Zinc complexes enzymes

Some enzymes require metal ions - such as cobalt, manganese or zinc - for their activity if these are removed by the ionic liquid by complexation, enzyme inactivation may occur. 

Pyridyl functionalized tris(pyrazolyl)borate ligands show some interesting properties including the formation of polynuclear zinc complexes.23,1 Some of these contain extensive H bonding and have potential as models for multinuclear zinc enzymes such as phospholipase C or PI nuclease.235 A bis-ligand complex of the hydrotris(5-methyl-3-(3-pyridyl)pyrazolyl)borate ligand (23) shows octahedral coordination of all six pyrazole nitrogen donors despite the steric bulk. 

Tris(2-aminoethyl)amine (tren) and hexamethyl tren form pentacoordinate complexes with a bound water. The enthalpies of ionization have been determined.242 These results dispute the data from the systems that led to the view that solvent structure mediates the pAia of zinc bound water in zinc hydrolytic enzymes. The effect was shown to be entirely enthalpic. 

The ligand tris[2-(l-methylbenzimidazol-2-yl)ethyl] nitromethane (25) has been used in the formation of zinc complexes as models of the active site of carbonic anhydrase, and the formed complexes reveal affinity for the sulfonamide-containing enzyme inhibitor acetazolamide.248... 

CO3 species was formed and the X-ray structure solved. It is thought that the carbonate species forms on reaction with water, which was problematic in the selected strategy, as water was produced in the formation of the dialkyl carbonates. Other problems included compound solubility and the stability of the monoalkyl carbonate complex. Van Eldik and co-workers also carried out a detailed kinetic study of the hydration of carbon dioxide and the dehydration of bicarbonate both in the presence and absence of the zinc complex of 1,5,9-triazacyclododecane (12[ane]N3). The zinc hydroxo form is shown to catalyze the hydration reaction and only the aquo complex catalyzes the dehydration of bicarbonate. Kinetic data including second order rate constants were discussed in reference to other model systems and the enzyme carbonic anhy-drase.459 The zinc complex of the tetraamine 1,4,7,10-tetraazacyclododecane (cyclen) was also studied as a catalyst for these reactions in aqueous solution and comparison of activity suggests formation of a bidentate bicarbonate intermediate inhibits the catalytic activity. Van Eldik concludes that a unidentate bicarbonate intermediate is most likely to the active species in the enzyme carbonic anhydrase.460... 

Zinc is the active metal in the largest group of metalloproteins found in the nature. Recently a new class of zinc enzymes with a sulfur-rich environment has emerged the thiolate-alkylating enzimes, the most prominent of which is the cobalamine-independent methionine synthase.126 For these reasons several monothiolate zinc complexes have been prepared for the modelling of these enzymes with different N2S as (13),127 130 N20,13° 132 N3,132,133 S3,134 tripod ligands, or with Cd because of the favourable spectroscopic properties with an S3 tripod ligand.135... 

The goal of the experiments we report was to create new structural model complexes for gluzincins or carboxypeptidases. With [Zn (bdtbpza)Cl] (12) for the first time a tetrahedral zinc complex with a monoanionic W,W,0-tridentate using a carboxylate 0-donor was synthesized (41). A comparison of the molecular structure of 12 with the coordination environment of the enzymes indicates its significance... 

In humans, 18 HDACs have been identified and classified according to their homology to yeast HDACs [6]. Class I, II and IV HDACs are zinc-dependent enzymes, whereas the third class (sirtuins) are NAD -dependent enzymes and are covered elsewhere in this book. Class I (H DACs 1, 2, 3, 8) are closely related to yeast Rpd3 class Ila (HDACs 4, 5, 7, 9) and class Ilb (HDACs 6, 10) are related to yeast Hdal and this latter subclass contains two catalytic sites. Finally, class IV H DACs contain just one member (HDAC 11). Whilst classes I and IV HDACs are mainly found in the nucleus of cells, class II H DACs are free to shuttle between the nucleus and the cytoplasm. The exact physiological role of each of the individual H DAC isoforms in cells is far from fully understood, yet it is known that these enzymes act on many other nonhistone substrates. They also often function as part of larger multiprotein complexes and are frequently associated with other HDAC isoforms and/or require the presence of several coregulators. 

Another zinc-utilizing enzyme is carbonate/dehydratase C (Kannan et al., 1972). Here, the zinc is firmly bound by three histidyl side chains and a water molecule or a hydroxyl ion (Fig. 27). The coordination is that of a distorted tetrahedron. Metals such as Cu(II), Co(Il), and Mn(ll) bind at the same site as zinc. Hg(II) also binds near, but not precisely at, this site (Kannan et al., 1972). Horse liver alcohol dehydrogenase (Schneider et al., 1983) contains two zinc sites, one catalytic and one noncatalytic. X-Ray studies showed that the catalytic Zn(II), bound tetrahedrally to two cysteines, one histidine, and water (or hydroxyl), can be replaced by Co(II) and that the tetrahedral geometry is maintained. This is also true with Ni(Il). Insulin also binds zinc (Adams etai, 1969 Bordas etal., 1983) and forms rhombohedral 2Zn insulin crystals. The coordination of the zinc consists of three symmetry-related histidines (from BIO) and three symmetry-related water molecules. These give an octahedral complex... 

The unique size, polarizability, and geomertric properties of the C-Se anion may ultimately be exploited toward zinc complexation in a selenocysteine-engineered protein alternatively, this group might be incorporated into a potent zinc-enzyme inhibitor. 

In its behavior with Zn2+, other metal ions, and EDTA, rat-epi-didymal a-D-mannosidase closely resembles the jack-bean enzyme. The greater ease of dissociation of the epididymal protein-zinc complex has been discussed under pH and Stability (see Section 11,6 p. 413). 

A number of important structural aspects of zinc complexes as found in enzymes are introduced in this section to serve as background information for the subsequent sections. Aquated Zn(II) ions exist as octahedral [Zn(H20)6] + complexes in aqueous solution. The coordinated water molecules are loosely bound to the Zn + metal center and exchange rapidly with water molecules in the second coordination sphere (see Figure 1) with a rate constant of ca 10 s at 25 °C extrapolated from complex-formation rate constants of Zn + ions with a series of nucleophiles. The mechanism of the water exchange reaction on Zn(II) was studied theoretically, from which it was concluded that the reaction follows a dissociative mechanism as outlined in Figure 2. ... 

We shall first explore some of the important structural features of zinc and cadmium complexes and, to anticipate our findings a little, we shall find a rich variety of stereochemistry for each of these elements. One of their most striking features is their stereochemical flexibility each is willing to submit readily to the structural demands of the ligand, but they often do so in different ways. In the second part of this survey we shall see how this ready variation of stereochemistry is put to good use in the active site environment—and probably function—of the supremely important zinc metalloenzymes, enzymes which are capable of dramatic catalysis of a wide range of reactions. 

A crystal structure of a dinuclear zinc complex of the porphin precursor, l,2,3,7,8,12,13,17,18,19-decamethylbiladiene-a,c (174) has been described1190,1191 and the octaethyhsobacteriochlorin complex (175) has been studied as a model for siroheme enzymes.1192... 

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