RESEARCH INTEREST: Amino Acid Oxidation and Metabolism

 

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.

RESEARCH PROJECTS

 

 ‣    Mechanistic enzymology of tryptophan-kynurenine pathway and its relation to neuropsychiatry and cancer immunotherapy
 ‣    Cofactor biogenesis in iron and copper proteins to endow new functions or maximize the catalytic power
 ‣    Heme-dependent chemistry in tyrosine oxidations for anticancer and antimicrobial drug development
 ‣    Metalloprotein-mediated redox sensing in response to oxidative stress

 

SCHOLARLY ACTIVITIES since 01/2016 @ UTSA

 

✓    We discovered a novel catalytic heme cofactor with a single thioether bond and a new heme-binding motif.

✓    We obtained a high-resolution ferric-hydroperoxo intermediate crystal structure. This is a long-awaited intermediate structure in the heme chemistry field obtained directly in a heme enzyme during catalysis with a substrate.

✓    We discovered the missing human gene for a dehydrogenase in the primary tryptophan catabolic pathway, which was erroneously assigned (by others) to 9-cis-retinal dehydrogenase previously.

✓    We discovered a genetic disorder, hypertryptophanemia, through collaboration with a medical geneticist and revealed its biochemistry origin.

✓    We described a competing catalytic C–H/C–F bond activation by a single iron center and discovered a new C-F bond cleavage mechanism.

✓    We brought the genetic code expansion technology to study protein-derived cofactors with site-specific substitution of unnatural amino acids.

✓    We identified a novel heme cofactor in a hydroxylase (oxygenases) and determined its crystal structure, spectroscopic properties, and reactivities.

✓    We defined a new histidyl-ligated heme-dependent aromatic oxygenase (HDAO) superfamily.

 

REPRESENTATIVE PUBLICATIONS

 

  List of significant papers published from the work at UTSA (01/2016 - present) 

 

  Selected representive papers published from the work before joining UTSA  

✓    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*
Nat. Commun., 2015, 6:5935 [DOI]: 10.1038/ncomms6935)

✓    Probing bis-Fe(IV) MauG: Experimental evidence for the long-range charge-resonance model
Geng J, Davis I, and Liu A*
Angew. Chem., 2015, 1 54, 3692-3696 [DOI]: 10.1002/anie.201410247 

✓    Pirin is an iron-dependent redox regulator of NF-κB
Liu F, Rehmani I, Esaki S, Fu R, Chen L, Serroano V, and Liu A*
PNAS, 2013, 110(24), 9722-9727 (direct submission) [DOI]: 10.1073/pnas.1221743110 

✓    Tryptophan-mediated charge-resonance stabilization in the bis-Fe(IV) redox state of MauG
Geng J, Dornevil K, Davidson VL, and Liu A*
PNAS, 2013, 110(24), 9639-9644 (direct submission)  [DOI]: 10.1073/pnas.1301544110 

✓    Diradical intermediate within the context of tryptophan tryptophylquinone biosynthesis
Yukl ET, Liu F, Krzystek J, Shin S, Jensen LMR, Davidson VL, Wilmot CM*, and Liu A*
PNAS, 2013, 110(12), 4569-4573 (direct submission) [DOI]: 10.1073/pnas.1215011110) 

✓    Chemical rescue of the distal histidine mutants of tryptophan 2,3-dioxygenase
Geng J, Dornevil K, and Liu A*
JACS, 2012, 134, 12209-12218   [DOI]: 10.1021/ja304164b 

✓    The reactivation mechanism of tryptophan 2,3-dioxygenase by hydrogen peroxide (an over 80 years of mystery)
Wang Y, Liu KF, Yang Y, Davis I, and Liu A*
JBC, 2011, 286(30), 26541-26554   [DOI]: 10.1074/jbc.M111.253237

✓    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*
PNAS, 2008, 105(25), 8597-8600 (direct submission)  [DOI]: 10.1073/pnas.0801643105 

✓    Detection of transient intermediates in the metal-dependent non-oxidative decarboxylation catalyzed by α-amino-β-carboxymuconic-ε-semialdehyde decarboxylase
Li T, Ma J, Hosler JP, Davidson VL, and Liu A*
JACS, 2007, 129(30), 9278-9279   [DOI]: 10.1021/ja073648le 

✓    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*
JACS, 2005, 127(35), 12282–12290   [DOI]: 10.1021/ja0532234 

 

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 to UTSA)

2016     Lutcher Brown Distinguished Chair in Biochemistry, The University of Texas at San Antonio

2021     Fellow of the Royal Society of Chemistry (FRSC)

2021     Elected into The UTSA Academy of Distinguished Researchers (ADR)

2021     Elected 2021 AAAS Fellows

2022     National Science Foundation (NSF) Accomplishment-Based Renewal (ABR) award

 

OUTREACH & SERVICE

 

Panel service & grant review

 

 ‣    Charter Member, The Macromolecular Structure and Function A (MSFA) Study Section, NIH Center for Scientific Review, 7/2019-6/2023

 ‣    Panelist, NIH Center for Scientific Review Special Emphasis Panel for Continuous Submission and Conflict Review, 2017/03 ZRG1 BCMB-H 02 M

 ‣    Panelist, NIH Center for Scientific Review Special Emphasis Panel, Biochemistry and Biophysical Chemistry, 2016/03 ZRG1 F04B-D (20)

 ‣    Panelist, NIH Center for Scientific Review Special Emphasis Panel, Biochemistry and Biophysical Chemistry, 2014/10 ZRG1 F04B-D (20) L

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

 ‣    Panelist, NSF proposal review panels, 2009 (MCB), 2015 (MCB), 2019 (CLP), and 2021 (CLP)

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

 ‣    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 reviewer for beamline and spectroscopic proposals for national labs and facilities.

 ‣    Panelist, NRC Research Associateship Programs on the Chemistry review panel, Office of the National Academies of Sciences, Engineering, and Medicine, 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 (elected at large seat)

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

 

 

CURRENTLY ACTIVE EXTRAMURAL FUNDING

 

 ‣     NIH R01GM108988, PI, 08/01/2022 - 08/31/2026

 ‣     NIH R21CA270879, MPI, 02/01/2022 - 01/31/2024

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

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

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

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

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

 

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