Genetic variants of human serum cholinesterase influence metabolism of the muscle relaxant succinylcholine

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180 Scopus citations

Abstract

People with genetic variants of cholinestrase respond abnormally to succinylcholine, experiencing substantial prolongation of muscle paralysis with apnea rather than the usual 2-6 min. The structure of usual cholinesterase has been determined including the complete amino acid and nucleotide sequence. This has allowed identification of altered amino acids and nucleotides. The variant most frequently found in patients who respond abnormally to succinylcholine is atypical cholonesterase, which occurs in homozygous from in 1 out of 3500 Caucasians. Atypical cholinesterase has a single substitution at nucleotide 209 which changes aspartic acid 70 to glycine. This suggests that Asp 70 is part of the anionic site, and that the absence of this negatively charged amino acid explains the reduced affinity of atypical cholinesterase for positively charged substrates and inhibitors. The clinical consequence of reduced affinity for succinylcholine is that one of the succinylcholine is hydrolyzed in blood and a large overdose reaches the nerve-muscle junction where junction where it causes prolonged muscle paralysis. Silent cholinesterase has a frame mutation at glycine 117 which prenaturely terminates protein synthesis and yields no enzyme. The K variant, named in honor of W. Kalow, has threonine in place of alanine 539. The K variant is associated with 33% lower activity. All variants arise from a single locus as there is only one gene for human cholinestrase (EC 3.1.1.8). Comparison of amino acid sequences of esterases and proteases shows that cholinesterase belongs to a new family of serine esterases which is different from the serine proteases.

Original languageEnglish (US)
Pages (from-to)35-60
Number of pages26
JournalPharmacology and Therapeutics
Volume47
Issue number1
DOIs
StatePublished - 1990

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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