Carboxylesterase 1

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. 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.

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.

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. The loss of this protein in monocytes is one product of organophosphate poisoning.

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. Genetic variants of CES1 can significantly affect both pharmacokinetics and pharmacodynamics of drugs metabolized by CES1, such as methylphenidate and clopidogrel. The ability of CES1 to metabolize heroin and cocaine among other drugs has suggested a therapeutic role for the enzyme.

Interactive pathway map

References

References

1. (Aug 1991). "cDNA cloning and characterization of human monocyte/macrophage serine esterase-1". Blood.
2. "Entrez Gene: CES1 carboxylesterase 1 (monocyte/macrophage serine esterase 1)".
3. Imai T. (Jun 2006). "Human Carboxylesterase Isozymes: Catalytic Properties and Rational Drug Design". Drug Metabolism and Pharmacokinetics.
4. (Dec 1985). "The relevance of alpha-naphthyl acetate esterases to various monocyte functions". Br J Haematol.
5. Markey GM. (Feb 2011). "Carboxylesterase 1 (Ces1): from monocyte marker to major player". J Clin Pathol.
6. (Jan 2009). "Role of carboxylesterase 1 and impact of natural genetic variants on the hydrolysis of trandolapril". Biochem Pharmacol.
7. (Jan 2014). "In vitro drug metabolism by human carboxylesterase 1: focus on angiotensin-converting enzyme inhibitors". Drug Metab Dispos.
8. (Feb 2009). "Activation of the antiviral prodrug oseltamivir is impaired by two newly identified carboxylesterase 1 variants". Drug Metab Dispos.
9. (Apr 2013). "Genetic determinants of dabigatran plasma levels and their relation to bleeding". Circulation.
10. (Jun 2008). "Two CES1 gene mutations lead to dysfunctional carboxylesterase 1 activity in man: clinical significance and molecular basis". Am J Hum Genet.
11. (Jun 2003). "Human carboxylesterase 1: from drug metabolism to drug discovery". Biochem Soc Trans.