Structural, Kinetic, and Theoretical Studies on Models of the Zinc-Containing Phosphodiesterase Active Center: Medium-Dependent Reaction Mechanisms

• Published in: Chemistry : a European journal Vol. 13; no. 32; pp. 9093 - 9106
• Main Authors: Selmeczi, Katalin, Michel, Carine, Milet, Anne, Gautier-Luneau, Isabelle, Philouze, Christian, Pierre, Jean-Louis, Schnieders, David, Rompel, Annette, Belle, Catherine
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01.01.2007; WILEY‐VCH Verlag
• Subjects: ab initio calculations; Binding Sites; bioinorganic chemistry; Crystallography, X-Ray; Enzyme Activation; Hydrogen-Ion Concentration; Kinetics; Magnetic Resonance Spectroscopy - methods; Magnetic Resonance Spectroscopy - standards; Models, Biological; Models, Molecular; Molecular Structure; Organometallic Compounds - chemical synthesis; Organometallic Compounds - chemistry; phosphodiesters; Phosphoric Diester Hydrolases - chemistry; reaction mechanisms; Reference Standards; Ribonucleases - chemistry; Sensitivity and Specificity; Spectrometry, Mass, Electrospray Ionization - methods; Spectrophotometry, Ultraviolet - methods; Stereoisomerism; zinc; Zinc - chemistry
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.200700104

Dinuclear zinc(II) complexes [Zn2(bpmp)(μ‐OH)](ClO4)2 (1) and [Zn2(bpmp)(H2O)2](ClO4)3 (2) (H‐BPMP=2,6‐bis[bis(2‐pyridylmethyl)aminomethyl]‐4‐methylphenol) have been synthesized, structurally characterized, and pH‐driven changes in metal coordination observed. The transesterification reaction of 2‐hydroxypropyl p‐nitrophenyl phosphate (HPNP) in the presence of the two complexes was studied both in a water/DMSO (70:30) mixture and in DMSO. Complex 2 was not reactive whereas for 1 considerable rate enhancement of the spontaneous hydrolysis reaction was observed. A detailed mechanistic investigation by kinetic studies, spectroscopic measurements (1H, 31P NMR spectroscopy), and ESI‐MS analysis in conjunction with ab initio calculations was performed on 1. Based on these results, two medium‐dependent mechanisms are presented and an unusual bridging phosphate intermediate is proposed for the process in DMSO. Media influences catalysis! Two different catalytic pathways for the hydrolytic activity of a dinuclear zinc complex are proposed as a function of solvent (DMSO, H2O/DMSO; see illustration). Combined experimental studies and theoretical calculations support both reaction pathways.