Executive Summary : | The class I-c ribonucleotide reductases (RNRIc) and R2-like ligand-binding oxidases (R2lox) are known to harbor heterobimetallic MnFe cofactors. RNRIc is involved in the reduction of ribonucleotides to deoxyribonucleotides, the building blocks of DNA, while the R2lox is suggested as a virulence factor. Both these enzymes are found in pathogens like Chlamydia trachomatis (RNRIc) and Mycobacterium tuberculosis (R2lox). These pathogens are often exposed to reactive oxygen and nitrogen species that are present in their surrounding environment or produced by the host’s immune system and therefore, it is proposed that the preference for a more robust MnFe cofactor over the canonical diiron cofactor, provides them with a mechanism to deal with the oxidative stress. Because of their crucial role in the life-sustaining process of DNA biosynthesis, RNRs have been a therapeutic target for the treatment of cancer and against multidrug-resistant pathogens. Therefore, it is important to study the structure-reactivity-function relationship of the heterobimetallic MnFe cofactors of RNRIc and R2lox as they can be excellent targets for the development of new therapeutics against deadly pathogens like Chlamydia trachomatis and Mycobacterium tuberculosis. Extensive studies on biomimetic models of nonheme diiron cofactors have contributed significantly towards our understanding of the coordination environment, function, and reactivity of the corresponding metalloenzymes and their short-lived intermediates. However, synthetic complexes mimicking the redox-active heterobimetallic MnFe cofactors of RNRIc and R2lox, remain mostly unexplored. Most importantly the absence of model systems that mimic the high-valent oxidation states of the proposed enzymatic intermediates in the catalytic pathways of RNR1c and R2lox largely limits our understanding of the enzyme mechanism. To address these issues, our research will explore biomimetic MnFe complexes as models of the RNR1c and R2lox cofactors with a specific emphasis on understanding the metal selectivity, structure, redox properties, and reactivity of these enzymes. |