verger (1997) purified and characterized porcine liver microsomal triacylglycerol hydrolase (CES1). They presented evidence indicating that CES1 is involved in hepatic very low density lipoprotein synthesis.
Ghosh (2000) found that human CEH showed dose-dependent cholesterol ester hydrolase activity in transfected COS cells. Overexpression of CEH in Chinese hamster ovary cells impaired upregulation of low density lipoprotein receptor (LDLR; 606945) mRNA when cells were grown in a cholesterol-deficient environment.
Using CEH deletion constructs and reporter genes transfected into COS-7 cells, Ghosh and Natarajan (2001) identified positive cis-acting and repressor elements in the promoter region of human CEH. CEH promoter activity was downregulated in the presence of PPARA (170998) and PPARG (601487) ligands, and the downregulation was dependent upon PPREs in the CEH promoter region. Decreased promoter activity was also observed in the presence of the RXR (see 180245) ligand 9-cis-retinoic acid.
In studies in mice, Soni et al. (2004) found that carboxylesterase-3, which is the homolog of human carboxylesterase-1, accounts for a major fraction of hormone-sensitive lipase (HSL) triglyceride hydrolase activity in white adipose tissue and may mediate some or all HSL-independent lipolysis in adipocytes.
Using steady state kinetic studies, Sanghani et al. (2004) determined that the carboxylesterases CES1A1, CES2, and CES3 (605279) could metabolize CPT-11 (irinotecan) and its oxidative metabolites 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxycamptothecin (APC), and 7-ethyl-10-[4-(1-piperidino)-1-amino]-carbonyloxycamptothecin (NPC) to the active metabolite SN-38, a potent topoisomerase I inhibitor. CES2 showed the highest catalytic activity for all 3 substrates and CES3 showed the lowest.
During the course of a pharmacokinetic study of methylphenidate (MPH), which is widely used to treat attention-deficit/hyperactivity disorder (ADHD; 143465), Zhu et al. (2008) observed profoundly elevated MPH concentrations, distorted isomer dispositions, and increases in hemodynamic measures in a Caucasian male of European descent who had a concentration-versus-time profile suggestive of a metabolic deficiency in CES1. DNA sequencing revealed compound heterozygosity for mutations (G143E; 114835.0001 and 114835.0002) in the CES1 gene. In vitro functional studies demonstrated substantial impairment of catalytic function for both variants. Zhu et al. (2008) concluded that specific CES1 gene variants can lead to clinically significant alterations in pharmacokinetics and drug responses of carboxylesterase-1 substrates.
Using several incubation studies, Shi et al. (2016) showed that the prodrug sacubitril is a selective CES1 substrate. In vitro transfection studies showed that the CES1 G143E variant is a loss-of-function variant for sacubitril activation. Sacubitril activation was significantly impaired in human livers carrying the G143E variant.
Stage et al. (2017) studied the impact of CES1 variation on the pharmacogenetics of methylphenidate in 44 healthy Danish individuals, grouped according to number of CES1 copies (2, 3, or 4), presence of the G143E allele, and presence of the CES1A1c variant. They found that mean area under the curve (AUC) of methylphenidate was significantly larger in the group with the G143E allele and the group with homozygous duplication of the CES1 gene compared to that in the control group, suggesting a significantly decreased CES1 enzyme activity.
Zhao et al. (2007) generated transgenic mice with macrophage-specific overexpression of human CES1 crossed into an Ldlr (606945) -/- background and found that these mice had significant reduction in the lesion area and cholesterol content of high-fat, high-cholesterol diet-induced atherosclerotic lesions. The lesions did not have increased free cholesterol, were less necrotic, and contained significantly higher numbers of viable macrophage foam cells. There was higher CES1-mediated free cholesterol efflux of free cholesterol from macrophages to gallbladder bile and feces in vivo. Zhao et al. (2007) concluded that by enhancing cholesterol efflux and reverse cholesterol transport, macrophage-specific overexpression of CES1 is antiatherogenic.
Mori et al. (1999) reported the cloning of human CES3, which they called Br3; however, the sequence they reported actually matched mouse Ces3, which is the homolog of human CES1.
In a Caucasian male of European descent participating in a study of the pharmacokinetics of methylphenidate (see 618057), who displayed a highly unusual concentration-versus-time profile suggestive of a metabolic deficiency in CES1, Zhu et al. (2008) identified compound heterozygosity for a 428G-A transition in exon 4 of the CES1 gene, resulting in a gly143-to-glu (G143E) substitution, and a 1-bp deletion (780delT; 114835.0002) in exon 6 of CES1, resulting in a frameshift and premature termination. His father was heterozygous for G143E and his mother for 780delT. In vitro functional studies demonstrated that the catalytic functions of both G143E and 780delT are substantially impaired, with a complete loss of hydrolytic activity toward methylphenidate and only 12.4% and 0.6% catalytic efficiency, respectively, toward the more sensitive substrate p-nitrophenyl acetate.
In a study of the G143E variant in 455 white, 117 black, 299 Hispanic, and 45 Asian individuals, Zhu et al. (2008) found a minor allele frequency of 3.7%, 4.3%, 2.0%, and 0% in these populations, respectively. The 1-bp deletion was not found in 925 DNA samples examined.
Lewis et al. (2013) genotyped the CES1 G143E variant in the 566 participants of the Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study and in 350 patients with coronary heart disease treated with clopidogrel. The levels of clopidogrel active metabolite were significantly greater in G143E allele carriers (p = 00.1). Individuals who carried this allele showed a better clopidogrel response as measured by ADP-stimulated platelet aggregation in participants of the PAPI study (p = 0.003) as well as in clopidogrel-treated coronary heart disease patients (p = -.03).
Using several incubation studies, Shi et al. (2016) showed that the prodrug sacubitril is a selective CES1 substrate. In vitro transfection studies showed that the CES1 G143E variant is a loss-of-function variant for sacubitril activation. Sacubitril activation was significantly impaired in human livers carrying the G143E variant.
Using several in vitro approaches, Shi et al. (2016) showed that activation of the oral anticoagulant prodrug dabigatran etexilate (DABE) and its intermediate metabolites M1 And M2 were impaired in human livers carrying the G143E variant. An incubation study of DABE with supernatant fractions (S9) prepared from the G143E-transfected cells showed that the G143E is a loss-of-function variant for DABE metabolism. In addition, hepatic CES1 activity on M2 activation was significantly higher in female than in male liver samples.
For discussion of the 1-bp deletion in the CES1 gene (780delT) that was found in compound heterozygous state in a patient treated with methylphenidate (see 618057) by Zhu et al. (2008), see 114835.0001.
Becker, A., Bottcher, A., Lackner, K. J., Fehringer, P., Notka, F., Aslanidis, C., Schmitz, G. Purification, cloning, and expression of a human enzyme with acyl coenzyme A:cholesterol acyltransferase activity, which is identical to liver carboxylesterase. Arterioscler. Thromb. 14: 1346-1355, 1994. [PubMed: 8049197] [Full Text: https://doi.org/10.1161/01.atv.14.8.1346]
Becker-Follmann, J., Zschunke, F., Parwaresch, M. R., Radzun, H. J., Scherer, G. Assignment of human monocyte/macrophage serine esterase 1 (HMSE1) to human chromosome 16q13-q22.1 and of its homologue to the proximal esterase cluster on mouse chromosome 8. (Abstract) Cytogenet. Cell Genet. 58: 1997 only, 1991.
Ghosh, S., Natarajan, R. Cloning of the human cholesteryl ester hydrolase promoter: identification of functional peroxisomal proliferator-activated receptor responsive elements. Biochem. Biophys. Res. Commun. 284: 1065-1070, 2001. [PubMed: 11409902] [Full Text: https://doi.org/10.1006/bbrc.2001.5078]
Ghosh, S. Cholesteryl ester hydrolase in human monocyte/macrophage: cloning, sequencing, and expression of full-length cDNA. Physiol. Genomics 2: 1-8, 2000. [PubMed: 11015575] [Full Text: https://doi.org/10.1152/physiolgenomics.2000.2.1.1]
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Sanghani, S. P., Quinney, S. K., Fredenburg, T. B., Davis, W. I., Murry, D. J., Bosron, W. F. Hydrolysis of irinotecan and its oxidative metabolites, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxycamptothecin and 7-ethyl-10-[4-(1-piperidino)-1-amino]-carbonyloxycamptothecin by human carboxylesterases CES1A1, CES2, and a newly expressed carboxylesterase isoenzyme, CES3. Drug Metab. Dispos. 32: 505-513, 2004. [PubMed: 15100172] [Full Text: https://doi.org/10.1124/dmd.32.5.505]
Satoh, T. Role of carboxylesterase in xenobiotic metabolism. Rev. Biochem. Toxicol. 8: 155-181, 1987.
Shi, J., Wang, X., Nguyen, J., Wu, A. H., Bleske, B. E., Zhu, H.-J. Sacubitril is selectively activated by carboxylesterase 1 (CES1) in the liver and the activation is affected by CES1 genetic variation. Drug Metab. Dispos. 44: 554-559, 2016. [PubMed: 26817948] [Full Text: https://doi.org/10.1124/dmd.115.068536]
Shi, J., Wang, X., Nguyen, J.-H., Bleske, B. E., Liang, Y., Liu, L., Zhu, H.-J. Dabigatran etexilate activation is affected by the CES1 genetic polymorphism G143E (rs71647871) and gender. Biochem. Pharm. 119: 76-84, 2016. [PubMed: 27614009] [Full Text: https://doi.org/10.1016/j.bcp.2016.09.003]
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Stage, C., Jurgens, G., Guski, L. S., Thomsen, R., Bjerre, D., Ferrero-Miliani, L., Lyauk, Y. K., Rasmussen, H. B., Dalhoff, K., The INDICES Consortium. The impact of CES1 genotypes on the pharmacokinetics of methylphenidate in healthy Danish subjects. Brit. J. Clin. Pharm. 83: 1506-1514, 2017. [PubMed: 28087982] [Full Text: https://doi.org/10.1111/bcp.13237]
Tanimoto, K., Kaneyasu, M., Shimokuni, T., Hiyama, K., Nishiyama, M. Human carboxylesterase 1A2 expressed from carboxylesterase 1A1 and 1A2 genes is a potent predictor of CPT-11 cytotoxicity in vitro. Pharmacogenet. Genomics 17: 1-10, 2007. [PubMed: 17264798] [Full Text: https://doi.org/10.1097/01.fpc.0000230110.18957.50]
Zhao, B., Song, J., Chow, W. N., St. Clair, R. W., Rudel, L. L., Ghosh, S. Macrophage-specific transgenic expression of cholesteryl ester hydrolase significantly reduces atherosclerosis and lesion necrosis in Ldlr-/- mice. J. Clin. Invest. 117: 2983-2992, 2007. [PubMed: 17885686] [Full Text: https://doi.org/10.1172/JCI30485]
Zhu, H.-J., Patrick, K. S., Yuan, H.-J., Wang, J.-S., Donovan, J. L., DeVane, C. L., Malcolm, R., Johnson, J. A., Youngblood, G. L., Sweet, D. H., Langaee, T. Y., Markowitz, J. S. Two CES1 gene mutations lead to dysfunctional carboxylesterase 1 activity in man: clinical significance and molecular basis. Am. J. Hum. Genet. 82: 1241-1248, 2008. [PubMed: 18485328] [Full Text: https://doi.org/10.1016/j.ajhg.2008.04.015]