How Lanthanide Ions Affect the Addition–Elimination Step of Methanol Dehydrogenases

Abstract

The recently discovered methanol dehydrogenase, XoxF, is a widespread enzyme used by methylotrophic bacteria to oxidize methanol for carbon and energy, and requires lanthanide ions for its activity. This enzyme represents an essential component of methanol utilization by both methanol‐ and methane‐utilizing bacteria. The present investigation looks on the electronic, energetic and geometrical behavior of the methanol dehydrogenase from Methylacidiphilum fumariolicum SolV, which is strictly dependent on early lanthanide metals with +3 oxidation states, by examining enzyme‐substrate complexes of all the lanthanides. We focus on the catalytic reaction mechanism of two methanol dehydrogenases having as cofactor europium and ytterbium belonging to the mid‐ and later‐ series of lanthanides, in comparison with the methanol dehydrogenase containing the cerium, one early lanthanide. Our results provide evidence for the influence of the lanthanide contraction effect in all the elementary steps of the catalytic reaction mechanism. This indication may prove useful for developing new catalytic machineries of enzymes that adopt new‐to‐nature transformations.

The Effects of the Metal Ion Substitution into the Active Site of Metalloenzymes: A Theoretical Insight on Some Selected Cases

“…In fact, formaldehyde lies practically outside of the reaction site, even if it is retained in the The obtained PES was compared with that of calcium-containing MDH in our previous investigation [107]. One obvious fact, which we have widely supported in our previous works [105,106], is that despite the different charge, size, and number of coordinated residues of the ions, the topology of the active site as well as the course of the catalytic cycle for the two enzymes is very similar. This striking similarity between lanthanides and Ca 2+ ions, is, as already mentioned before, widely reported in the literature [90][91][92][93][94][95][96][97][98][99][100]105,106].…”

“…In the case of Lns-dependent MDH, the role of the Ce 3+ and Eu 3+ in the first phase of the reaction was to facilitate the attack of the substrate's oxygen (TS1, see Figure 11A), enhancing its nucleophilicity, to the C5 of PQQ. In addition, the LUMO of PQQ cofactor was more stabilized in the case of Ce, with respect to the Eu, [100,106] thus explaining the energy difference of about 4 kcal/mol calculated for the addition step (see Figure 4). The values obtained for the two Lns were substantially lower than the rate-determining step (the elimination), in which the presence of metal ions mainly ensure the stability of the architecture of the active site.…”

“…Table 1. Geometrical parameters obtained for the isolated stationary point along the reaction mechanism of Ce 3+ -MDH and Eu 3 +-MDH (in parenthesis) [105,106]. Data not available, due to the release of the product, are indicated with "n.a."…”

“…The model consists of 113 atoms, and has a total charge of zero. Among the various mechanisms proposed for MDH enzymes over the years [8][9][10]74,75,86,87,89,91,98,99,[104][105][106][107], we have chosen to explore that reported in the Scheme 2 that revealed to be the most reliable one as proposed in previous studies [100,[105][106][107].…”

PQQ-Aza-Crown Ether Complexes as Biomimetics for Lanthanide and Calcium Dependent Alcohol Dehydrogenases

“…It is however possible, and this was demonstrated by several computational studies, that Lu 3+ is too small to effectively bind to PQQ. [23][24][25] Moreover, the NMR investigations of the metal interactions with ligand 1 described in the previous section suggests a slightly different coordination environment for Ca 2+ and Ba 2+ in comparison to the Ln 3+ ions.…”