Abstract
An estimated third of the proteome are metalloproteins, proteins in which a metal plays structural, catalytic, or cocatalytic roles. Iron-dependent metalloproteins make up a significant subset of these, owing in part to the unique redox sensitivity of iron that allows it to function as an electron reservoir and outlet. This feature is a double-edged sword, it makes iron nigh irreplaceable as a metallocofactor in oxidoreductases but also disfavors the use of iron in enzymes such as hydrolases where oxidation of the cofactor can preclude catalysis. For this reason, the catalytic role of iron in hydrolases has often been ignored or overlooked. In this work, we show that iron plays core structural and catalytic roles in SAMHD1, a human metallohydrolase and antiviral restriction enzyme where evolution has seemingly found a way to buffer the enzyme against oxidative inactivation. Further, we investigate how a novel bacterial protein superfamily, heme oxygenase-like domain-containing oxidases, utilize iron to catalyze diverse reactions. In total, this work investigates the two opposing faces of iron in biochemistry, its role as a redox cofactor in oxidases, as well as non-redox roles in hydrolases.