Metal ions' central role in PQQ-dependent alcohol dehydrogenases

In the past fifteen years, there has been an increase in research on lanthanide (Ln) biochemistry due to the discovery of Ln-using bacteria in 2011, and the identification of the first and only known family of Ln-dependent enzymes, namely Ln-dependent alcohol dehydrogenases (Ln-ADH). These enzymes are closely related to Ca-dependent alcohol dehydrogenases (Ca-ADH), although the two enzyme families are encoded by different genes. Ln³⁺ ions tune Ln-ADH reactivity to an extent that was unexpected. The enzyme is highly active with early less Lewis acidic Ln³⁺ ions and inactive with late Ln³⁺ ions. Several studies have tried to understand this contrasting reactivity, either by looking directly at the enzyme or by designing enzyme mimics, and by combining experimental evidence and computational modeling. Despite these efforts, a clear understanding of the role of the metal ion (Ca²⁺, Ln³⁺) in the catalysis is still lacking. This review provides an overview of the actual knowledge on the reactivity of Ln-ADH and the closely related Ca-ADH. In light of these data, it critically presents and discusses the actual hypotheses proposed to explain the central role of the metal ion in the catalysis.