Coord. Chem. Rev. [BCB]

Abstract :

Copper (Cu) is an essential micronutrient for most organisms and serves mainly as a redox-active catalytic centre in enzymes cycling between Cu⁺ and Cu²⁺. Membrane transporters and shuttles are involved to bring and insert Cu into these enzymes and to control tightly the copper metabolism, whose failure can lead to severe diseases. The main oxidation state intracellularly is Cu⁺, whereas Cu²⁺ is mainly found in extracellular fluids. A basic approach to investigate Cu metabolism in vivo and in cellulo contemplates the use of luminescent (mostly fluorescent) or magnetic resonance imaging (MRI)-active probes. Here, we focus on sensors of the Cu²⁺ state. First, Cu metabolism and speciation are revised, focusing on the main extracellular fluids (blood plasma, urine, cerebrospinal fluid, synaptic cleft, milk, saliva, sweat) and cell culture media, and highlighting the notion of exchangeable Cu²⁺ pool. Indeed, in contrast to bulk Cu measurements, sensors can only detect Cu²⁺ that is labile and thermodynamically accessible. Thus, the kinetics and thermodynamics of the exchangeable pools determine the quantity of Cu²⁺ that can be measured and influence the design of the sensor. The study of the best-known exchangeable Cu²⁺ pool in blood plasma, i.e. serum albumin, shows that a sensor might need a sub-femtomolar affinity for Cu²⁺ to compete with endogenous Cu²⁺ ligands. The selectivity of the probe for Cu²⁺ is also discussed, in particular against Zn²⁺, which is much more available than Cu²⁺ in the extracellular fluids (e.g. at least 10⁶ times in the blood). Finally, the analysis of the literature on luminescent and MRI-active Cu²⁺ sensors applied in extracellular media show indeed how challenging such measurement is, and that none of the sensors reported convincingly and specifically detects Cu²⁺ in a biological system. Indeed, when considering all the sought parameters, i.e. thermodynamics and kinetics of the Cu²⁺-sensor, the specificity towards Cu²⁺, the reversibility, the sensitivity of the luminescent or MRI response and hence the required sensor concentration, it becomes clear that this is a huge challenge and that we stand just at the dawn of this field.

Reference :

Enrico Falcone, Michael Okafor, Nicolas Vitale, Laurent Raibaut, Angélique Sour and Peter Faller

Extracellular Cu²⁺ pools and their detection: From current knowledge to next-generation probes 

Coordination Chemistry Reviews, Vol. 433, 15 April 2021, 21372 - DOI: https://doi.org/10.1016/j.ccr.2020.213727

 

Contacts:

Enrico Falcone, Angélique Sour and Peter Faller - équipe BCB, Institut de Chimie (UMR 7177)