Biology:Carboxylesterase 1

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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

References

  1. ↑ "cDNA cloning and characterization of human monocyte/macrophage serine esterase-1". Blood 78 (2): 506–12. Aug 1991. doi:10.1182/blood.V78.2.506.506. PMID 2070086. 
  2. ↑ 2.0 2.1 2.2 "Entrez Gene: CES1 carboxylesterase 1 (monocyte/macrophage serine esterase 1)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1066. 
  3. ↑ 3.0 3.1 3.2 Imai T (Jun 2006). "Human Carboxylesterase Isozymes: Catalytic Properties and Rational Drug Design". Drug Metabolism and Pharmacokinetics 21 (3): 173–185. doi:10.2133/dmpk.21.173. PMID 16858120. 
  4. ↑ "The relevance of alpha-naphthyl acetate esterases to various monocyte functions". Br J Haematol 61 (4): 717–26. Dec 1985. doi:10.1111/j.1365-2141.1985.tb02886.x. PMID 4084460. 
  5. ↑ 5.0 5.1 Markey GM (Feb 2011). "Carboxylesterase 1 (Ces1): from monocyte marker to major player". J Clin Pathol 64 (2): 107–9. doi:10.1136/jcp.2010.084657. PMID 21177752. 
  6. ↑ "Role of carboxylesterase 1 and impact of natural genetic variants on the hydrolysis of trandolapril". Biochem Pharmacol 77 (7): 1266–72. Jan 2009. doi:10.1016/j.bcp.2008.12.017. PMID 19185566. 
  7. ↑ "In vitro drug metabolism by human carboxylesterase 1: focus on angiotensin-converting enzyme inhibitors". Drug Metab Dispos 42 (1): 126–33. Jan 2014. doi:10.1124/dmd.113.053512. PMID 24141856. 
  8. ↑ "Activation of the antiviral prodrug oseltamivir is impaired by two newly identified carboxylesterase 1 variants". Drug Metab Dispos 37 (2): 264–7. Feb 2009. doi:10.1124/dmd.108.024943. PMID 19022936. 
  9. ↑ "Genetic determinants of dabigatran plasma levels and their relation to bleeding". Circulation 127 (13): 1404–12. Apr 2013. doi:10.1161/CIRCULATIONAHA.112.001233. PMID 23467860. 
  10. ↑ "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. doi:10.1016/j.ajhg.2008.04.015. PMID 18485328. 
  11. ↑ "Human carboxylesterase 1: from drug metabolism to drug discovery". Biochem Soc Trans 31 (Pt 3): 620–4. Jun 2003. doi:10.1042/bst0310620. PMID 12773168. 

Further reading



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