Composite Aromatic Boxes for Enzymatic Transformations of Quaternary Ammonium Substrates

Abstract

Cation-π interactions to cognate ligands in enzymes have key roles in ligand binding and enzymatic catalysis. We have deciphered the key functional role of both charged and aromatic residues within the choline binding subsite of CTP:phosphocholine cytidylyltransferase and choline kinase from Plasmodium falciparum. Comparison of quaternary ammonium binding site structures revealed a general composite aromatic box pattern of enzyme recognition sites, well distinguished from the aromatic box recognition site of receptors.

Thermodynamic consequences of Tyr to Trp mutations in the cation–π-mediated binding of trimethyllysine by the HP1 chromodomain

“…5,6 Nonetheless, there is a dearth of direct experimental data in proteins demonstrating that Trp provides a greater driving force for cation-p interactions than Phe or Tyr. [7][8][9][10][11][12][13] The recognition of trimethyllysine (Kme3) on histone proteins by Kme3 reader proteins is a biologically and medicinally relevant group of PPIs mediated by cation-p interactions. These epigenetic PPIs, which mediate gene expression, have Electrostatic potentials were calculated in Spartan at the B3LYP/6-31G* level of theory (+100 to À100 kcal mol À1 ).…”

Cation–π Interactions Contribute to Substrate Recognition in γ‐Butyrobetaine Hydroxylase Catalysis

“…Functionally and structurally diverse proteins contain aromatic cages (or aromatic boxes) as recognition modules for substrate binding. Aromatic cages typically comprise the sidechains of 2–4 aromatic residues (Trp, Tyr, Phe), and are observed on both exposed and buried sites . Work by Dougherty and coworkers has demonstrated that aromatic cages can recognize positively charged quaternary ammonium species via favorable cation–π interactions …”

“…Aromatic cages typicallyc omprise the sidechainso f2 -4 aromatic residues (Trp, Tyr, Phe), and are observedo nb oth exposed and buried sites. [14][15][16] Work by Dougherty and coworkers has demonstrated that aromatic cages can recognize positivelyc harged quaternary ammonium species via favorable cation-p interactions. [17][18][19] Cation-p interactions are involved in associations of Cysloop receptors and G-protein-coupled receptors with neurotransmitters, including acetylcholine, serotonin,d opamine, epinephrine, and histamine.…”

Recognition of shorter and longer trimethyllysine analogues by epigenetic reader proteins

“…The importance of cation-π interactions in biomolecular recognition has been well established; [12][13][14][15] they appear as a dominant driving force for the recognition of quaternary ammonium cations in several biologically relevant protein-ligand interactions. [16][17][18][19] Fmoc-protected OrnMe3 and hKMe3 were synthesised from Fmoc-Orn-OH and Fmoc-hK(Boc)-OH, and subsequently incorporated into the position 4 of histone H3 peptide (sequence: ARTXQTARKS) ( Fig. 1C, and Scheme S1 and Fig.…”