2.B.1 The Valinomycin Carrier (Valinomycin) Family

Valinomycin is an ionophoric antibiotic that functions as a carrier to shuttle K⁺ across a biological membrane, down its electrochemical gradient, thereby eliminating the membrane potential and the K⁺ concentration gradient. It is synthesized by Streptomyces fulrissimus and contains in sequence: D-valine, L-lactate, L-valine, and D-hydroxy isovalerate repeated three times. It is extremely selective for K⁺ and renders both artificial and biological membranes permeable to this cation. The valinomycin-K⁺ complex shields the hydrophilic groups of valinomycin on the interior of the complex when K⁺ is bound and leaves the hydrophobic rich chains on the external surface exposed to the membrane phospholipid side chains. Hydroxylated analogues of valinomycin are also potassium transporters with different energetics; The presence of the hydroxyl group at three different positions is of importance because they pave the way for subsequent chemical modifications and the synthesis of new antiviral agents with reduced intrinsic toxicity (Sessa et al. 2023).  Valinomycin and monensin enhance the antibacterial activity of fluoride (Dias et al. 2023).

Valinomycin and cereulide have similar chemical structure and properties but different toxic effects. Emetic poisoning is induced by cereulide but not by valinomycin, but both are potassium-specific ionophores that affect mitochondrial function. Both compounds cause a potassium-dependent drop in the transmembrane inner membrane potential due to the uptake of K⁺ as positively charged ionophore complexes. Valinomycin is more potent than cereulide at high K⁺ (>80 mM), whereas cereulide is active at <1 mM. With cereulide, there is a substantial lag, while valinomycin acts without lag. Both ionophores induce mitochondrial swelling in the presence of K⁺. These toxins strongly inhibited respiration at the level of complex IV when used at higher concentrations than that used for detection of ionophoretic transport of K⁺.This explains the higher toxicity of cereulide at low concentrations with the positively charged potassium complex being accumulated in the cell by transport through the plasma membrane driven by the membrane potential (Teplova et al. 2006).

The generalized reaction normally catalyzed by valinomycin is:

K⁺ (out) K⁺ (in).

That for anionophoric valinomycin derivatives is:

anion (out) ⇌ anion (in).

Berezin 2015 used theory and modeling to investigate K⁺ valinomycin (Vln) carrier as a classical anionophore. This author discussed formation of the ion pair Vln:K⁺ or Vln:Cl^- versus encapsulation of the anion into a Vln:Cl^- complex as two alternative mechanisms that could account for high anionophoretic activity of the cyclic peptide (Riddell and Zhou 1994).  Constructing kinetic models helped distinguish between the two (Berezin 2015).