Interchangeable utilization of metals: New perspectives on the impacts of metal ions employed in ancient and extant biomolecules

Abstract

Metal ions provide considerable functionality across biological systems, and their utilization within biomolecules has adapted through changes in the chemical environment to maintain the activity they facilitate. While ancient earth's atmosphere was rich in iron and manganese and low in oxygen, periods of atmospheric oxygenation significantly altered the availability of certain metal ions, resulting in ion replacement within biomolecules. This adaptation mechanism has given rise to the phenomenon of metal cofactor interchangeability, whereby contemporary proteins and nucleic acids interact with multiple metal ions interchangeably, with different coordinated metals influencing biological activity, stability, and toxic potential. The ability of extant organisms to adapt to fluctuating metal availability remains relevant in a number of crucial biomolecules, including the superoxide dismutases of the antioxidant defense systems and ribonucleotide reductases. These well-studied and ancient enzymes illustrate the potential for metal interchangeability and adaptive utilization. More recently, the ribosome has also been demonstrated to exhibit interchangeable interactions with metal ions with impacts on function, stability, and stress adaptation. Using these and other examples, here we review the biological significance of interchangeable metal ions from a new angle that combines both biochemical and evolutionary viewpoints. The geochemical pressures and chemical properties that underlie biological metal utilization are discussed in the context of their impact on modern disease states and treatments.

Keywords: interchangeability; iron; magnesium; manganese; metalloprotein; metals; reactive oxygen species; redox regulation; ribosome; superoxide dismutase.

Figure 1

Transition metals and oxidative stress.A, transition metals. A section of the periodic table showing s-block (orange), d-block (cyan), and p-block (green) chemical elements. Transition metals of the first row, characterized by partially filled d-subshells, are shown in dark cyan squares in bolded black lettering. Zn (which possesses a complete d-subshell) is also shown in this group. The electronic structures of the d-block elements are shown in blue lettering. B, reactions of the superoxide anion; iron and redox cycling. Negatively charged free radical superoxide (O₂^•−, shown in red lettering) is the product of one-electron (e⁻) reduction of dioxygen (O₂). Upon protonation, O₂^•− can form the hydroperoxyl radical (HO₂^•). Superoxide dismutase (SOD, cyan oval) catalyzes the dismutation (disproportionation) of O₂^•−, thereby generating O₂ and hydrogen peroxide (H₂O₂). H₂O₂ is converted to H₂O by various antioxidant enzymes, such as catalases (CAT), glutathione peroxidases (GPX), and peroxiredoxins (PRX). Redox-active Fe²⁺ ions are oxidized by H₂O₂, generating highly reactive hydroxyl radicals (OH^•) and Fe³⁺ through the Fenton reaction. Fe³⁺ can be reduced to Fe²⁺ by O₂^•−, resulting in redox cycling (purple arrows). By itself, O₂^•− can reduce Fe³⁺ to Fe²⁺ within iron–sulfur cluster proteins, resulting in enzyme inactivation and accumulation of Fe²⁺, which further powers Fenton chemistry. Modified from Ref. (271).

Figure 2

The six- and five-coordinate geometries. Diagrams (2D on the left; 3D on the right) of the six-coordinate octahedral geometry (A) and the atypical five-coordinate trigonal bipyramidal geometry (B) of various metal ions within biomolecules discussed in the article. M represents the ion of iron or manganese; L represents a ligand. Modified from Ref. (128).

Figure 3

Schematic representation of concentrations of oxygen and selected metal cations in earth oceans. Estimates of the appearance of metal-utilizing biomolecules are shown above the graph in gradient-colored horizontal bars, indicating the early appearance of the ribosome. The most ancient superoxide dismutases (SODs), likely Fe-SODs, gave rise to Mn-SODs as oxygenation increased, with Cu/Zn-SODs appearing subsequently as copper and zinc became available. Oxygen levels (red line, right axis) are given as p_O2 (partial pressure of oxygen) relative to PAL (present atmospheric level). The dotted line indicates the time of the great oxidation event (GOE). Modified from Refs. (103, 173, 272).

Figure 4

Structural properties of Mn-specific, Fe-specific, and cambialistic Mn/Fe-SODs.A, comparison of the crystal structures (top) and the metal-bound active sites (bottom) of Fe-SOD from Escherichia coli, Mn-SOD (SodA) and cambialistic Mn/Fe-SOD (cam-SOD, SodM) from Staphylococcus aureus. Metal ions (shown as colored spheres; orange for iron ion and green for manganese ion) are coordinated by three histidine (His) residues and one aspartic acid (Asp) residue and a solvent molecule (not shown). The figure is generated using PyMol; Protein Data Bank IDs are indicated in the figure. B, superimposed ribbon representation of Mn-specific SodA (orange) and cambialistic Mn/Fe-SodM (cyan) monomer structures from Staphylococcus aureus is shown on the left. Superimposed structures of active centers of SodA and SodM are shown on the right. Four residues from the primary coordination sphere (His27, His81, Asp161, and His165, black lettering) coordinate a metal ion (Mn is shown as a green sphere). Two residues from the secondary coordination sphere (SodA: Gly159, Leu160, orange lettering; SodM: Leu159, Phe160, cyan lettering) provide cambialistic properties to SodM. SOD, superoxide dismutase.

Figure 5

rRNA is a substrate for the site-specific Fenton reaction.A, the highly conserved part of the expansion segment 7 (ES7L) of the large ribosomal subunit 60S from Saccharomyces cerevisiae. The depicted fragment corresponds to nucleotide pairs A501:U612 and U502:A611 of the ES7L and is shown in colors, surrounding bases are shown in gray. Dashed lines indicate predicted polar contacts between the four conserved bases (A501:U612 and U502:A611). Mg²⁺ ions are shown as green spheres. The Protein Data Bank file 4V88 was used. Replacement of Mg²⁺ with Fe²⁺ (shown as an orange sphere) powers the rRNA-localized Fenton reaction under oxidative conditions, whereupon the hydroxyl radical (•OH) is formed. •OH hydrolyses the sugar phosphate backbone at the specific site between A611 and U612. Modified from Ref. (21). B, Mg²⁺, Fe²⁺, and Mn²⁺ interchangeability on the ribosome. Unstressed cells contain active ribosomes, which bind divalent metal cations throughout their structure (bottom). These are predominantly Mg²⁺ but include a number of Fe²⁺ ions. In oxidative stress conditions, Fe²⁺ participates in Fenton reactions generating •OH radicals, which cleave the rRNA and fragment the ribosome (top left). However, if sufficient Mn²⁺ is available, the Fe²⁺ is displaced and Mn²⁺ occupies these sites. Under oxidative stress, a ribosome that coordinates Mn²⁺ in place of Fe²⁺ is not subjected to the generation of hydrolytic radical species and, thereby, is resistant to the stress-induced damages (top right). Modified from Ref. (123).