Incorporation Of Metals In Bioactive Molecules In The Process Of Evolution

In the modern version of Mendeleev's table, transition metals are in the center and clearly share many attributes. They exist as (MnO42-, WO42- exceptions) charged cations in solution under biological conditions. Many of these ions can have similar ionic radii, so they tend to bind to similar classes of ligands. Indeed, ligating atoms that bind metal in a particular protein are found in four types of amino acid side chains: histidines, cysteine, glutamic, and aspartic acids. Less frequently, tyrosine and methionine coordination is found. Nature generally uses an array of two or five of these coordinating side chains in the majority of metalloenzymes.

Once it gathers these different metals, how does the cell know which metal to put into which enzyme-active site? A traditional view in the field of bioinorganic chemistry has been that metal selectivity is due to very sophisticated chelating properties of the individual apo-proteins. In this scenario, apo-proteins are thought to poise the exact orientation of these side chains to match the precise ionic radius and electronic preference of the functional metal ions, for example, Zn2+, and to discriminate against all others, such as Cu2+ or Fe2+ ions. In some of these cases, very little difference is present in ionic radii. The proteins are thus viewed as highly specific chelating agents with finely tuned kinetic and thermodynamic properties that have been selected through evolution to bind only one type of transition metal ion. In this model, each apo-protein as it is produced in the cell simply selects a metal ion from the cytoplasm. In general, however, the field has moved to the point of thinking of membrane-bound proteins as transporters.

A breakthrough in the process of evolution of bioactive molecules from simple atoms must be the spontaneous association of small molecules to generate big molecules (i.e., polymers such as polypeptides and polynucleotides) that organized and resulted in the emergence of a giant molecule with structure and characteristics distinct from the inanimate matter in terms of its stability, spontaneous development, and awareness of environment. In that simplest form of the primitive life, it is possible that the minimum cellular processes were governed through inorganic catalysts.

In such reactions, the simplest redox reactions of the biological molecules were likely to be mediated and catalyzed by metal ions.

The primitive life processes evolved in Archean water were definitely anoxic and the environment was reducing the metal ions remained in the sparingly soluble state, limiting their concentration. When the reducing environment no longer existed upon exhaustion of readily available hydrogen, oxygen started appearing in the available form in the environment by splitting water by the photosynthetic apparatus. It is argued that metals available at that period at relatively higher concentration were selected by and encrypted in the bioactive molecules to perform the specific catalytic or other functions and thus became essential metals in the life processes. During transition from anoxic to oxic environment, some elements, like Cu, Fe, Ni, Zn, Mo, and Co, began to participate in biological functions.

The cells had to incorporate some of those metals in their life processes to scavenge the increasing oxygen availability. For instance, in catalase, cytochrome oxidase, or dismutase, metals such as copper, iron, or zinc are the cofactors and part of the active site of the enzyme is used in the production of oxygen or in the oxygen defense mechanisms. Among several thousand proteins expressed in a typical bacterium, about 30% are metalloproteins. The general order of prevalence of major transition metals in enzymes in Escherichia coli is Zn, Fe, Cu, Mo, Mn, Co, and Ni [8]. Although many of the metals thus became essential in the vital processes, the cell must face a difficult situation in uptake of the required metals only from the environment. The uptake system must be specific and regulated so that the system not only recognizes the specific metal ion but also senses any changes in the concentration of the metal in the surrounding environment. The microbial genome is the information bank and can be credited when needed in response to the signal from the environment.

11.5.1 Concepts of Heavy Metal Toxicity, Tolerance, and Resistance

Because nonspecific transporters are expressed constitutively, the cell hyperaccumulates heavy metal ions in the face of high concentration of any heavy metal in the environment. Once inside the cell, heavy metal cations like Hg2+, Cd2+, and Ag+ with high atomic numbers tend to bind to -SH groups. The minimal inhibitory concentration of these metal ions is a function of the complex dissociation constants of the respective sulfides. By binding to SH groups, the metals may inhibit the activity of sensitive enzymes. Other heavy metal cations may interact with physiological ions (Cd2+ with Zn2+ or Ca2+; Ni2+ and Co2+ with Fe2+; Zn2+ with Mg2+), thereby inhibiting the function of the respective physiological cation.

Heavy metal cations may bind to glutathione; the resulting bis-glutathione complexes tend to react with molecular oxygen to oxidized bis-glutathione GS-SG [17], the metal cation and H2O2. Because the oxidized bis-glutathione must be reduced again in an NADPH-dependent reaction and the metal cations immediately catch another two glutathione molecules, heavy metal cations cause considerable oxidative stress. Finally, heavy metal oxyanions interfere with the metabolism of the structurally related nonmetal (chromate with sulfate; arsenate with phosphate) and reduction of heavy metal oxyanion leads to the production of radicals, e.g., in the case of chromate. Therefore, the "gate" that was always "open" for Mg2+ or phosphate uptake turns out to be responsible for the heavy metal toxicity.

11.5.2 Emergence of Heavy Metal Tolerant Mutants: Misfit in Evolutionary Selection

Metal-tolerant mutants may arise out of mutations that affect the expression of the gene for the rapid and nonspecific transporters. In fact, corA and pit mutants with a tolerant phenotype towards cobalt and arsenate, respectively, have been isolated [18-20]. However, tolerant mutants are less fit than the wild type in the medium without toxic heavy metal ion and are thus rapidly overgrown by the revertant strain.

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