Skip to Search Skip to Navigation Skip to Content

 

Metalloprotein Research Laboratory in San Antonio 


Principal Investigator: Aimin Liu (Feradical), Ph.D., Professor of Chemistry & Lutcher Brown Distinguished Chair in Biochemistry  

 

RESEARCH INTEREST: Chemistry of Amino Acids in Biology

 

In our lab, we engage with metals, unraveling their role in conducting the life-sustaining chemistry of amino acids. Bridging the realms of chemistry and biology, we delve into diverse themes such as enzymatic symphonies, oxygen's activation tango with metalloproteins, and the intricate sculpting of C–H/C–F bonds. Our curiosity spans the vibrant palette of natural product biosynthesis, the delicate choreography of protein cofactor assembly, and the free radical orchestration driven by enzymes. We tune into the murmurs of metal-mediated redox sensing and signal transduction. To illuminate these concealed worlds, we employ diverse chemical and biophysical techniques: crafting small molecule mechanistic probes through synthesis, capturing insights through EPR, ENDOR, NMR, and Raman, dissecting molecules with LC-MS and calorimetry, seizing fleeting moments with freeze-quench and in crystallo chemical reactions, examining protein structures with X-rays, and even rewriting the genetic code to incorporate non-canonical (unnatural) amino acids into proteins. Through this comprehensive exploration, we paint a vivid portrait of the metal-mediated amino acid enchantment that underlies life itself.

 

A BRIEF ACCOUNT OF OUR RESEARCH ACCOMPLISHMENT

 

  Conceptual Contributions

✓  The discovery of a groundbreaking redox-sensing mechanism in the cell nucleus involves the iron-containing protein Pirin. Human Pirin utilizes an iron redox state-mediated structural switch to detect and respond to redox bursts, activating NF-κB pathways (doi: 10.1073/pnas.1221743110). This reveals a novel bioinorganic chemistry and protein structure-based redox sensing and signaling mechanism.

✓  The identification of biological charge resonance (CR) stabilization phenomenon, characterized by a distinct near-infrared spectroscopic signature (doi: 10.1073/pnas.1301544110 & 10.1002/anie.201410247), represents a significant discovery. Subsequent resonance of biological CR in various systems by other laboratories underscores its broader implications.

✓  The determination of a metal-dependent, dioxygen-independent, non-oxidative decarboxylation is unprecedented (10.1021/ja0532234). This discovery, published under "New Concepts in Biochemistry" (doi: 10.1021/bi061031v), introduces a novel form of biological decarboxylation.

✓  We introduce the concept of charge maintenance in non-heme iron enzyme catalysis, offering untapped insights into oxygen activation by metalloenzymes. (doi: 10.1021/acscatal.1c04770). This concept builds upon Lipscomb and colleagues' earlier notion of charge balance, previously underexplored for decades.

 

 

  Describing Unprecedented Intermediates in Metalloenzymes

✓  Our identification of a high-valence bis-Fe(IV) intermediate in the di-heme enzyme MauG represents a significant breakthrough (doi: 10.1073/pnas.0801643105). This discovery unveils a novel natural mechanism for storing two oxidizing equivalents in two distinct centers, spanning a considerable area of the protein. Subsequently characterized as Nature's sniper for long-distance specific oxidation of a substrate protein (doi: 10.1073/pnas.1215011110), this intermediate offers intriguing insights into a novel enzyme-mediated long-range remote catalysis.

✓  Discovery of a protein-based diradical intermediate located on a tryptophan residue and an adjacent 7-hydroxyl-tryptophan residue. Not only the di-tryptophanyl radical but also the 7-OH-Trp radical is the first of its kind (doi: 10.1073/pnas.1215011110).

✓  Captured and structurally illustrated the first compound 0 intermediate, i.e., heme Fe(III)-OOH, in a reaction with bound substrate in tyrosine hydroxylase (TyrH) (doi: 10.1021/jacs.1c00175). All previous compound 0 intermediate structures were obtained through cryoradiolytic reduction of oxy-ferrous complexes.

✓  Discovery of the first high-spin (S = 5/2) compound 0 intermediate (doi: 10.1074/jbc.M117.794099) in Mycobacterium tuberculosis P450 enzyme CYP121 and determined its structure (10.1021/jacs.3c04991).

  Uncovering New Metalloenzyme Activities

✓  Discovery of novel C–F bond cleavage reactions mediated by dioxygen- and none-heme iron-dependent enzymes (doi: 10.1038/s41589-018-0085-5) and hydrogen peroxide- and heme iron-dependent enzymes (10.1021/acscatal.9b00231 & 10.1021/jacs.1c00175).

✓  Discovery of enzyme-mediated O-demethylation in a P450 enzyme and determined its mechanism by characterizing an intermediate (doi: 10.1021/acscatal.9b04596).

 

  Describing New Protein-bound Cofactor and Motif

✓  Discovery of a novel catalytic heme cofactor; it is neither type b nor type c heme, but in between, with a single thioether bond in a cysteine–vinyl link. The cofactor has an unusual HxnHxxxC motif in its protein sequence (doi: 10.1039/D0SC06369J).

✓  Discovery of a transition metal cofactor in the kynurenine pathway decarboxylase, an enzyme that had long been thought cofactor-free before our work (doi: 10.1021/ja0532234).

✓  Discovery of a C-X-X-C-G-X(n)-C-P-X-C-G rubredoxin-like metal-binding motif functioning as an iron reservoir, which is shown in over 2,000 protein structures without a known function and present in over 74,071 non-redundant protein sequences (doi: 10.1074/jbc.M115.650259).

 

  Defining New Protein Families or Redefining and Expanding Existing Superfamilies

✓  Discovery of a new protein subfamily within the amidohydrolase superfamily, which helped to annotate correctly over 700 genes previously misannotated. The subfamily enzymes (now over 3,500) are decarboxylases and hydratases distinct from the rest of the hydrolase enzymes (doi: 10.1021/bi060108c). This subfamily with new catalytic functions is now widely recognized as amidohydrolase-2 in various protein databases.

✓  Discovery of a heme-dependent aromatic oxygenase (HDAO) superfamily that utilizes a histidyl-ligated heme to mediate oxidation and oxygenation of aromaticsubstrates (doi: 10.1073/pnas.2106561118).

 

  Kynurenine Pathway for Tryptophan Catabolism: Structure, Mechanism, and Regulation

✓  Discovery of the missing gene for dehydrogenase of the kynurenine pathway. This human dehydrogenase was incorrectly assigned by others to a retinal dehydrogenase, causing missing enzymes for the dehydrogenation and the following steps in an important metabolic pathway (doi: 10.1074/jbc.RA118.003320).

✓  Making the kynurenine pathway's non-heme Fe dioxygenase the best-understood oxygen activation enzyme by capturing and structurally and spectroscopically defining seven catalytic intermediates, five of which are after the arrival of the dioxygen substrate at the iron center (doi: 10.1073/pnas.2005327117).

✓  Making the kynurenine pathway's NAD-dependent dehydrogenase the best-understood dehydrogenase through trapping and structurally characterizing the first thiohemiacetal intermediate along with its first structure, binary and ternary enzyme-substrate complex structures and a subsequent thioacyl intermediate of the enzymatic reaction (doi: 10.1038/ncomms6935).

✓  Discovery of a genetic disorder, hypertryptophanemia, and defined its molecular rationale, and provided a novel strategy to target tryptophan dioxygenase that cancer cells overexpress for immune escaping (doi: 10.1016/j.ymgme.2017.02.009).

✓  Discovery of a natural strategy by which an enzyme employs loop dynamics to accommodate two substrates with disparate polarities (doi: 10.1074/jbc.RA118.002698).

✓  Describing of a pitcher-and-catcher isomerization mechanism in dehydrogenase to prepare substrate in the correct conformation for oxidation (doi: 10.1074/jbc.M116.759712).

✓  Discovery of a substrate-induced Fe(II) enzyme reactivation mechanism from catalytically primed but dormant Fe(III) state in two independent cases, one of which (tryptophan dioxygenase) solved over 80 years of mystery (doi: 10.1074/jbc.M111.253237 & 10.1074/jbc.RA120.013915).

✓  Experimentally observing protein quaternary structure as a means to regulate enzyme catalytic activities (doi: 10.1074/jbc.M113.496869 & 10.1074/jbc.RA119.009035). We demonstrated that a tightly associated protein dimer could dynamically dissociate and reassociate. This was achieved in a decarboxylase with two catalytically critical Arg residues with one from its neighboring subunit. We found that the mixture of two inactive Arg single mutants is catalytically active. We determined the crystal structure of the mixture and demonstrated the formation of a heterodimer, with one subunit having an intact active site but the other having a double mutation. Before this work, protein subunit association/dissociation had never been demonstrated by crystallography.

 

  Determining the De Novo or the First Crystal Structure of Enzymes

✓  Determination of the de novo crystal structure of 3-methyl-L-tyrosine hydroxylase (doi: 10.1039/D0SC06369J) L-DOPA dioxygenase (doi: 10.1021/acs.biochem.9b00396), α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (doi: 10.1021/bi060903q) by the multiwavelength anomalous dispersion (MAD) phasing method and the first crystal structure of 2-aminomuconate-6-semialdehyde dehydrogenase by molecular replacement method (doi: 10.1038/ncomms6935).

 

  Method Development in Studying Metalloenzyme Mechanisms and Protein-Derived Cofactors

✓  We were amnong the first to introduce the existing genetic code expansion technology to study the protein-derived cofactors by site-specifically substituting the cofactor-bearing residue(s) to non-canonical (unnatural) amino acids (doi: 10.1038/s41589-018-0085-5 & 10.1002/anie.201803907). The unnatural amino acid approach has proven powerful in studying amino acid crosslinking mechanisms and biological functions. This innovative approach has revivided the field of the biogeneisis of protein-derived cofactors (doi: 10.1021/jacs.0c08992 & 10.1021/acs.biochem.9b00006).

✓  We used equivalent multiple single crystals to conduct single-crystal EPR for enzymes and reactive intermediates in multiple pieces of enzymatic mechanism studies (doi: 10.1073/pnas.2005327117 & 10.1021/jacs.3c04991).

 

ACCOLADE (selected)

 

1991     Presidential Award for Scholar Excellence of Graduate Research, Chinese Academy of Sciences (CAS), China

1996     Royal Society - K.C. Wong Fellow, The Royal Society, London, UK

2002     Paul D. Boyer Award for Research Excellence, University of Minnesota, MN

2003     Ralph E. Powe Junior Faculty Enhancement Award in Life Sciences, The Oak Ridge Associated Universities (ORAU)

2008     Visiting Professorship at Kansai University, Osaka, Japan

2009     Georgia Research Alliance (GCC) Distinguished Cancer Scholar, State of Georgia

2014     Outstanding Senior Faculty Award, College of Arts and Sciences, Georgia State University

2015     Distinguished University Professor, Georgia State University (relinquished on 01/2016 due to relocation)

2016     Lutcher Brown Distinguished Chair in Biochemistry (endowed academic title)

2021     Fellow of the Royal Society of Chemistry (FRSC)

2021     Elected into UTSA Academy of Distinguished Researchers (ADR)

2021     Elected 2021 AAAS Fellow in Chemistry

2022     National Science Foundation (NSF) accomplishment-based renewal (ABR) award

 

OUTREACH & SERVICE

 

Major panel service & grant review

 

 ‣    Panelist, Special Emphasis Panel, National Center for Advancing Translational Sciences, Center for Scientific Review, NIH, 2024

 ‣    Regular member, Macromolecular Structure and Function A (MSFA) Study Section, Center for Scientific Review, NIH, 2019 - 2023

 ‣    Panelist, Special Emphasis Panel on Special Topics and Members Conflict, BCMB-H 02 M, Center for Scientific Review, NIH, 2017

 ‣    Panelist, multiple NIH Special Emphasis Panels for F30/F31/F32, Biochemistry and Biophysical Chemistry, F04B-D (20), 2014 and 2016

 ‣    Panelist, multiple NSF proposal review panels for the Division of Molecular and Cellular Biosciences (MCB) 2009 and 2015

 ‣    Panelist, multiple NSF CAREER Proposal Review Panels: 2012 (CLP-MCB joint panel), 2017 (CLP), and 2018 (CLP)

 ‣    Panelist, multiple NSF proposal review panels for the Chemistry of Life Processes (CLP) program 2019 and 2021

 ‣    ad hoc Panelist, Macromolecular Structure and Function A (MSFA) Study Section, Center for Scientific Review, NIH, 2006

 ‣    External reviewer of the outcome of the Pennsylvania Department of Health Formula Grants adminstrated by ORAU 2021

 ‣    Florida Department of Health (FLDOH) proposal review panel adminstrated by ORAU, 2023

 ‣    External reviewer for ACS PRF, Biotechnology and Biological Sciences Research Council (BBSRC) of UK, Medical Research Council (MRC) of UK,  ‣    Le financement sur projet au service de la Recherche (ANR, French National Research Agency), and Einstein Stiftung Berlin of Germany

 ‣    A frequent ad hoc reviewer for beamline (SLAC) and high magnetic field spectroscopic (MagLab) proposals for national labs and facilities

 ‣    Panelist, Chemistry Panel, NRC Research Associateship Programs, Office of the National Academies of Sciences, Engineering, and Medicine, 12/2022 - present

 

Current Editorial Board service

 

 ‣    Molecules, Bioorganic Chemistry section, Academic Editor, 2021 - present

 ‣    The Journal of Biological Chemistry (JBC), 7/01/2024 - 7/31/2029

 

Elected role in professional organization

 

2010-2  Elected member, EMR User Committee, The National High Magnetic Field Laboratory

2013     Elected member, College promotion & tenure committee – the natural and computational sciences

2014-6  Faculty senator, Georgia State University Senate

2015     Elected member, Triennial evaluation committee of College of Arts & Sciences Dean

2015-7  Alternate councilor, American Chemical Society (ACS) Division of Biological Chemistry

 

Leadership role in scientific conferences

 

2010     Session Chair, The Inaugural Annual Southeast Enzyme Conference

2011     Chair, 40th Southeastern Magnetic Resonance Conference (SEMRC 2011)

2012     Discussion Lead, Gordon Research Conference - Protein Cofactors, Radicals & Quinones, South Hadley, MA

2014-5  Program Committee Member, Enzymes in Drug Discovery

2016     Discussion Lead, Gordon Research Conference - Metals in Biology, Ventura, CA

2017     Symposium Chair: Metalloprotein-initiated signaling transduction response to redox stress, the 253rd ACS National Meeting, San Francisco

2017     Discussion Lead, Gordon Research Conference – Enzymes, Coenzymes, Metabolic Pathways, Waterville Valley, NH

2019     Session Chair, 26th Enzyme Mechanisms Conference (EMC2019), New Orleans, LA

2022     Discussion lead, Gordon Research Conference - Chemistry and Biology of Tetrapyrroles, Newport, RI

 

 

ONGOING EXTRAMURAL FUNDING

 

 ‣     NSF CHE-2204225, PI, 10/01/2022 - 09/30/2025

 ‣     NIH R01GM108988, PI, 08/01/2014 - 08/31/2026

 ‣     NIH R21AG078775, MPI, 9/01/2022 - 08/31/2024

 ‣     NIH R21CA270879, MPI, 02/01/2022 - 01/31/2025

 ‣     NIH R01CA247379, Co-I and subaward PI, 07/01/2020 - 06/30/2025

 ‣     Welch AX-2110-20220331, PI, 06/01/2022 - 05/30/2025

 ‣     Fellowship funding from NIH F31GM145187, ET, 07/01/2022 - 06/30/2025

 

                              ORCID      Twitter      ResearchGate      Google Scholar     RateMyProfessors.com