The structure of a metal site in metalloenzymes critically influences the fine-tuning of some of the most complicated reactions in the chemistry of life processes.
We study the structure-function of the intracellular iron-sulfur world in aerobic and thermophilic archaea, and engineer new Escherichia coli auxotrophic expression host strains for deeper metalloenzyme analyses.LinkIcon

"...evolution does not produce innovations from scratch. It works on what already exists..."

François Jacob    

The structure of a metal site in metalloenzymes critically influences the fine-tuning of redox and/or catalytic activities in biology. The substitution and/or displacement events at the local metal-binding site(s) in a protein might have greatly enhanced their capabilities of conducting a wide range of unique redox chemistry in biological electron transfer conduits which often use a limited number of basic protein scaffolds. Iron-sulfur (Fe-S) cluster prosthetic groups, consisting of nonheme iron and acid-labile inorganic sulfide atoms, are functionally highly versatile and may be among the most ancient modular metallo-cofactors. These cofactors sustain biologically and evolutionary indispensable processes in the early days of primitive life on Earth, such as electron transfer, substrate binding/activation in the hydrogen, nitrogen, carbon and sulfur metabolisms, anaerobic respiration, and photosynthesis—some of the most complicated reactions in the chemistry of life processes.

Figure 1. Simple iron-sulfur centers in biology. Dark brown and green spheres, bound iron and sulfide atoms, respectively.

Among protein-bound Fe-S redox sites, which usually contain terminal sulfur ligands from cysteinyl groups, the mononuclear Fe atom in a tetrahedral environment of S ligands is the simplest form, as seen in the rubredoxin family (Fig. 1). Other major forms are polynuclear clusters, such as those containing [2Fe-2S], [3Fe-4S], [4Fe-4S] (Fig. 1), or [8Fe-7S] (Fig. 2) core units, found in a variety of ferredoxins and complex Fe-S enzymes. In addition to their electron transfer roles, Fe-S proteins are also known to participate in substrate binding/activation, environmental sensing and gene regulation, and more recently are suggested to be potentially involved in several human diseases (e.g. Parkinson's disease, Friedreich's ataxia). Thus, the potential relationship between some metalloenzymes and human healthcare is also at an interesting stage of development, where a main focus is on the structure-function-physiology interface.

Figure 2. Hybrid metallo-sulfur clusters in nitrogenase MoFe-protein (FeMo-cofactor, left), anaerobic carbon monoxide dehydrogenase II (Ni,Fe,S-containing cluster C, middle), and [NiFe]-hydrogenase (Ni-A state, right).

All major electron transfer chains in biology incorporate Fe-S clusters, and the protein environment of the Fe-S cluster core is the main determinant of the redox and/or catalytic activity. Their roles in catalysis of energy conversion are of central importance in aerobic respiration, photosynthesis, hydrogen metabolism, and many interrelated metabolic processes that drive the biosphere on Earth. Our understanding of these determinants is essential to a deeper knowledge how these processes work, and of critical importance in knowing how to optimize such processes, e.g., in bioremediation, generation of biofuels and biodegradation of some toxic compounds.


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