The 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 Oxidation, Metabolism, and Redox Biology
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Research in our lab @UTSA investigates how biomolecules utilize metals to perform the chemistry necessary for life. Our ongoing research projects lie at the nexus of chemistry and biology and span a broad range of topics,
including mechanistic enzymology, chemical biology, bioinorganic chemistry, and biophysics. Specifically, we study amino acid metabolism, the mechanisms of oxygen activation by metalloproteins, C-H/C-F bond functionalization, natural product biosynthesis, protein cofactor biogenesis, free radical enzymology,
and metalloproteins-mediated signal transduction and gene regulation. To explore these phenomena, we utilize a wide array of chemical and biophysical techniques, such as EPR, ENDOR, NMR, and resonance Raman spectroscopies, LC-MS spectrometry, Isothermal titration calorimetry, stopped-flow and rapid freeze-quench kinetics, protein X-ray crystallography, and genetic code expansion strategies for specific unnatural amino acid incorporation into proteins. |
A BRIEF ACCOUNT OF OUR RESEARCH ACCOMPLISHMENT
✓ Discovery of the biological charge resonance (CR) stabilization phenomenon, which shows a characteristic spectroscopic signature in the near-infrared region (doi:
10.1073/pnas.1301544110 & 10.1002/anie.201410247).
The biological CR has later been resonated by similar findings in many other systems by other laboratories.
✓ Discovery of the metal-dependent, dioxygen-independent, non-oxidative decarboxylation is the first of its kind. It represents a new type of biological decarboxylation (doi: 10.1021/bi061031v - published under "New Concepts in Biochemistry") and original work (10.1021/ja0532234).
✓
Elaborating the existing charge maintenance hypothesis during catalysis in non-heme iron enzymes initially proposed by Lipscomb and others but left unattended for decades (doi: 10.1021/acscatal.1c04770).
‣ Describing a Bioinorganic Chemistry & Protein Structure-based Redox Sensing and Signaling Mechanism
✓
Discovery of a groundbreaking redox-sensing mechanism that initiates the immune system by an iron-containing protein Pirin, in the cell nucleus.
We found that human Pirin utilizes an iron redox state-mediated structural switch to sense redox bursts in the cell nucleus and activates the NF-κB pathways (doi: 10.1073/pnas.1221743110).
This is also a piece of conceptual contribution.
‣
Describing Unprecedented Intermediates in Metalloenzymes
✓ Discovery of a high-valence bis-Fe(IV) intermediate in the di-heme enzyme MauG, which uncovered a novel natural strategy for storing two oxidizing equivalents (doi: 10.1073/pnas.0801643105).
This is described as a Nature's sniper for long-range remote catalysis (doi: 10.1007/s00775-014-1123-8).
✓ 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 the first group to introduce the existing genetic code expansion technology to the protein-derived cofactors by site-specifically substituting the cofactor-bearing residue(s) to non-canonical amino acid(s) (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 the 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
‣ Regular member, Macromolecular Structure and Function A (MSFA) Study Section, NIH Center for Scientific Review, 2019 - 2023
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
Scientific conference/meeting
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
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