Structure and Reaction Mechanism of Phosphoethanolamine Methyltransferase from the Malaria Parasite Plasmodium falciparum

Conformational changes in the di-domain structure of Arabidopsis phosphoethanolamine methyltransferase leads to active-site formation

“…S3) showed a 2:1 ligand/protein stoichiometry consistent with the predicted di-domain structure. The K d value for SAH (4.6 Ϯ 0.4 M) and the binding energy (⌬G ϭ Ϫ7.19 Ϯ 0.20 kcal mol Ϫ1 ), which was largely driven by the enthalpic contribution (⌬H ϭ Ϫ10.8 Ϯ 0.2 kcal mol Ϫ1 ; T⌬S ϭ 3.6 kcal mol Ϫ1 ), were similar to those reported for the nematode and Plasmodium PMT (15)(16)(17).…”

Structural and Functional Studies of Pavine N-Methyltransferase from Thalictrum flavum Reveal Novel Insights into Substrate Recognition and Catalytic Mechanism

“…In addition to this domain, a primarily ␣-helical BIA-binding domain forms the majority of the putative binding site for the methyl group acceptor. The sequence, structure, and topology of the lid domain appear most similar to the Plasmodium phosphoethanolamine NMTs (PfPMT) (8,9) and the mycolic acid cyclopropane synthases (10) from Mycobacterium tuberculosis (supplemental Movies 1 and 2). Although the sequence identity is Ͻ20% and the root mean square deviation for C-␣ atoms is over 3-4 Å after filtering away the most different parts of the structures, the fairly high DALI Z-scores (ϳ28 -29) for these structures indicate substantial similarity in the arrangement of secondary structure elements (11).…”

“…Mutagenesis studies have also implicated His 132 and Tyr 19 in PfPMT for a possible role in catalysis, but quantum mechanics/ molecular modeling calculations do not support a role in base catalysis as initially proposed (8,14). Recent work examining changes in the kinetic and binding isotope effects of mutations to the Tyr 21 residue of glycine N-methyltransferase (GNMT) suggests that the bulky aromatic side chain of the tyrosine residue may play a role in activating the donor methyl group in SAM (16).…”

“…Recent studies of PfPMT from P. falciparum proposed that Tyr 19 , His 132 , Asp 128 , and a bound water molecule combine to provide general base catalysis and electrostatic positioning effects to increase the reactivity of the amino group of the methyl acceptor phosphoethanolamine (8,14). Asp 128 appears to be particularly important for the primary amine substrate but does not appear to play the same role for secondary or tertiary amine substrates.…”

“…Three related NMTs with relatively distinct substrate specificities have been reported and include a coclaurine NMT (CNMT) involved in the formation of the branch-point intermediate (S)-reticuline (5); tetrahydroprotoberberine NMT (TNMT) (6), which participates in the formation of several BIAs, such as noscapine and sanguinarine; and pavine NMT (PavNMT) (7,8) (Fig. 1).…”