The Chemistry of Lanthanides in Biology: Recent Discoveries, Emerging Principles, and Technological Applications

Abstract

The essential biological role of rare earth elements lay hidden until the discovery in 2011 that lanthanides are specifically incorporated into a bacterial methanol dehydrogenase. Only recently has this observation gone from a curiosity to a major research area, with the appreciation for the widespread nature of lanthanide-utilizing organisms in the environment and the discovery of other lanthanide-binding proteins and systems for selective uptake. While seemingly exotic at first glance, biological utilization of lanthanides is very logical from a chemical perspective. The early lanthanides (La, Ce, Pr, Nd) primarily used by biology are abundant in the environment, perform similar chemistry to other biologically useful metals and do so more efficiently due to higher Lewis acidity, and possess sufficiently distinct coordination chemistry to allow for selective uptake, trafficking, and incorporation into enzymes. Indeed, recent advances in the field illustrate clear analogies with the biological coordination chemistry of other metals, particularly Ca^II and Fe^III, but with unique twists-including cooperative metal binding to magnify the effects of small ionic radius differences-enabling selectivity. This Outlook summarizes the recent developments in this young but rapidly expanding field and looks forward to potential future discoveries, emphasizing continuity with principles of bioinorganic chemistry established by studies of other metals. We also highlight how a more thorough understanding of the central chemical question-selective lanthanide recognition in biology-may impact the challenging problems of sensing, capture, recycling, and separations of rare earths.

Figure 1

Properties of the lanthanide series. The elements are scaled by ionic radius (Ln^III, CN = 8); Lewis acidity increases from La to Lu. Elemental abundances in the crust range from blue (most abundant) to gray (least abundant). Pm has no stable isotopes and is not found in Nature. Boxes are colored according to currently known biological utilization. The other two REs, Y and Sc, are not shown. The ionic radius of Y is similar to that of Ho, and abundance is similar to that of La. Sc is not discussed in this Outlook.

Figure 2

Model for lanthanide uptake and utilization in M. extorquens based on the work of the Cotruvo,⁻ Vorholt, and Martinez-Gomez and Skovran laboratories. Unknown/postulated functions (the exact ligand for p1778, functions of p1779 and p1781, and LanM–MxcQ interaction) are indicated with parentheses and question marks.

Figure 3

(A) Reaction catalyzed by MDHs, with E_m of the c-type cytochrome redox partners of Me Ca-MDH (MxaG) and Ln-MDH (XoxG) shown. The reactive C5 position of PQQ is denoted. Modified from ref (43). (B) Active site of Mf Ln-MDH (PDB code 4MAE), modeled with Ce. Ce^III is a cream sphere; protein ligands are in gray sticks, and PQQ is in salmon. A ligand from the crystallization solution has been omitted.

Figure 4

Lanmodulin as a model system to study biological principles of selective RE recognition. (A) Solution structure of Y^III–LanM (PDB code 6MI5). Y^III ions are in cyan, and EF loops are shown in gray. Metal coordination by EF4 is weak and likely not physiologically relevant. (B) Detail of Y^III coordination in LanM (EF3), with coordinating residues and the N_i+1–H···N_i hydrogen bond involving the proline residue shown. (C) The hydrogen bonding connectivity of the EF2/3 pair illustrates the importance of cooperativity in RE recognition. (D) Working model for selectivity for Ln^III (and Y^III) over Ca^II.

Figure 5

M. extorquens selectively uptakes early lanthanides into its cytosol. Cells expressing the LaMP1 sensor were grown without lanthanides, and at t = 0, 2 μM Ln^III was added to each culture. Increased FRET ratio indicates increased sensor-bound Ln^III ions. Error bars omitted for clarity. * p < 0.05 (Sm vs Ca), ** p < 0.01 (La–Nd vs Ca). Modified from ref (41).