Discovery of A New Subclass of Class I Ribonucleotide Reductase

Ribonucleotide reductases (RNRs) catalyze de novo biosynthesis of deoxynucleotides in almost all organisms that use DNA as their genetic material. They are current drug targets for both cancer and infectious diseases. All RNRs share a common catalytic mechanism initiated by a cysteinyl radical, while the radical generation varies greatly and provides the biochemical basis dividing the RNRs into the three major classes and several subclasses. All class I RNRs contain two subunits, R1 and R2, that are both essential for enzyme activity. The R2 subunit in canonical class I enzymes harbors a tyrosyl radical to generate the active site cysteinyl radical in the R1 subunit via reversible long-range proton-coupled electron transfer (PCET), ¹ and transition metal ions are necessary cofactors for the radical initiation. However, two independent groups recently reported a new class I RNR from human pathogens, adding a class Ie RNR to the enzyme family. ^2,3 Surprisingly, a stable, tyrosine-derived dihydroxyphenylalanine (DOPA) radical is found in the class Ie R2 subunit in the absence of a metallocofactor. The metal-free aerobic RNR requires new mechanisms for radical generation and stabilization, which is valuable to developing novel strategies to combat pathogens encoding this type of RNR. More recently, a high-resolution room temperature structure of the RNRs class Ie R2 protein radical was captured by X-ray free electron laser serial femtosecond crystallography, providing insights into radical handling and mobilization in RNRs. ⁴ This literature seminar will introduce the newly discovered class Ie RNR, compare it with other subclasses, and discuss how the studies advance the knowledge of radical enzymology. 

Reference

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