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PDBsum entry 1mx9

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protein ligands Protein-protein interface(s) links
Hydrolase PDB id
1mx9
Jmol
Contents
Protein chain
(+ 6 more) 532 a.a. *
Ligands
NAG ×13
NLX ×12
Waters ×1129
* Residue conservation analysis
PDB id:
1mx9
Name: Hydrolase
Title: Crystal structure of human liver carboxylesterase in complex naloxone methiodide, a heroin analogue
Structure: Liver carboxylesterase i. Chain: a, b, c, d, e, f, g, h, i, j, k, l. Synonym: hcev, acyl coenzyme a:cholesterol acyltransferase, monocyte/macrophage serine esterase, hmse, serine esterase engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf21.
Biol. unit: Hexamer (from PQS)
Resolution:
2.90Å     R-factor:   0.214     R-free:   0.280
Authors: S.Bencharit,C.L.Morton,Y.Xue,P.M.Potter,M.R.Redinbo
Key ref:
S.Bencharit et al. (2003). Structural basis of heroin and cocaine metabolism by a promiscuous human drug-processing enzyme. Nat Struct Biol, 10, 349-356. PubMed id: 12679808 DOI: 10.1038/nsb919
Date:
01-Oct-02     Release date:   08-Apr-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P23141  (EST1_HUMAN) -  Liver carboxylesterase 1
Seq:
Struc:
 
Seq:
Struc:
567 a.a.
532 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class 2: E.C.3.1.1.1  - Carboxylesterase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: A carboxylic ester + H2O = an alcohol + a carboxylate
carboxylic ester
+ H(2)O
= alcohol
+ carboxylate
   Enzyme class 3: E.C.3.1.1.56  - Methylumbelliferyl-acetate deacetylase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: 4-methylumbelliferyl acetate + H2O = 4-methylumbelliferone + acetate
4-methylumbelliferyl acetate
+ H(2)O
= 4-methylumbelliferone
+ acetate
Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     endoplasmic reticulum   2 terms 
  Biological process     metabolic process   3 terms 
  Biochemical function     carboxylic ester hydrolase activity     3 terms  

 

 
    reference    
 
 
DOI no: 10.1038/nsb919 Nat Struct Biol 10:349-356 (2003)
PubMed id: 12679808  
 
 
Structural basis of heroin and cocaine metabolism by a promiscuous human drug-processing enzyme.
S.Bencharit, C.L.Morton, Y.Xue, P.M.Potter, M.R.Redinbo.
 
  ABSTRACT  
 
We present the first crystal structures of a human protein bound to analogs of cocaine and heroin. Human carboxylesterase 1 (hCE1) is a broad-spectrum bioscavenger that catalyzes the hydrolysis of heroin and cocaine, and the detoxification of organophosphate chemical weapons, such as sarin, soman and tabun. Crystal structures of the hCE1 glycoprotein in complex with the cocaine analog homatropine and the heroin analog naloxone provide explicit details about narcotic metabolism in humans. The hCE1 active site contains both specific and promiscuous compartments, which enable the enzyme to act on structurally distinct chemicals. A selective surface ligand-binding site regulates the trimer-hexamer equilibrium of hCE1 and allows each hCE1 monomer to bind two narcotic molecules simultaneously. The bioscavenger properties of hCE1 can likely be used to treat both narcotic overdose and chemical weapon exposure.
 
  Selected figure(s)  
 
Figure 3.
Figure 3. Cocaine metabolism by hCE1.
Figure 4.
Figure 4. Heroin metabolism by hCE1. a, Stereo view of two orientations of naloxone methiodide (green and orange) bound within the hCE1 catalytic pocket. The two binding modes of this heroin analog are related by a two-fold rotation about the vertical axis. The molecular surfaces of the catalytic binding pocket corresponding to the two orientations of the naloxone ligand are rendered in transparent green and orange, and demonstrate the induced fit property of the substrate-binding pocket. b, Schematic representation of one of the two experimentally observed binding modes of the heroin analog naloxone (green) in the active site of hCE1. In this orientation, naloxone places its 3-hydroxyl group (position 3) adjacent to the rigid region of the hCE1 active site. Average distances between amino acid side chains and atoms in naloxone are indicated with solid green lines (<4 ) or dotted gray lines (>4 ). The nine residues that comprise the flexible pocket are labeled blue; the five residues that form the rigid pocket, red; and the three residues in the serine hydrolase catalytic triad, black. c, Schematic representation of the other of the two experimentally observed binding modes of the heroin analog naloxone (orange) in the active site of hCE1. In this orientation, naloxone places its 6-ketone oxygen (position 6) adjacent to the rigid region of the hCE1 active site. Average distances between amino acid side chains and atoms in naloxone are indicated with solid green lines (<4 ) or dotted gray lines (>4 ). Residues are labeled as in (b).
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Biol (2003, 10, 349-356) copyright 2003.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20966115 G.Li, J.E.Janecka, and W.J.Murphy (2011).
Accelerated evolution of CES7, a gene encoding a novel major urinary protein in the cat family.
  Mol Biol Evol, 28, 911-920.  
21332315 M.R.Meyer, and H.H.Maurer (2011).
Absorption, distribution, metabolism and excretion pharmacogenomics of drugs of abuse.
  Pharmacogenomics, 12, 215-233.  
20163318 J.L.Staudinger, C.Xu, Y.J.Cui, and C.D.Klaassen (2010).
Nuclear receptor-mediated regulation of carboxylesterase expression and activity.
  Expert Opin Drug Metab Toxicol, 6, 261-271.  
20422440 R.S.Holmes, L.A.Cox, and J.L.VandeBerg (2010).
Mammalian carboxylesterase 3: comparative genomics and proteomics.
  Genetica, 138, 695-708.  
20931200 R.S.Holmes, M.W.Wright, S.J.Laulederkind, L.A.Cox, M.Hosokawa, T.Imai, S.Ishibashi, R.Lehner, M.Miyazaki, E.J.Perkins, P.M.Potter, M.R.Redinbo, J.Robert, T.Satoh, T.Yamashita, B.Yan, T.Yokoi, R.Zechner, and L.J.Maltais (2010).
Recommended nomenclature for five mammalian carboxylesterase gene families: human, mouse, and rat genes and proteins.
  Mamm Genome, 21, 427-441.  
19634903 B.L.Barthel, Z.Zhang, D.L.Rudnicki, C.D.Coldren, M.Polinkovsky, H.Sun, G.G.Koch, D.C.Chan, and T.H.Koch (2009).
Preclinical efficacy of a carboxylesterase 2-activated prodrug of doxazolidine.
  J Med Chem, 52, 7678-7688.  
18797848 J.A.Zombeck, T.Gupta, and J.S.Rhodes (2009).
Evaluation of a pharmacokinetic hypothesis for reduced locomotor stimulation from methamphetamine and cocaine in adolescent versus adult male C57BL/6J mice.
  Psychopharmacology (Berl), 201, 589-599.  
19534556 L.D.Hicks, J.L.Hyatt, S.Stoddard, L.Tsurkan, C.C.Edwards, R.M.Wadkins, and P.M.Potter (2009).
Improved, selective, human intestinal carboxylesterase inhibitors designed to modulate 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (Irinotecan; CPT-11) toxicity.
  J Med Chem, 52, 3742-3752.  
  20664805 N.S.Lamango, R.Duverna, W.Zhang, and S.Y.Ablordeppey (2009).
Porcine Liver Carboxylesterase Requires Polyisoprenylation for High Affinity Binding to Cysteinyl Substrates.
  Open Enzym Inhib J, 2, 12-27.  
19187434 R.S.Holmes, J.P.Glenn, J.L.VandeBerg, and L.A.Cox (2009).
Baboon carboxylesterases 1 and 2: sequences, structures and phylogenetic relationships with human and other primate carboxylesterases.
  J Med Primatol, 38, 27-38.  
20161041 R.S.Holmes, L.A.Cox, and J.L.Vandeberg (2009).
A new class of mammalian carboxylesterase CES6.
  Comp Biochem Physiol Part D Genomics Proteomics, 4, 209-217.  
20161341 R.S.Holmes, L.A.Cox, and J.L.Vandeberg (2009).
Bovine Carboxylesterases: Evidence for Two CES1 and Five Families of CES Genes on Chromosome 18.
  Comp Biochem Physiol Part D Genomics Proteomics, 4, 11-20.  
20403742 R.S.Holmes, L.A.Cox, and J.L.Vandeberg (2009).
Horse carboxylesterases: evidence for six CES1 and four families of CES genes on chromosome 3.
  Comp Biochem Physiol Part D Genomics Proteomics, 4, 54-65.  
19062296 T.Harada, Y.Nakagawa, R.M.Wadkins, P.M.Potter, and C.E.Wheelock (2009).
Comparison of benzil and trifluoromethyl ketone (TFK)-mediated carboxylesterase inhibition using classical and 3D-quantitative structure-activity relationship analysis.
  Bioorg Med Chem, 17, 149-164.  
19683009 Z.Qian, J.R.Horton, X.Cheng, and S.Lutz (2009).
Structural redesign of lipase B from Candida antarctica by circular permutation and incremental truncation.
  J Mol Biol, 393, 191-201.
PDB codes: 3icv 3icw
18721110 J.M.Hatfield, M.Wierdl, R.M.Wadkins, and P.M.Potter (2008).
Modifications of human carboxylesterase for improved prodrug activation.
  Expert Opin Drug Metab Toxicol, 4, 1153-1165.  
18188187 M.Wierdl, L.Tsurkan, J.L.Hyatt, C.C.Edwards, M.J.Hatfield, C.L.Morton, P.J.Houghton, M.K.Danks, M.R.Redinbo, and P.M.Potter (2008).
An improved human carboxylesterase for enzyme/prodrug therapy with CPT-11.
  Cancer Gene Ther, 15, 183-192.  
18273909 O.T.Oboh, and N.S.Lamango (2008).
Liver prenylated methylated protein methyl esterase is the same enzyme as Sus scrofa carboxylesterase.
  J Biochem Mol Toxicol, 22, 51-62.  
18289373 R.S.Holmes, J.Chan, L.A.Cox, W.J.Murphy, and J.L.VandeBerg (2008).
Opossum carboxylesterases: sequences, phylogeny and evidence for CES gene duplication events predating the marsupial-eutherian common ancestor.
  BMC Evol Biol, 8, 54.  
19727319 R.S.Holmes, L.A.Cox, and J.L.Vandeberg (2008).
Mammalian carboxylesterase 5: comparative biochemistry and genomics.
  Comp Biochem Physiol Part D Genomics Proteomics, 3, 195-204.  
18383336 S.Takahashi, M.Katoh, T.Saitoh, M.Nakajima, and T.Yokoi (2008).
Allosteric kinetics of human carboxylesterase 1: species differences and interindividual variability.
  J Pharm Sci, 97, 5434-5445.  
17407327 C.D.Fleming, C.C.Edwards, S.D.Kirby, D.M.Maxwell, P.M.Potter, D.M.Cerasoli, and M.R.Redinbo (2007).
Crystal structures of human carboxylesterase 1 in covalent complexes with the chemical warfare agents soman and tabun.
  Biochemistry, 46, 5063-5071.
PDB codes: 2hrq 2hrr
17593363 E.Brüsehaber, D.Böttcher, A.Musidlowska-Persson, D.Albrecht, M.Hecker, K.Doderer, and U.T.Bornscheuer (2007).
Identification of pig liver esterase variants by tandem mass spectroscopy analysis and their characterization.
  Appl Microbiol Biotechnol, 76, 853-859.  
17167034 R.M.Wadkins, J.L.Hyatt, C.C.Edwards, L.Tsurkan, M.R.Redinbo, C.E.Wheelock, P.D.Jones, B.D.Hammock, and P.M.Potter (2007).
Analysis of mammalian carboxylesterase inhibition by trifluoromethylketone-containing compounds.
  Mol Pharmacol, 71, 713-723.  
17125253 D.J.Burkhart, B.L.Barthel, G.C.Post, B.T.Kalet, J.W.Nafie, R.K.Shoemaker, and T.H.Koch (2006).
Design, synthesis, and preliminary evaluation of doxazolidine carbamates as prodrugs activated by carboxylesterases.
  J Med Chem, 49, 7002-7012.  
16778732 H.H.Maurer, C.Sauer, and D.S.Theobald (2006).
Toxicokinetics of drugs of abuse: current knowledge of the isoenzymes involved in the human metabolism of tetrahydrocannabinol, cocaine, heroin, morphine, and codeine.
  Ther Drug Monit, 28, 447-453.  
16359636 K.Nishi, H.Huang, S.G.Kamita, I.H.Kim, C.Morisseau, and B.D.Hammock (2006).
Characterization of pyrethroid hydrolysis by the human liver carboxylesterases hCE-1 and hCE-2.
  Arch Biochem Biophys, 445, 115-123.  
16962139 S.Bencharit, C.C.Edwards, C.L.Morton, E.L.Howard-Williams, P.Kuhn, P.M.Potter, and M.R.Redinbo (2006).
Multisite promiscuity in the processing of endogenous substrates by human carboxylesterase 1.
  J Mol Biol, 363, 201-214.
PDB codes: 2dqy 2dqz 2dr0 2h7c
16858120 T.Imai (2006).
Human carboxylesterase isozymes: catalytic properties and rational drug design.
  Drug Metab Pharmacokinet, 21, 173-185.  
15601899 D.Gilham, M.Alam, W.Gao, D.E.Vance, and R.Lehner (2005).
Triacylglycerol hydrolase is localized to the endoplasmic reticulum by an unusual retrieval sequence where it participates in VLDL assembly without utilizing VLDL lipids as substrates.
  Mol Biol Cell, 16, 984-996.  
16167828 H.Huang, C.D.Fleming, K.Nishi, M.R.Redinbo, and B.D.Hammock (2005).
Stereoselective hydrolysis of pyrethroid-like fluorescent substrates by human and other mammalian liver carboxylesterases.
  Chem Res Toxicol, 18, 1371-1377.  
15909078 L.Merone, L.Mandrich, M.Rossi, and G.Manco (2005).
A thermostable phosphotriesterase from the archaeon Sulfolobus solfataricus: cloning, overexpression and properties.
  Extremophiles, 9, 297-305.  
14617621 G.De Simone, L.Mandrich, V.Menchise, V.Giordano, F.Febbraio, M.Rossi, C.Pedone, and G.Manco (2004).
A substrate-induced switch in the reaction mechanism of a thermophilic esterase: kinetic evidences and structural basis.
  J Biol Chem, 279, 6815-6823.
PDB code: 1qz3
15098021 M.Harel, A.Aharoni, L.Gaidukov, B.Brumshtein, O.Khersonsky, R.Meged, H.Dvir, R.B.Ravelli, A.McCarthy, L.Toker, I.Silman, J.L.Sussman, and D.S.Tawfik (2004).
Structure and evolution of the serum paraoxonase family of detoxifying and anti-atherosclerotic enzymes.
  Nat Struct Mol Biol, 11, 412-419.
PDB code: 1v04
15618752 S.R.Kim, T.Nakamura, Y.Saito, K.Sai, T.Nakajima, H.Saito, K.Shirao, H.Minami, A.Ohtsu, T.Yoshida, N.Saijo, S.Ozawa, and J.Sawada (2003).
Twelve novel single nucleotide polymorphisms in the CES2 gene encoding human carboxylesterase 2 (hCE-2).
  Drug Metab Pharmacokinet, 18, 327-332.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.