Zinc proteins models

Until recently, it was difficult to approach the question of how zinc concentrations are sensed within cells. Zinc proteins are abundant, and total zinc concentrations are quite high within cells (0.2 mM), even though most zinc is tightly bound to proteins and is therefore unlikely to be sensed by cytosolic regulatory proteins. The idea that cytosolic regulatory proteins sample a pool of free or loosely bound zinc at micromolar to picomolar concentrations has recently been discarded in favor of a model in which it is postulated that there is virtually... 

The generated model was validated experimentally by a representative series of electropherograms of CAB in capillaries partially hlled with increasing concentrations of (0-25pM) of 1 run at optimized conditions (Fig. 3.3). CAB is a zinc protein of the lyase class that catalyzes the equilibration of dissolved carbon dioxide and carbonic acid. It is strongly inhibited by sulfonamide-containing molecules. 

Copper(II)-substituted zinc proteins are generally inactive with respect to the natural and most artificial substrates (Table 2.4). In model compounds cop-per(II) is often principally four-coordinate, with at most two more ligands present at metal-ligand distances that are longer than normal coordination bonds. As a consequence, tbe ability of zinc to switch between four- and five-coordinate species without any appreciable barrier and with usual metal-donor distances is not mimicked by copper. Furthermore, binding at the four principal coordination positions is generally stronger for copper than for zinc. It follows that substrates may have slow detachment kinetics. These properties are unfavorable for catalysis. 

J. Zhang, W. Yang, J. P. Piquemal, and P. Ren,/. Chem. Theory Comput., 8, 1314—1324 (2012). Modeling Structural Coordination and Ligand Binding in Zinc Proteins with a Polarizable Potential. 

Before our work [39], only one catalytic mechanism for zinc dependent HDACs has been proposed in the literature, which was originated from the crystallographic study of HDLP [47], a histone-deacetylase-like protein that is widely used as a model for class-I HDACs. In the enzyme active site, the catalytic metal zinc is penta-coordinated by two asp residues, one histidine residues as well as the inhibitor [47], Based on their crystal structures, Finnin et al. [47] postulated a catalytic mechanism for HDACs in which the first reaction step is analogous to the hydroxide mechanism for zinc proteases zinc-bound water is a nucleophile and Zn2+ is five-fold coordinated during the reaction process. However, recent experimental studies by Kapustin et al. suggested that the transition state of HDACs may not be analogous to zinc-proteases [48], which cast some doubts on this mechanism. 

Crystal structures of a histone deacetylase-like protein (HDLP) and HDAC8 have confirmed a general pharmacophore model for HDAC inhibitors, comprising a cap joined by a hydrophobic linker to a zinc-binding group (ZBG). This model is exemplified by SAHA and the natural product HDACi Trichostatin A (TSA) 2. 

Figure 18.16 Hypothetical model for the metallobiology of AP in Alzheimer s disease. (From Bush, 2003. Copyright 2003, with permission from Elsevier.) The proposed sequence of events (1) concentration of iron and copper increase in the cortex with aging. There is an overproduction of APP and AP in an attempt to suppress cellular metal-ion levels. (2) Hyper-metallation of AP occurs which may facilitate H202 production. (3) Hyper-metallated AP reacts with H202 to generate oxidized and cross-linked forms, which are liberated from the membrane. (4) Soluble AP is released from the membrane and is precipitated by zinc which is released from the synaptic vesicles. Oxidized AP is the major component of the plaque deposits. (5) Oxidized AP initiates microglia activation. (6) H202 crosses cellular membranes to react with Cu and Fe, and generate hydroxyl radicals which oxidize a variety of proteins and lipids.

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