Title: "Spectroscopic Investigations of Iron-Containing Metalloenzymes: New Intermediates and Novel Mechanisms"

Yisong Guo

Professor, Dept of Chemistry, Mellon College of Science

Carnegie Mellon University

Host: Vencenzo Venditti

Abstract: Metal-containing enzymes (metalloenzymes) play essential roles in numerous metabolic pathways in all kingdoms of life. They catalyze key chemical steps for biosynthesis of natural products, for bioenergy transduction, and for gene/protein expression and regulations. A fundamental understanding of their reaction mechanisms has far-reaching impact on human health and global energy sustainability.  
Our laboratory investigates the intricate structure-function relationships of iron-containing metalloenzymes by trapping reactive intermediates and characterizing their electronic structures using a combined spectroscopic (Mössbauer, EPR, X-ray) and computational (MD, QM) approach. In this talk, I will highlight two recent discoveries involving non-heme mononuclear iron (NHM-Fe) and iron-sulfur (FeS) cluster enzymes. First, I will discuss the spin-state-reactivity correlation of high-valent iron intermediates in NHM-Fe. While the high-spin (S = 2) oxyferryl (Fe(IV)=O) species is a well-known reactive intermediate, the existence and relative reactivity of intermediate-spin (S = 1) counterparts have remained elusive. I will present our recent discovery of the first S = 1 Fe(IV)=O intermediate in an NHM-Fe enzyme that catalyzes a novel oxidative carbon-sulfur bond formation between histidine and cysteine. The broader implications of our study will also be discussed in the context of general reaction mechanisms of NHM-Fe enzymes. Second, I will present our work on Ferredoxin:Thioredoxin Reductase from Methanosarcina acetivorans (MaAFTR), a [4Fe-4S]-containing enzyme. Using biochemical and spectroscopic methods, we identified a novel reduced [Fe4S4]+ cluster with an S = 7/2 ground spin state, contrasting sharply with the canonical S = 1/2 state found in almost all other protein-bound [Fe4S4]+ clusters. We show that this S = 7/2 state is stabilized by a protonation of a core bridging sulfide with pKa ~ 10, suggesting it functions as a proton-coupled electron transfer agent. I will conclude by discussing how this unique cluster state impacts our understanding of biological redox regulation and mechanism of other FeS enzymes. 

Bio: Yisong (Alex) Guo is a Professor of Chemistry at Carnegie Mellon University whose research lies at the interface of bioinorganic chemistry, spectroscopy, and enzymology. He earned his B.S. in Materials Science and Engineering from Fudan University and his Ph.D. in Applied Science from the University of California, Davis. 

Professor Guo's research focuses on understanding how metal-containing proteins carry out complex chemical transformations essential to life. His group employs advanced spectroscopic techniques, including Mössbauer, EPR, and nuclear resonance vibrational spectroscopy, together with computational methods to investigate the structure and function of metalloproteins involved in processes such as nitrogen fixation, oxygen activation, and energy conversion. His work provides fundamental insights into biological catalysis and helps guide the development of new catalysts for applications in energy and human health. 

Dr. Guo has published extensively in the fields of bioinorganic chemistry and enzymology, and his research has contributed significantly to our understanding of the mechanisms of metalloenzymes and their roles in important biological processes.