Effects of cadmium and mercury on the upper part of skeletal muscle glycolysis in mice.
The effects of pre-incubation with mercury (Hg(2+)) and cadmium (Cd(2+)) on the activities of individual glycolytic enzymes, on the flux and on internal metabolite concentrations of the upper part of glycolysis were investigated in mouse muscle extracts. In the range of metal concentrations analysed we found that only hexokinase and phosphofructokinase, the enzymes that shared the control of the flux, were inhibited by Hg(2+) and Cd(2+). The concentrations of the internal metabolites glucose-6-phosphate and fructose-6-phosphate did not change significantly when Hg(2+) and Cd(2+) were added. A mathematical model was constructed to explore the mechanisms of inhibition of Hg(2+) and Cd(2+) on hexokinase and phosphofructokinase. Equations derived from detailed mechanistic models for each inhibition were fitted to the experimental data. In a concentration-dependent manner these equations describe the observed inhibition of enzyme activity. Under the conditions analysed, the integral model showed that the simultaneous inhibition of hexokinase and phosphofructokinase explains the observation that the concentrations of glucose-6-phosphate and fructose-6-phosphate did not change as the heavy metals decreased the glycolytic flux.
Department of Biochemistry and Molecular Biology and IBUB, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain.
Maria José
MJ
Ramírez-Bajo
Department of Biochemistry and Molecular Biology and IBUB, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain ; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Pedro
P
de Atauri
Department of Biochemistry and Molecular Biology and IBUB, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain.
Fernando
F
Ortega
Department of Molecular Cell Physiology, BioCentrum Amsterdam, Faculty of Biology, Vrije Universiteit, Amsterdam, The Netherlands ; Manchester Interdisciplinary Biocentre-3.018, School of Chemical Engineering and Analytical Science, The University of Manchester, Manchester, United Kingdom ; Synthetic Systems Biology, SILS and NISB, University of Amsterdam, Amsterdam, The Netherlands.
Hans V
HV
Westerhoff
Department of Biochemistry and Molecular Biology and IBUB, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain.
Josep Lluis
JL
Gelpí
Department of Biochemistry and Molecular Biology and IBUB, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain ; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Josep J
JJ
Centelles
Department of Biochemistry and Molecular Biology and IBUB, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain ; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Marta
M
Cascante
D000818:Animals; D002104:Cadmium / Q000633:toxicity*; D005636:Fructosephosphates / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D019298:Glucose-6-Phosphate / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects*; D006593:Hexokinase / Q000378:metabolism; D066298:In Vitro Techniques; D008628:Mercury / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism*; D010732:Phosphofructokinase-1 / Q000378:metabolism; D025221:Phosphofructokinases / Q000378:metabolism
D005636:Fructosephosphates; D002104:Cadmium; D019298:Glucose-6-Phosphate; C027618:fructose-6-phosphate; D025221:Phosphofructokinases; D006593:Hexokinase; D010732:Phosphofructokinase-1; D008628:Mercury; D005947:Glucose