Carboxylesterase 1 Explained

Liver carboxylesterase 1 also known as carboxylesterase 1 (CES1, hCE-1 or CES1A1) is an enzyme that in humans is encoded by the CES1 gene.^{[1] [2]} The protein is also historically known as serine esterase 1 (SES1), monocyte esterase and cholesterol ester hydrolase (CEH). Three transcript variants encoding three different isoforms have been found for this gene.^[2] The various protein products from isoform a, b and c range in size from 568, 567 and 566 amino acids long, respectively.

CES1 is present in most tissues with higher levels in the liver and low levels in the gastrointestinal tract.^[3]

Function

Carboxylesterase 1 is a serine esterase and member of a large multigene carboxylesterase family. It is also part of the alpha/beta fold hydrolase family.^[3] These enzymes are responsible for the hydrolysis of ester- and amide-bond-containing xenobiotics and drugs such as cocaine and heroin. They also hydrolyze long-chain fatty acid esters and thioesters. As part of phase II metabolism, the resulting carboxylates are then often conjugated by other enzymes to increase solubility and eventually excreted.

This enzyme is known to hydrolyze aromatic and aliphatic esters and can manage cellular cholesterol esterification levels. It may also play a role in detoxification in the lung and/or protection of the central nervous system from ester or amide compounds.^[2]

The protein contains an amino acid sequence at its N-terminus that sends it into the endoplasmic reticulum where a C-terminal sequence can bind to a KDEL receptor.^[3]

Clinical significance

Carboxylesterase 1 deficiency may be associated with non-Hodgkin lymphoma or B-cell lymphocytic leukemia. Inhibition of CES1 by in particular organophosphates reduces tumor-killing activity by monocytes.^{[4] [5]} The loss of this protein in monocytes is one product of organophosphate poisoning.^[5]

CES1 can activate or deactivate various drugs. CES1 is responsible for the activation of many prodrugs such as angiotensin-converting enzyme (ACE) inhibitors, oseltamivir, and dabigatran.^{[6] [7] [8] [9]} Genetic variants of CES1 can significantly affect both pharmacokinetics and pharmacodynamics of drugs metabolized by CES1, such as methylphenidate and clopidogrel.^[10] The ability of CES1 to metabolize heroin and cocaine among other drugs has suggested a therapeutic role for the enzyme.^[11]

Interactive pathway map

Further reading

• Riddles PW, Richards LJ, Bowles MR, Pond SM . Cloning and analysis of a cDNA encoding a human liver carboxylesterase. . Gene . 108 . 2 . 289–92 . 1992 . 1748313 . 10.1016/0378-1119(91)90448-K .
• Munger JS, Shi GP, Mark EA . A serine esterase released by human alveolar macrophages is closely related to liver microsomal carboxylesterases. . J. Biol. Chem. . 266 . 28 . 18832–8 . 1991 . 10.1016/S0021-9258(18)55139-5 . 1918003 . etal. free .
• Long RM, Calabrese MR, Martin BM, Pohl LR . Cloning and sequencing of a human liver carboxylesterase isoenzyme. . Life Sci. . 48 . 11 . PL43–9 . 1991 . 1997784 . 10.1016/0024-3205(91)90515-D .
• Ketterman AJ, Bowles MR, Pond SM . Purification and characterization of two human liver carboxylesterases. . Int. J. Biochem. . 21 . 12 . 1303–12 . 1990 . 2612723 . 10.1016/0020-711X(89)90149-3 .
• Becker A, Böttcher A, Lackner KJ . Purification, cloning, and expression of a human enzyme with acyl coenzyme A: cholesterol acyltransferase activity, which is identical to liver carboxylesterase. . Arterioscler. Thromb. . 14 . 8 . 1346–55 . 1994 . 8049197 . 10.1161/01.atv.14.8.1346. etal. free .
• Kroetz DL, McBride OW, Gonzalez FJ . Glycosylation-dependent activity of baculovirus-expressed human liver carboxylesterases: cDNA cloning and characterization of two highly similar enzyme forms. . Biochemistry . 32 . 43 . 11606–17 . 1993 . 8218228 . 10.1021/bi00094a018 .
• Shibata F, Takagi Y, Kitajima M . Molecular cloning and characterization of a human carboxylesterase gene. . Genomics . 17 . 1 . 76–82 . 1993 . 8406473 . 10.1006/geno.1993.1285 . etal.
• Langmann T, Becker A, Aslanidis C . Structural organization and characterization of the promoter region of a human carboxylesterase gene. . Biochim. Biophys. Acta . 1350 . 1 . 65–74 . 1997 . 9003459 . 10.1016/S0167-4781(96)00142-X. etal.
• Brzezinski MR, Spink BJ, Dean RA . Human liver carboxylesterase hCE-1: binding specificity for cocaine, heroin, and their metabolites and analogs. . Drug Metab. Dispos. . 25 . 9 . 1089–96 . 1997 . 9311626 . etal.
• Yan B, Matoney L, Yang D . Human carboxylesterases in term placentae: enzymatic characterization, molecular cloning and evidence for the existence of multiple forms. . Placenta . 20 . 7 . 599–607 . 1999 . 10452915 . 10.1053/plac.1999.0407 .
• Mori M, Hosokawa M, Ogasawara Y . cDNA cloning, characterization and stable expression of novel human brain carboxylesterase. . FEBS Lett. . 458 . 1 . 17–22 . 1999 . 10518925 . 10.1016/S0014-5793(99)01111-4 . 5792413 . etal. free .
• Islam MR, Waheed A, Shah GN . Human egasyn binds beta-glucuronidase but neither the esterase active site of egasyn nor the C terminus of beta-glucuronidase is involved in their interaction. . Arch. Biochem. Biophys. . 372 . 1 . 53–61 . 1999 . 10562416 . 10.1006/abbi.1999.1449 . etal.
• Ghosh S . Cholesteryl ester hydrolase in human monocyte/macrophage: cloning, sequencing, and expression of full-length cDNA. . Physiol. Genomics . 2 . 1 . 1–8 . 2001 . 11015575 . 10.1152/physiolgenomics.2000.2.1.1. 1657010 .
• 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 . 4 . 1065–70 . 2001 . 11409902 . 10.1006/bbrc.2001.5078 .
• Alam M, Ho S, Vance DE, Lehner R . Heterologous expression, purification, and characterization of human triacylglycerol hydrolase. . Protein Expr. Purif. . 24 . 1 . 33–42 . 2002 . 11812220 . 10.1006/prep.2001.1553 .
• Satoh T, Taylor P, Bosron WF . Current progress on esterases: from molecular structure to function. . Drug Metab. Dispos. . 30 . 5 . 488–93 . 2002 . 11950776 . 10.1124/dmd.30.5.488 . 5802731 . etal.
• Alam M, Vance DE, Lehner R . Structure-function analysis of human triacylglycerol hydrolase by site-directed mutagenesis: identification of the catalytic triad and a glycosylation site. . Biochemistry . 41 . 21 . 6679–87 . 2002 . 12022871 . 10.1021/bi0255625 .
• Strausberg RL, Feingold EA, Grouse LH . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–903 . 2003 . 12477932 . 10.1073/pnas.242603899 . 139241. 2002PNAS...9916899M . etal. free .
• Bencharit S, Morton CL, Xue Y . Structural basis of heroin and cocaine metabolism by a promiscuous human drug-processing enzyme. . Nat. Struct. Biol. . 10 . 5 . 349–56 . 2003 . 12679808 . 10.1038/nsb919 . 1108060 . etal.
• Zhu HJ, Brinda B, Froehlich TE, Markowitz JS . A discriminative analytical method for detection of CES1A1 and CES1A2/CES1A3 genetic variants. . Pharmacogenet Genomics. . 22 . 3 . 215–8 . 2012 . 22237548 . 10.1097/FPC.0b013e32834f03eb . 3412537.

Notes and References

1. Zschunke F, Salmassi A, Kreipe H, Buck F, Parwaresch MR, Radzun HJ . cDNA cloning and characterization of human monocyte/macrophage serine esterase-1 . Blood . 78 . 2 . 506–12 . Aug 1991 . 2070086 . 10.1182/blood.V78.2.506.506. free .
2. Web site: Entrez Gene: CES1 carboxylesterase 1 (monocyte/macrophage serine esterase 1).
3. Imai T . Human Carboxylesterase Isozymes: Catalytic Properties and Rational Drug Design . Drug Metabolism and Pharmacokinetics . 21 . 3 . 173–185 . Jun 2006 . 16858120 . 10.2133/dmpk.21.173 .
4. Oertel J, Hagner G, Kastner M, Huhn D . The relevance of alpha-naphthyl acetate esterases to various monocyte functions . Br J Haematol . 61 . 4 . 717–26 . Dec 1985 . 4084460 . 10.1111/j.1365-2141.1985.tb02886.x. 84899499 .
5. Markey GM . Carboxylesterase 1 (Ces1): from monocyte marker to major player . J Clin Pathol . 64 . 2 . 107–9 . Feb 2011. 21177752 . 10.1136/jcp.2010.084657 . 32622794 .
6. Zhu HJ, Appel DI, Johnson JA, Chavin KD, Markowitz JS . Role of carboxylesterase 1 and impact of natural genetic variants on the hydrolysis of trandolapril . Biochem Pharmacol . 77 . 7 . 1266–72 . Jan 2009 . 19185566 . 10.1016/j.bcp.2008.12.017.
7. Thomsen R, Rasmussen HB, Linnet K, ((INDICES Consortium)) . In vitro drug metabolism by human carboxylesterase 1: focus on angiotensin-converting enzyme inhibitors . Drug Metab Dispos . 42 . 1 . 126–33 . Jan 2014 . 24141856 . 10.1124/dmd.113.053512. 206496779 .
8. Zhu HJ, Markowitz JS . Activation of the antiviral prodrug oseltamivir is impaired by two newly identified carboxylesterase 1 variants . Drug Metab Dispos . 37 . 2 . 264–7 . Feb 2009 . 19022936 . 10.1124/dmd.108.024943. 9277216 .
9. Paré G, Eriksson N, Lehr T, Connolly S, Eikelboom J, Ezekowitz MD, Axelsson T, Haertter S, Oldgren J, Reilly P, Siegbahn A, Syvanen AC, Wadelius C, Wadelius M, Zimdahl-Gelling H, Yusuf S, Wallentin L . Genetic determinants of dabigatran plasma levels and their relation to bleeding . Circulation . 127 . 13 . 1404–12 . Apr 2013 . 23467860 . 10.1161/CIRCULATIONAHA.112.001233. free .
10. Zhu HJ, Patrick KS, Yuan HJ, Wang JS, Donovan JL, DeVane CL, Malcolm R, Johnson JA, Youngblood GL, Sweet DH, Langaee TY, Markowitz JS . Two CES1 gene mutations lead to dysfunctional carboxylesterase 1 activity in man: clinical significance and molecular basis . Am J Hum Genet . 82. 6 . 1241–8 . Jun 2008 . 18485328 . 2427248 . 10.1016/j.ajhg.2008.04.015 .
11. Redinbo MR, Bencharit S, Potter PM . Human carboxylesterase 1: from drug metabolism to drug discovery . Biochem Soc Trans . 31 . Pt 3 . 620–4 . Jun 2003 . 12773168 . 10.1042/bst0310620.