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Instant insight: Essential metals
21 May 2007
Xiangyang Liang, Dominic Campopiano and Peter Sadler at the University of Edinburgh, UK, examine how and why metals cross membranes.
Cell membranes are natural barriers, surrounding the cytoplasm and cell compartments and separating them from the external environment. They comprise a lipid bilayer with transmembrane proteins and proteins attached to the membrane surface. These membrane proteins perform various functions, serving as channels, pumps, transporters, enzymes and receptors (sensory proteins). Metal ions are essential in many of these biological processes.
Membrane proteins can be involved in transporting metal ions (and sometimes their associated ligands) through membranes. Ion channels are transmembrane proteins that form pores that allow ions to cross into or out of a cell. Ions crossing ion channels always flow in the same direction as diffusion: from a more to a less concentrated solution, or from positive to negative potential. The channel pores are gated. For ligand-gated channels, the gates open or close in response to a ligand such as Ca(II), a guanine nucleotide binding protein (G-protein), or glutamate; for voltage-gated channels, the gates respond to a change in membrane potential. These channels are highly selective and recognise only certain ions and allow them to pass through.
Transmembrane proteins allow metal ions and complexes to cross cell membranes
A metal ion's passage across a membrane can be passive, without energy requirement, or active, with energy supplied from adenosine triphosphate (ATP) hydrolysis. Ion pumps and transporters transfer metal ions against the direction of diffusion using this energy of hydrolysis. These include P-type ATPase pumps, enzymes that catalyse the conversion of ATP to adenosine diphosphate (ADP). The released phosphate is transferred to an aspartate residue to form a phosphorylated (P) intermediate, hence the term P-type. Ion transporters are a very large and diverse family of membrane proteins, including ATP-binding cassette transporters, the Zip family of zinc transporters, the cation diffusion facilitator family, the copper transporters Ctr and COPT and iron-regulated transporters, which also actively transport various metal ions, as is apparent from their names.
There is a variety of other enzymes in membranes, including receptor-like kinases and respiratory enzymes. Kinases are a class of enzymes that phosphorylate substrates by transferring phosphate onto them. Metal ions such as Mg2+ or Mn2+ are essential for the phosphorylation process. Receptor-like kinases play dual roles, acting as both receptors and kinases. Respiratory enzymes are mainly metalloproteins, containing metals such as iron and copper. In the inner membrane of cell mitochondria, electrons are passed along a series of respiratory enzyme complexes. These electrons are generated from NADH (reduced nicotinamide adenine dinucleotide), produced by oxidation of nutrients such as glucose, and are ultimately transferred to molecular oxygen. The passage of electrons between the complexes releases energy that is stored in the form of a proton gradient across the membrane and is then used by ATP synthase to make ATP from ADP and phosphate.
Metal ion affinity for ligands in a lipid environment can differ from that in aqueous media (extra- and intracellular environments). The thermodynamically-preferred binding sites for metal ions in membranes cannot easily be predicted given current knowledge of metal-ligand stabilities, since most have been determined for aqueous solutions only. Seemingly poor ligands could bind tightly to metal ions in protein cavities with low dielectric constants. Understanding the interactions of metals with transmembrane proteins will aid the design of more effective metallodrugs.
Binding to metal ions means antiviral drug AMD3100 shows higher affinity for its target
GPCRs have a negatively-charged electrostatic surface directed towards the cell membrane exterior and are strong potential targets for metal ions. The affinity of the antiviral drug AMD3100 for its target, the chemokine receptor CXCR4, is enhanced by binding to Cu(II), Ni(II) or Zn(II). In models, metal ions bound in the macrocyclic rings of AMD3100 can coordinate to specific aspartic and glutamic acid carboxylate groups in the extracellular loops of CXCR4 and amine groups in the macrocycles can form hydrogen bonds to CXCR4 side-chains. Also, hydrophobic interactions between the indole rings of tryptophan residues in CXCR4 and the carbon backbone of the bicyclam are possible. It should be possible to design new generations of metal complexes that will bind specifically to different GPCRs based on such interactions.
These examples provide a stimulus for further exploration of the chemistry of metal ions in membranes and offer promise for the discovery of drugs with novel modes of action.
Read Xiangyang Liang, Dominic Campopiano and Peter Sadler's critical review: 'Metals in membranes' in issue 6 of Chemical Society Reviews.