Metalloprotein Research Laboratory in San Antonio
Principal Investigator: Aimin Liu (Feradical), Ph.D., Professor of Chemistry & Lutcher Brown Distinguished Chair in Biochemistry
RESEARCH INTEREST: Amino Acid Innovation: Metabolism, Biosynthesis, and Protein-Derived Cofactor
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Research Directions
Our lab explores the essential role of metals in amino acid chemistry, which drives life’s fundamental processes. Working at the intersection of chemistry and biology, we investigate how enzymes function, inlcuding how metalloproteins activate oxygen and how precise control over C–H, C–C, and C–X bond formation/cleavage enables diverse biochemical transformations. Our research interests include natural product biosynthesis, protein cofactor assembly, enzyme-catalyzed free radical chemistry, and metalloprotein-mediated signal transduction regulation. To uncover these molecular mechanisms, we use a diverse set of tools, including advanced spectroscopies (EPR, ENDOR, NMR, resonance Raman), mass spectrometry (LC-MS), calorimetry, rapid kinetics (freeze-quench, stopped-flow), and structural biology methods (cryo-EM and X-ray crystallography). We also apply genetic code expansion to incorporate unnatural amino acids into proteins and design synethetic mechanistic probes. Through these integrated approaches, we aim to unravel how metals and amino acids shape biological chemistry while developing innovative strategies to control enzyme activity. |
A BRIEF ACCOUNT OF OUR RESEARCH ACCOMPLISHMENT
✓
Identification of biological charge resonance (CR) stabilization phenomenon, characterized by a distinct near-infrared spectroscopic
signature (doi:
10.1073/pnas.1221743110
&
10.1002/anie.201410247
), represents a significant discovery.
Subsequent resonance of biological CR in various systems by other laboratories underscores its broader implications.
✓
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.
✓ 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 introduced 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 among 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 have been using 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
Accomplishment-Based Renewal (ABR) award from the National Science Foundation (NSF)
OUTREACH & SERVICE
Panel service & grant review
‣ Panelist, Special Emphasis Panel, National Center for Advancing Translational Sciences, Center for Scientific Review, NIH, 2024
Current Editorial Board service
‣ Molecules, Bioorganic Chemistry section, Academic Editor, 2021 - present
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, The 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
2025
Co-vice Chair, Gordon Research Conference – Enzymes, Coenzymes, Metabolic Pathways, Waterville Valley, NH
2026
Co-Chair, Gordon Research Conference – Enzymes, Coenzymes, Metabolic Pathways (elected)
ONGOING EXTRAMURAL FUNDING
‣ NSF CHE-2204225, PI, 10/01/2022 - 09/30/2025
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