Mismetalation

Mismetalation is the inappropriate incorporation of metal ions into metalloproteins, in which a non-canonical metal occupies a cofactor site that normally binds another metal. This mis-metalation can occur during protein maturation, folding, or post-translational metal exchange when intracellular metal concentrations are imbalanced or when cellular metallochaperone systems fail or are overwhelmed. The result is altered activity of the affected enzyme and potential disturbances to metal homeostasis.

Metal ions bind to protein sites according to affinity and coordination geometry. If a competing metal is present at sufficient concentration, it can outcompete the physiological cofactor during folding or maturation, yielding an enzyme with reduced activity, altered specificity, or novel and often deleterious properties. Cells normally use metallochaperones, specific transporters, and buffering networks to promote correct metalation, but disruptions in these systems—genetic mutations, environmental metal stress, or nutritional deficiencies—increase the likelihood of mismetalation.

Consequences vary by enzyme but can include loss of catalytic efficiency, misregulation of metabolic pathways, abnormal redox behavior, and generation of reactive species. Mis-metalated proteins may be targeted for degradation or repaired via metal exchange pathways when available.

Common metal cofactors include iron, manganese, zinc, copper, cobalt, and nickel. Well-studied examples include ribonucleotide reductase (Fe vs Mn), superoxide dismutase (Cu/Zn or Mn), and carbonic anhydrase (Zn), where improper metalation markedly changes function. In research and biotechnology, mismetalation complicates heterologous expression of metalloenzymes and can affect product yield and stability. In medicine and toxicology, mismetalation contributes to disease by perturbing metal homeostasis. Detection relies on enzymatic activity assays, spectroscopic signatures, and measurements of metal content by inductively coupled plasma mass spectrometry or X-ray absorption spectroscopy.