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Welcome to Feradical's Metalloprotein Research Laboratory 

Dr. Aimin Liu (a.k.a.: Feradical), Lutcher Brown Distinguished Professor in Biochemistry (讲座教授)  

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Research in our lab studies how biomolecules utilize metals to perform the chemistry necessary for life. Specifically, we study mechanisms of oxygen activation by metalloenzymes and metalloproteins-mediated signal transduction regulation. To explore these phenomena, we utilize a wide array of techniques such as EPR spectroscopy, stopped-flow rapid kinetics, and protein X-ray crystallography. Our on-going research projects lie at the interface of chemistry and biology and span a broad range of topics including mechanistic enzymology, cofactor biogenesis, radical enzymology, and metalloprotein-mediated redox stress-linked transcriptional activation and gene regulation mechanisms.


Project 1: Heme and Protein Radical-Mediated Remote Enzyme Catalysis

Understanding how an enzyme specifically oxidizes a protein substrate that is much larger than the enzyme itself will illuminate the mechanism by which proteins mature through enzyme-mediated posttranslational modifications. Given the interconnectedness of protein posttranslational modification, metabolic chemistry, and diseases, the question of how enzymes preserve specificity for large protein substrates is fundamental to enzymology. We are studying the long-range remote enzyme catalysis mechanism required for the biogenesis of a protein-derived tryptophan tryptophylquinone (TTQ) cofactor. TTQ is the catalytic center of methylamine dehydrogenase. This project seeks to determine the chemical properties of two reactive intermediates previously found in our laboratory, an unprecedented bis-Fe(IV) state of a di-heme enzyme MauG and a novel tryptophan-based di-radical in the substrate protein preMADH. Both are critical catalytic intermediates that occur sequentially in the catalytic cycle of TTQ biogenesis. Characterization of these key intermediates will lead to comprehension of the TTQ biogenesis mechanism, which in turn will provide insight into long-range enzyme-mediated remote oxidative and oxygenation chemical modification strategies.

Project 2: NF-κB Regulation by Human Pirin

The inducible transcription factor NF-κB is a critical mediator of intracellular signaling which has been linked to cellular responses to pro-inflammatory signals by expressing a vast array of genes involved in immune and stress mechanisms, cancer, and apoptosis. While the process of NF-κB activation in the cytoplasm is well understood, little is known about the mechanism of its activation inside the cell nucleus and how NF-κB selectively targets specific genes. We propose to study the mechanism by which NF-κB is regulated in the cell nucleus in response to oxidative stress. In our recent work, we have shown that a human metalloprotein, Pirin, is a nuclear regulator of NF-κB that potentially initiates the nuclear response to redox stress. The long-term objective of this study is to elucidate the regulatory mechanisms by which Pirin participates in the nuclear regulation of NF-κB. Pirin is a non-heme iron protein expressed in all human tissues, and we have recently found that its metal center plays a significant role in its formation of a complex with NF-κB and κB genes. Specifically, the ferric, not ferrous, form of Pirin substantially facilitates the binding of NF-κB proteins to target κB genes, suggesting that Pirin performs a redox-sensing role in NF-κB regulation.

Project 3: An Enzyme Trio for Partitioning Kynurenine Metabolic Intermediates

Following indoleamine 2,3-dioxygenase and kynureninase, three consecutive enzymes of the kynurenine pathway determine the metabolic partitioning of tryptophan metabolites to quinolinic acid (QUIN), picolinic acid, or further metabolism. The first enzyme of the kynurenine trio is an iron-dependent 3-hydroxyanthranilic acid dioxygenase; the second is a zinc-dependent α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase; and, the third is presumably an NAD+-dependent 2-aminomuconic semialdehyde dehydrogenase. A unique feature of these enzymes is that either their substrate or product or both in the case of the second enzyme, is unstable and spontaneously decays. Thus, the metabolic pathway branches with non-enzymatic reactions and “leaking” products. QUIN is one of such side products. In humans, a low-level production of QUIN is necessary for de novo NAD+ biosynthesis. Elevation of QUIN has been implicated in numerous neurological disorders and correlated with depression in patients who have been administered inflammatory cytokines. It remains unresolved how QUIN production is limited at its basal level in the highly active metabolic states such as well-fed conditions. This project tests a new hypothesis on a novel regulatory mechanism of non-enzymatic reactions in a metabolic pathway so that QUIN production regulation will be understood.

Project 4: Mechanistic Enzymology of Biosynthesis of Novel Antitumor Products and Antibiotics

We have begun to investigate several Fe-dependent enzymes involved in the biosynthesis of antitumor compounds or novel antibiotics, including those targeting multidrug-resistant tuberculosis. We will be determining the structure and catalytic mechanism the enzymes. We will design and synthesize mechanism-based transition state analogue inhibitors of which and test them with the enzymes and in cells.


Our recent mechanistic enzymology and spectroscopic characterization of catalytic intermediates have also resulted in notable advances including trapping and determining the structure of five catalytic intermediates in one catalytic cycle of a dehydrogenase, identification of an Fe(V) equivalent bis-Fe(IV) intermediate . The protein-based high-valent iron intermediate is a potent oxidant, yet remarkably stable when its primary substrate (a large protein known as preMADH) is absent. This highly powerful bis-Fe(IV) intermediate does not permanently oxidize the enzyme's own aromatic residues (including tyrosine and tryptophan residues) because of a novel electron-transfer-mediated charge resonance (CR) stabilization phenomenon discovered in our recent study. Through a hole hopping mechanism, the bis-Fe(IV) intermediate will be reduced by the substrate protein. Concurrently, a tryptophan residue-based diradical intermediate is produced. Thus, the bis-Fe(IV) intermediate is the linchpin species in operating a remarkable long-range remote enzyme catalysis. For more details, see our publications.


Our research on signal transduction has led to the discovery of a new metalloprotein-based redox sensor for NF-κB signal transduction regulation. This is the ground-breaking finding of the function of a human nuclear iron protein, Pirin. In its resting ferrous state, Pirin is predictably inactive. Under conditions of oxidative stress, Pirin becomes oxidized, inducing structural changes remotely by the iron center on a particular surface region of charged residues. Consequently, it binds NF-κB proteins and the resulting protein complex binds and activates specific κB sequence-containing genes to initiate anti-oxidative signaling cascades. We are just now starting to understand such an elegantly simple, yet highly efficient, regulation mechanism and the impact of the NF-κB signaling pathways. Unlike the commonly thiol-based redox sensing devices, the redox sensing by Pirin does not involve posttranslational modifications of the target NF-κB transcription factors.



Biophysical Spectroscopy: EPR, QCM-D, ITC, fluorescence, stopped-flow UV-Vis, RFQ, NMR, and mass spectrometry; Structural Biology: macromolecular X-ray crystallography (see our recent structures published); Biochemistry & Molecular Biology: cloning, expression, purification, site-directed mutagenesis, and unnatural amino acid incorporation into proteins.



  Probing ligand exchange in the P450 enzyme CYP121 from Mycobacterium tuberculosis: Dynamic equilibrium of the distal heme ligand as a function of pH and temperature
Fielding AJ, Fielding K, Ma L, Davis I, and Liu A
J. Am. Chem. Chem., 2017, 139(48), 17484-17499 [DOI]: 10.1021/jacs.7b08911   [PDF]

  Crosslinking of dicyclotyrosine by the cytochrome P450 enzyme CYP121 from Mycobacterium tuberculosis proceeds through a catalytic shunt pathway
Dornevil K, Davis I, Fielding AJ, Terrell JR, Ma L, and Liu A
J. Biol. Chem., 2017, 292(33), 13645-13657 [DOI]: 10.1074/jbc.M117.794099   [PDF]

@    Hypertryptophanemia due to tryptophan 2,3-dioxygenase deficiency
Ferreira F, Shin I, Sosova I, Dornevil K, Jain Shailly, Dewey D, Liu F, and Liu A
Molecular Genetics and Metabolism, 2017, 120(4), 317-324.

   A pitcher-and-catcher mechanism drives endogenous substrate isomerization by a dehydrogenase in kynurenine metabolism
Yang Y, Davis I, Ha U, Wang Y, Shin I, and Liu A
J. Biol. Chem., 2016, 291(51), 26252-26261 [DOI]: 10.1074/jbc.M116.759712
(designated by the editors as a "Papers of the Week" and selected, after publication, in a collection of a representative snapshot of recent papers in the field of Enzymology in a virtual issue)

@    An iron reservoir to the catalytic metal: The rubredoxin iron in an extradiol dioxygenase
Liu F, Geng J, Gumpper RH, Barman A, Davis I, Ozarowski A, Hamelberg D, and Liu A
J. Biol. Chem., 2015, 290(25), 15621-15634   [PDF]

@    Probing bis-Fe(IV) MauG: Experimental evidence for the long-range charge-resonance model
Geng J, Davis I, and Liu A
Angew. Chem. Int. Ed., 2015, 54, 3692-3696. DOI: 10.1002/anie.201410247   [PDF]

@    Crystallographic and spectroscopic snapshots reveal a dehydrogenase in action
Huo L, Davis I, Liu F, Andi B, Esaki S, Hiroaki I, Li T, Hasegawa Y, Orville AM, and Liu A
Nature Communications, 2015, 6:5935 [PDF]

@    Human α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD): A structural and mechanistic unveiling
Huo L, Liu F, Hiroaki I, Hasegawa Y, and Liu A
PROTEINS, 2014, 83(1), 178-187 [PDF]

@    Pirin is an iron-dependent redox regulator of NF-κB     (F1000Prime Recommended Article)
Liu F, Rehmani I, Esaki S, Fu R, Chen L, Serroano V, and Liu A
Proc. Natl. Acad. Sci. U.S.A., 2013, 110(24), 9722-9727 (PNAS Direct Submission)    [PDF]

@   Tryptophan-mediated charge-resonance stabilization in the bis-Fe(IV) redox state of MauG
J, Dornevil K, Davidson VL, and Liu A
Proc. Natl. Acad. Sci. U.S.A., 2013, 110(24), 9639-9644 (PNAS Direct Submission)     [PDF]

@   Diradical intermediate within the context of tryptophan tryptophylquinone biosynthesis     (F1000Prime Recommended Article)
ET, Liu F, Krzystek J, Shin S, Jensen LMR, Davidson VL, Wilmot CM, and Liu A
Proc. Natl. Acad. Sci. U.S.A., 2013, 110(12), 4569-4573 (PNAS Direct Submission)    [PDF]

@    The power of two: arginine 51 and arginine 239* from a neighboring subunit are essential for catalysis in ACMS decarboxylase
L, Davis I, Chen L, and Liu A
J. Biol. Chem., 2013, 288(43), 30862-30871     [DOI]

@    Chemical rescue of the distal histidine mutants of tryptophan 2,3-dioxygenase
J, Dornevil K, and Liu A
J. Am. Chem. Soc., 2012, 134(29), 12209-12218     [DOI]

@   Evidence for a dual role of an active site histidine in α-amino-β-carboxymuconic-ε-semialdehyde decarboxylase
L, Fielding AJ, Chen Y, Li T, Iwaki H, Hosler JP, Chen L, Hasegawa Y, Que Jr, L, and Liu A
Biochemistry, 2012, 51(29), 5811-5821     [DOI]

@   The role of calcium in metalloenzyme: Effects of calcium removal on the axial ligation geometry and magnetic properties of the catalytic diheme center in MauG
Chen Y, Naik SG, Krzystek J, Shin S, Nelson WH, Xue S, Yang JJ, Davidson VL, and Liu A
Biochemistry, 2012, 51(8), 1586-1597     [DOI]

@   Enzyme reactivation by hydrogen peroxide in heme-based tryptophan dioxygenase
Fu R, Gupta R, Geng J, Dornevil K, Wang S, Zhang Y, Hendrich MP, and Liu A
J. Biol. Chem., 2011, 286(30), 26541-26554     [PDF]

@    Mutagenesis of tryptophan199 suggests that electron hopping is required for MauG-dependent tryptophan tryptophylquinone biosynthesis
Tarboush NA, Jensen LMR, Yukl ET, Geng J, Liu A, Wilmot CM, and Davidson VL
Proc. Natl. Acad. Sci. U.S.A., 2011, 108(41), 16956-16961     [PDF]

@   EPR and Mossbauer spectroscopy show inequivalent hemes in tryptophan dioxygenase
Gupta R, Fu R, and Liu A, and Hendrich MP
J. Am. Chem. Soc., 2010, 132(3), 1098-1109     [DOI]

@   Heme iron nitrosyl complex of MauG reveals an efficient redox equilibrium between hemes with only one heme exclusively binding exogenous ligands
Fu R, Liu F, Davidson VL, and Liu A
Biochemistry, 2009, 48(49), 11603-11605     [DOI]

@   A catalytic di-heme bis-Fe(IV) form of MauG, alternative to an Fe(IV)=O porphyrin radical
Li X, Fu R, Lee S, Krebs C, Davidson VL, and Liu A
Proc. Natl. Acad. Sci. U.S.A., 2008, 105(25), 8597-8600 (PNAS Direct Submission)     [PDF]

@   Detection of transient intermediates in the metal-dependent nonoxidative decarboxylation catalyzed by α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase
Li T, Ma J, Hosler JP, Davidson VL and Liu A
J. Am. Chem. Soc., 2007, 129(30), 9278-9279     [DOI]

@   Transition metal-catalyzed nonoxidative decarboxylation reactions    (New Concepts Article)
Liu A and Zhang H
Biochemistry, 2006, 45(35), 10407-10411    [DOI]

@   α-Amino-β-carboxymuconic-ε-semialdehyde decarboxylase (ACMSD) is a new member of the amidohydrolase superfamily
Li T, Iwaki H, Fu R, Hasegawa Y, Zhang H, and Liu A
Biochemistry, 2006, 45(21), 6628-6634     [DOI]

@    Kinetic and spectroscopic characterization of ACMSD from Pseudomonas fluorescens reveals a pentacoordinate mononuclear metallocofactor
Li T, Walker AL, Iwaki H, Hasegawa Y, and Liu A
J. Am. Chem. Soc., 2005, 127(35), 12282-12290     [DOI]




2017     NSF Proposal Review Panelist

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

2017     Panelist, Special Emphasis Panel, Center for Scientific Review, NIH

2017     253rd ACS National Meeting - Biochemistry - Symposium Chair: Metalloprotein-Initiated Signaling Transduction Response to Redox Stress, San Francisco, CA

2016-    Lutcher Brown Distinguished Chair in Chemistry, University of Texas at San Antonio

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

2016     Panelist, Special Emphasis Panel, Center for Scientific Review, NIH

2015-6  Distinguished University Professor, Georgia State University (voluntarily relinquished in 01/2016 due to relocation to UTSA and appointed to Adjunct Professor)

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

2015     NSF Proposal Review Advisory Panelist

2015     Elected Member, Triennial Evaluation Committee of College of Arts & Sciences Dean, GSU

2015     Discussion Leader, GRC - Metals in Biology, Ventura, CA

2014     Outstanding Senior Faculty Award, College of Arts and Sciences, GSU

2014     Special Panelist, Speical Emphasis Panel, Center for Scientific Review, NIH

2014-    Faculty Senator, Georgia State University Senate

2013-    College Promotion & Tenure Committee – Natural and Computational Sciences (elected at-large seat)

2013-    International Expert - BBSRC & MRC, UK

2012     NSF Proposal Review Panelist

2012     Discussion Leader, GRC - Protein Cofactors, Radicals & Quinones, South Hadley, MA

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

2010-2  EMR Advisory Committee, The National High Magnetic Field Laboratory

2010-3  Director of Chemistry Core Facility, Natural Science Center, GSU

2009     NSF Proposal Review Panelist

2010     Session Chair, The Inaugural Annual Southeast Enzyme Conference

2009     Georgia Research Alliance Distinguished Cancer Scholar

2009     Cleon F. Arrington Research Initiation Award, Georgia State University

2008     Visiting Professor at Kansai University, Osaka, Japan

2006-8  Steering Committee Member, Neuroscience Graduate Curriculum, UMMC

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

2005     Young Investigator Travel Award, National Ataxia Foundation

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

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

2002     Cyrus P. and Anne R. Barnum Travel Award, Minnesota Medical Foundation, Minneapolis, MN

2002     Young Investigator Award, The Seventh International Symposium of Spin Trapping

1998-9  Recipient, Wenner-Gren Foundation Fellowship, Stockholm, Sweden

1997     Poster Award, Society of Chemical Industry (SCI), London, UK

1996     Royal Society K.C. Wong Fellowship, The Royal Society, London, UK

1995     National Prize for Promotion of Science and Technology from National Education Commission
            (Silver medal shared with four colleagues), Beijing, China

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



2013-    Editorial Board Member, BBA Proteins and Proteomics

2014-    Editorial Advisory Board, Journal of Biological Inorganic Chemistry (JBIC)

2016-9  Editorial Board Member, Reactive Oxygen Species (ROS)

2017-    Editorial Board Member, Frontiers in Bioscience

2017-    Editorial Board Member, Journal of Biochemistry and Chemical Sciences





NIH R01GM108988 (08/2014-03/2018), R01GM107529 (09/2014-04/2018), and R21MH107985 (5/2016-4/2018); NSF CHE-1309942 (09/2013-08/2016), CHE-1623856 (2/2016 - 8/2017), and MCB-0843537 (08/2009-08/2014); Georgia Research Alliance - Georgia Cancer Coalition Distinguished Cancer Scholar Program (2009 - 2016); and Lutcher Brown Distinguished Chair Endowment (2016 - ).