Electron Transfer-Oxy Radical Mechanism for Anticancer Agents: Etoposide, Cu Dips, and BIS(9-Aminoacridines)

Author(s):  
Peter Kovacic ◽  
James R. Ames ◽  
Michael D. Ryan
2017 ◽  
Vol 61 (2) ◽  
pp. 281-292 ◽  
Author(s):  
Steven Y. Reece ◽  
Mohammad R. Seyedsayamdost

Escherichia coli class Ia ribonucleotide reductase (RNR) catalyzes the conversion of nucleotides to 2′-deoxynucleotides using a radical mechanism. Each turnover requires radical transfer from an assembled diferric tyrosyl radical (Y•) cofactor to the enzyme active site over 35 Å away. This unprecedented reaction occurs via an amino acid radical hopping pathway spanning two protein subunits. To study the mechanism of radical transport in RNR, a suite of biochemical approaches have been developed, such as site-directed incorporation of unnatural amino acids with altered electronic properties and photochemical generation of radical intermediates. The resulting variant RNRs have been investigated using a variety of time-resolved physical techniques, including transient absorption and stopped-flow UV-Vis spectroscopy, as well as rapid freeze-quench EPR, ENDOR, and PELDOR spectroscopic methods. The data suggest that radical transport occurs via proton-coupled electron transfer (PCET) and that the protein structure has evolved to manage the proton and electron transfer co-ordinates in order to prevent ‘off-pathway’ reactivity and build-up of oxidised intermediates. Thus, precise design and control over the factors that govern PCET is key to enabling reversible and long-range charge transport by amino acid radicals in RNR.


2014 ◽  
Vol 118 (16) ◽  
pp. 8712-8721 ◽  
Author(s):  
Ivan Infante ◽  
Jon M. Azpiroz ◽  
Nina Gomez Blanco ◽  
Emmanuel Ruggiero ◽  
Jesus M. Ugalde ◽  
...  

2017 ◽  
Vol 9 (8) ◽  
pp. 66 ◽  
Author(s):  
Peter Kovacic ◽  
Ratnasamy Somanathan

A recent article deals with various nutrients in relation to bactericidal action. The present article focuses on a unifying mode of action for the nutrients, namely, resveratrol, epigallocatechin, polyene-ß-carotene, polyene lycopene, piperine, curcumin, genistein, luteolin, sulforaphane and pomegranate extract. The mechanism is based on electron transfer, reactive oxygen species and oxidative stress, which comprises an extension of earlier reports involving agents. Most of the compounds are precursors of electron transfer quinones, whereas others fit into the polyene category. The nutrients are better known as antioxidants. The dichotomy is addressed.


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