Other Metal Binding Antibiotics

Cys-34 also binds Au, Ag, Hg, Cd, and, to a lesser extent, Cu. Major interests in the unusual chemistry at this site include understanding the nature of bound pharmaceuticals, such as the antiarthritic auranohn, or other gold(l)-containing thiolates (Shaw, 1989). Other pharmaceutical interests involve reactions with non-metal-containing antibiotics and the recently identified complexation with nitric acid (Stamler et al., 1992). 

Several other cytotoxic agents appear to act as alkylators, although their structures do not include the classic alkylating groups. They are capable of binding covalently to cellular components and include procarbazine, dacarbazine, temozolamide, the heavy metal compounds, and some antitumor antibiotics (see Table 124-14). ... 

In general these enzymes catalyze the hydrolytic opening of the p-lactam ring according to the reaction depicted in Fig. 11.26. The hydrolytic product, unlikely the intact P-lactam, is not able to interfere with bacterial cell wall synthesis, the key effect of the antibiotic [229]. The crystal structures of several metaUo-p-lacta-mases have shown that the active site can have one or two Zn(ll) ions (Znl and Zn2) then separated by 3.5 A [242-247]. In these structures Znl is tetrahedraUy coordinated to three His and one water molecule. When present, Zn2 is either penta-coordinated to Cys, His and Asp residues and two water molecules, or to two His, one Asp and two water molecules, in a trigonal bipyramid. In the structure where the active site is composed of a binuclear Zn center, a H20/0H bridges the two metals. As in other binuclear centers with bridging solvent molecules, its activation provides the OH nucleophile for the reaction [248]. It should be pointed out that not all P-lactam antibiotics bind to the active site in the same way so mechanisms may differ from molecule to molecule. 

The chemical production of hydroxyl radical, either by metal-mediated redox reactions or as a result of radiolysis products, can induce strand breaks in DNA. An example of a chemotherapeutic agent whose chemical production of activated oxygen is believed to be the critical step in its action is bleomycin, a naturally occurring antibiotic. The binding of metals to this and other antibiotics has been summarized in detail [1—3] and the material presented here is based on these reviews. 

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