Zn-bound water

Kimura (225) studied a potentially attractive model Zn-complex of [12]aneN3. It confirms to a tetrahedral geometry with a H20 at the fourth coordination site [LZnnOH2] and pKa of Zn-bound water is... 

In astacin and MMPs, Zn " " ions are bound to three His s as in carbonic anhydrases (CAs). However, a nearby Glu C02 residue is required to act as a nucleophile or general base for the Zn -bound water (like CPD). 

CA provides the best-defined example of an ionized Zn -bound water mechanism. " Thrl99 and orientation residues such as Glul06, and proton shuttle residues such as His64, are needed to make CA the fastest biological catalyst. 6-Pyruvoly-tetrahydropterin synthase,E. coli fuculose-1-phosphate aldolase, " " and E. coli fructose-1,6-bisphosphate aldolase belong to the CA family, although the reactions these enzymes are involved in are different. 

Since Tyrl49 is located in a similar position to His231 of thermolysin (Scheme 3), it is considered that these two amino-acid residues have a similar function. Glu93 in astacin may work to shuttle protons between the Zn -bound water and the nitrogen atom of the scissile peptide bond (Schemes 6b-6d) in analogy to Glu270 of CPDA and Glul43 of thermolysin. 

E. coli cytidine deaminase (CDA) is an enzyme that catalyzes hydrolytic deamination of cytidine to uridine (or from 2 -deoxycytidine to 2 -deoxyuridine) (Scheme 8). This enzyme is considered to be a member of the MMP family, although the Zn -binding site contains two Cys and one His residues. On the basis of the X-ray crystal structure of a transition-state analogue complex,a mechanism was proposed as shown in Scheme 8, in which Glul04 serves multiple roles the deprotonation of the Zn " -bound water and simultaneous protonation to N3 of the substrate (Scheme 8a), stabilization of the first tetrahedral transition state (Scheme 8b), and protonation of the leaving amino group at the 4-position of the substrate in the second tetrahedral intermediate (Scheme 8c).Upon elimination of NH3, an E-P complex is formed (Scheme 8d) and the enzyme goes into the next turnover. The deamination mechanism of E. coli... 

B. cereus enzyme showed one Zn coordinated by His86, His88, and His 149, and a water in a tetrahedral arrangement. Scheme 9 represents a proposed mechanism for the monozinc(II)-/3-lactamase reaction with benzylpenicillin. Two values, p ai and pXa2, of /3-lactamase were found to be 5.6 and were assigned to a Zn +-bound water (Scheme 9a and 9b), and Asp90 carboxylic acid (Schemes 9c and 9d). The mechanism involves the binding of the substrate carbonyl to Zn (Scheme 9c), nucleophilic attack of the Zn -bound HO to the carbonyl carbon of the substrate (Scheme 9c), and subsequent stabilization of the oxyanion by Zn + (Schemes 9d and 9e).124,125,1 0... 

Moreover, the crystal structure of the complex of the anthrax LF with an intact natural substrate (Met-Leu-Ala-Arg-Arg-Lys-Pro-Val-Leu-Pro-Ala-Leu-Thr-Ile-Asn-Pro) was solved (Scheme 14), where the main-chain peptide bond between Alall and Leu 12 is to be cleaved. The amino-acid residue nearest to the Zn + ion was Pro 10, about 6 A away from the Zn -bound water, a fact suggesting that this structure represents a precleavage complex. 

A zinc(II) complex of the 12-membered macrocyclic tetraamine, cyclen (1,4,7,10-tetraazacyclo-dodecane) (34), was later shown to be a useful Zn -enzyme model, although the p a value (7.8) of the Zn -bound water (for (34a) (34b) + H ) was a little higher than that (7.3) for the triamine complex (33) (Scheme 28). These findings demonstrated that simple zinc(II) complexes can be used to activate H2O at physiological pH for catalytic reactions, in analogy to the monometallic zinc(II) enzymes. 

The coordination numbers as well as the geometry of the model complex correspond to the active center of carbonic anhydrase. The of 7.3 of the Zn " "-bound water is similar to that of the natural enzyme. With these characteristics, the Zn +-[12]aneN3-complex 1 is one of the best carbonic anhydrase models known so far and superior to other closely related macrocyclic polyamine complexes. For example, the analogous Cu -complex 2 or the similar Zn +-[12]aneN4-complex 3 shows a lower catalytic activity, mainly caused by the higher pA a values of the bound water. ... 

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