title: Skeletal muscle glycogen phosphorylase is irreversibly inhibited by mercury: molecular, cellular and kinetic aspects.
abstract: Muscle glycogen phosphorylase (GP) plays an important role in muscle functions. Mercury has toxic effects in skeletal muscle leading to muscle weakness or cramps. However, the mechanisms underlying these toxic effects are poorly understood. We report that GP is irreversibly inhibited by inorganic (Hg(2+)) and organic (CH3Hg(+)) mercury (IC50=380 nM and kinact=600 M(-1) s(-1) for Hg(2+) and IC50=43 μM and kinact=13 M(-1) s(-1) for CH3Hg(+)) through reaction of these compounds with cysteine residues of the enzyme. Our data suggest that the irreversible inhibition of GP could represent one of the mechanisms that contribute to mercury-dependent muscle toxicity.
authors.affiliation: Univ Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative, CNRS EAC 4413, 75013 Paris, France.
authors.forename: Ximing
authors.initials: X
authors.lastname: Xu
authors.affiliation: Univ Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative, CNRS EAC 4413, 75013 Paris, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Mathieu
authors.affiliation: Univ Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative, CNRS EAC 4413, 75013 Paris, France.
authors.forename: Solène Emmanuelle
authors.initials: SE
authors.lastname: Boitard
authors.affiliation: Univ Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative, CNRS EAC 4413, 75013 Paris, France; UFR des Sciences du Vivant, Univ Paris Diderot, 75013 Paris, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Dairou
authors.affiliation: Univ Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative, CNRS EAC 4413, 75013 Paris, France; UFR des Sciences du Vivant, Univ Paris Diderot, 75013 Paris, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Dupret
authors.affiliation: Univ Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative, CNRS EAC 4413, 75013 Paris, France; UFR des Sciences du Vivant, Univ Paris Diderot, 75013 Paris, France.
authors.forename: Onnik
authors.initials: O
authors.lastname: Agbulut
authors.affiliation: Univ Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative, CNRS EAC 4413, 75013 Paris, France; UFR des Sciences du Vivant, Univ Paris Diderot, 75013 Paris, France. Electronic address: fernando.rodrigues-lima@univ-paris-diderot.fr.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodrigues-Lima
mesh_terms: D000818:Animals; D002460:Cell Line; D003545:Cysteine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008627:Mercuric Chloride / Q000633:toxicity; D008628:Mercury / Q000633:toxicity*; D008767:Methylmercury Compounds / Q000633:toxicity; D051379:Mice; D018482:Muscle, Skeletal / Q000201:enzymology*; D013997:Time Factors
chemical_list: D008767:Methylmercury Compounds; D008627:Mercuric Chloride; D024981:Glycogen Phosphorylase; D008628:Mercury; D003545:Cysteine
keywords: Enzyme inhibition; Glycogen metabolism; Mechanistic toxicology; Mercury