title: Inhibitory zinc sites in enzymes.
abstract: Several pathways increase the concentrations of cellular free zinc(II) ions. Such fluctuations suggest that zinc(II) ions are signalling ions used for the regulation of proteins. One function is the inhibition of enzymes. It is quite common that enzymes bind zinc(II) ions with micro- or nanomolar affinities in their active sites that contain catalytic dyads or triads with a combination of glutamate (aspartate), histidine and cysteine residues, which are all typical zinc-binding ligands. However, for such binding to be physiologically significant, the binding constants must be compatible with the cellular availability of zinc(II) ions. The affinity of inhibitory zinc(II) ions for receptor protein tyrosine phosphatase β is particularly high (K i = 21 pM, pH 7.4), indicating that some enzymes bind zinc almost as strongly as zinc metalloenzymes. The competitive pattern of zinc inhibition for this phosphatase implicates its active site cysteine and nearby residues in the coordination of zinc. Quantitative biophysical data on both affinities of proteins for zinc and cellular zinc(II) ion concentrations provide the basis for examining the physiological significance of inhibitory zinc-binding sites in proteins and the role of zinc(II) ions in cellular signalling. Regulatory functions of zinc(II) ions add a significant level of complexity to biological control of metabolism and signal transduction and embody a new paradigm for the role of transition metal ions in cell biology.
authors: King's College London, Metal Metabolism Group, Diabetes and Nutritional Sciences Division, School of Medicine, Franklin-Wilkins Bldg., 150 Stamford St., London, SE1 9NH, UK. wolfgang.maret@kcl.ac.uk
authors: Wolfgang
authors: W
authors: Maret
mesh_terms: D001419:Bacteria / Q000201:enzymology; D002384:Catalysis; D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000737:chemistry*; D004798:Enzymes / Q000737:chemistry*; D006801:Humans; D008667:Metalloproteins / Q000737:chemistry / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry* / Q000378:metabolism; D015398:Signal Transduction; D015032:Zinc / Q000737:chemistry* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D004798:Enzymes; D008667:Metalloproteins; D017027:Protein Tyrosine Phosphatases; D015032:Zinc