Cocaine esterase explained

Cocaine esterase
Ec Number:3.1.1.84
Molecular Weight:62,128 Da

The chloride cocaine esterase (EC 3.1.1.84, CocE, hCE2, hCE-2, human carboxylesterase 2; systematic name cocaine benzoylhydrolase)[1] [2] [3] [4] [5] catalyses the reaction

cocaine + H2O

\rightleftharpoons

ecgonine methyl ester + benzoate

Rhodococcus sp. strain MB1 and Pseudomonas maltophilia strain MB11L can utilize cocaine as sole source of carbon and energy.

The theoretical molecular mass is 62,128 Da.[6] This enzyme and redesigned versions of it have been studied as a potential treatment for cocaine addiction in humans.[7]

TNX-1300 (T172R/G173Q double-mutant cocaine esterase 200 mg, i.v. solution)[8] is being developed under an Investigational New Drug application (IND) for the treatment of cocaine intoxication.[9] TNX-1300 (formerly known as RBP-8000) is a recombinant protein enzyme produced through rDNA technology in a non-disease-producing strain of E. coli bacteria. Cocaine Esterase (CocE) was identified in bacteria (Rhodococcus) that use cocaine as its sole source of carbon and nitrogen and that grow in soil surrounding coca plants.[10]  The gene encoding CocE was identified and the protein was extensively characterized.[11] CoCE catalyzes the breakdown of cocaine into metabolite ecgonine methyl ester and benzoic acid. Wild-type CocE is unstable at body temperature, so targeted mutations were introduced in the CocE gene and resulted in the T172R/G173Q Double-Mutant CocE, which is active for approximately 6 hours at body temperature. In a Phase 2 study, TNX-1300 at 100 mg or 200 mg i.v. doses was well tolerated and interrupted cocaine effects after cocaine 50 mg i.v. challenge.

The enzyme is important in bioremediation, levels of cocaine in European ocean water were cited at 20 ng/L, similar levels in which swollen muscles, and in some cases broken muscle fibers of eels were reported in a controlled study.[12]

External links

Notes and References

  1. Gao D, Narasimhan DL, Macdonald J, Brim R, Ko MC, Landry DW, Woods JH, Sunahara RK, Zhan CG . Thermostable variants of cocaine esterase for long-time protection against cocaine toxicity . Molecular Pharmacology . 75 . 2 . 318–23 . February 2009 . 18987161 . 2684895 . 10.1124/mol.108.049486 .
  2. Bresler MM, Rosser SJ, Basran A, Bruce NC . Gene cloning and nucleotide sequencing and properties of a cocaine esterase from Rhodococcus sp. strain MB1 . Applied and Environmental Microbiology . 66 . 3 . 904–8 . March 2000 . 10698749 . 91920 . 10.1128/aem.66.3.904-908.2000 . 2000ApEnM..66..904B .
  3. Britt AJ, Bruce NC, Lowe CR . Identification of a cocaine esterase in a strain of Pseudomonas maltophilia . Journal of Bacteriology . 174 . 7 . 2087–94 . April 1992 . 1551831 . 205824 . 10.1128/jb.174.7.2087-2094.1992 .
  4. Larsen NA, Turner JM, Stevens J, Rosser SJ, Basran A, Lerner RA, Bruce NC, Wilson IA . Crystal structure of a bacterial cocaine esterase . Nature Structural Biology . 9 . 1 . 17–21 . January 2002 . 11742345 . 10.1038/nsb742 . 847034 .
  5. Pindel EV, Kedishvili NY, Abraham TL, Brzezinski MR, Zhang J, Dean RA, Bosron WF . Purification and cloning of a broad substrate specificity human liver carboxylesterase that catalyzes the hydrolysis of cocaine and heroin . The Journal of Biological Chemistry . 272 . 23 . 14769–75 . June 1997 . 9169443 . 10.1074/jbc.272.23.14769 . free .
  6. Bresler. Matthew M.. Rosser. Susan J.. Basran. Amrik. Bruce. Neil C.. March 2000. Gene Cloning and Nucleotide Sequencing and Properties of a Cocaine Esterase from Rhodococcus sp. Strain MB1. Applied and Environmental Microbiology. 66. 3. 904–908. 10.1128/AEM.66.3.904-908.2000. 0099-2240. 10698749. 91920. 2000ApEnM..66..904B .
  7. Narasimhan D, Woods JH, Sunahara RK . Bacterial cocaine esterase: a protein-based therapy for cocaine overdose and addiction . . 4 . 2 . 137–50 . February 2012 . 22300094 . 10.4155/fmc.11.194 . 3290992 .
  8. Web site: Tonix boosts pipeline with Columbia University-developed cocaine intoxication drug. FierceBiotech. en. 2019-05-28.
  9. Nasser. Azmi F.. Fudala. Paul J.. Zheng. Bo. Liu. Yongzhen. Heidbreder. Christian. 2014-10-02. A Randomized, Double-Blind, Placebo-Controlled Trial of RBP-8000 in Cocaine Abusers: Pharmacokinetic Profile of RBP-8000 and Cocaine and Effects of RBP-8000 on Cocaine-Induced Physiological Effects. Journal of Addictive Diseases. en. 33. 4. 289–302. 10.1080/10550887.2014.969603. 25299069. 8417112. 1055-0887.
  10. Bresler. M. M.. Rosser. S. J.. Basran. A.. Bruce. N. C.. 2000. Gene cloning and nucleotide sequencing and properties of a cocaine esterase from Rhodococcus sp. strain MB1. Applied and Environmental Microbiology. 66. 3. 904–908. 10.1128/aem.66.3.904-908.2000. 0099-2240. 10698749. 91920. 2000ApEnM..66..904B .
  11. Turner. James M.. Larsen. Nicholas A.. Basran. Amrik. Barbas. Carlos F.. Bruce. Neil C.. Wilson. Ian A.. Lerner. Richard A.. 2002-10-15. Biochemical characterization and structural analysis of a highly proficient cocaine esterase. Biochemistry. 41. 41. 12297–12307. 0006-2960. 12369817. 10.1021/bi026131p.
  12. Web site: European eels found to suffer muscle damage due to cocaine in the water.

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