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Li-June Ming(明立君) Professor of Chemistry
The College of Chinese Culture (now Chinese Culture University), B.S., 1979 National Tsing Hua University, M.S., 1981 Second Lieutenant, Military Service, 1981-1983 University of California at Los Angeles, Ph.D., 1988 University of Minnesota, Postdoctoral Fellow, 1988-91
Bioinorganic Chemistry |
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A very old (young) picture which I don’t feel like to replace!! |
RESEARCH INTERESTS PUBLICATION LIST/EXPERIENCE
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Research Focus in the MetalloBiomolecule Interest Group (MBIG)
Our research involves the use of spectroscopic methods, especially paramagnetic nuclear magnetic resonance (NMR), electron paramagnetic resonance (EPR and pulsed EPR), and electronic spectroscopies, kinetic and thermodynamic methods, and biochemical methods for the study of hydrolytic chemistry and for the investigation of the structure-function correlations of some metalloproteins, metallopeptides, metalloantibiotics, and other metallo-biomolecules and synthetic model complexes.
(I) Hydrolytic and Oxidation/Oxygenation Chemistry
Hydrolysis is one of the most important chemical, biological, industrial, and environmental
processes that is involved in novel synthesis, food processing, and biological
digestion, regulation, and recycling, and degradation of pesticides and
stockpiles of nerve agents. A number of Zn(II) enzymes
are involved in various hydrolytic reactions, such as phosphoester and peptide
hydrolysis. One common feature among these enzymes is the presence of a
coordinated water molecule that is activated by the Zn(II)
to a factor of >107 in terms
of its pKa. A significant difference is the structures of the substrates. For
example, the tetrahedral configuration of phosphoesters only resembles the gem-diolate transition state configuration of peptides formed
upon nucleophilic attack at the scissile peptide bond by the Zn(II)-activated
water molecule during hydrolysis. (However, we have recently discovered a
unique "alternative catalysis" in which a phosphodiester is
hydrolyzed at a remarkable rate by a di-Zn aminopeptidase from Streptomyces.
See abstract.)
(A) Metallohydrolases
Several hydrolytic metalloenzymes are under investigation in our group,
including the unique Zn-containing endopeptidase astacin family (including BP10 from
sea urchin embryos expressed in our laboratory in collaboration with Dr. Brian
Livingston in the Biology Department of the University, now at California State University at Long
Beach, astacin from crayfish, and serralysin from Serratia), di-Zn aminopeptidase,
and tri-Zn phospholipase C.
(B) Model Systems
Chemical models that mimic the active site metal environment and/or the
function of metallohydrolases are built for the investigation of the
spectroscopic properties and water activation of the enzymes. Several model
systems have been studied in our laboratory to establish their hydrolytic
capability. These systems include metallopolymers,
metal-binding natural products and synthetic compounds, as well as
metallopeptides. (Read more here!) An investigation of the oxidation/oxygenation
reactions of an Fe-polymer system was published and featured
on the cover of European Journal of Inorganic Chemistry.
(II) "Metalloantibiotics" and
Microecology
While many antibiotics do not require metal ions for their biological activity,
there are several families of antibiotics which require metal ions to function
properly (or to exhibit some specific functions/activities), including bleomycin, streptonigrin, bacitracin, anthracyclines, and the salivary peptide histatins. In some
of these metal-dependent antibiotics, metal ions are bound tightly and are
integral parts of the structure and function of the antibiotics. Removal
of the metal ions from these antibiotics results in deactivation and change in
structure. Similar to the case of “metalloproteins”, these antibiotics
are thus dubbed “metalloantibiotics”
in our laboratory.
Many antibiotics form stable metal complexes, such as the di- and tri-valent complexes
of bleomycin and streptonigrin, Ca(II)/Mg(II) and
Fe(III) complexes of tetracyclines, and divalent metal complexes of bacitracin
and histatins. The metal ions are involved in the proper action of these
antibiotics. For example, the binding of redox active metal ions to bleomycin
and streptonigrin entitles these antibiotics to act as potent DNA cleaving
agents, and the divalent metal complexes of bacitracin can bind long-chain isoprenyl pyrophosphates which prevent the hydrolysis of
the pyrophosphate and subsequently inhibits cell wall synthesis.
(III) Chemistry of the Alzheimer's disease-related
metallo-β-amyloid and biological oxidative stress
The chemistry of redox-active metal complexes of
β-amyloid peptide (Aβ) has been an area of intense focus in the study
of Alzheimer's disease (AD). The aggregation of Aβ within the
neocortex is closely related to the pathology of AD and has been shown to be
induced by metal binding. The Aβ peptides are generated by the
cleavage of the ubiquitous amyloid precursor protein (APP) by α, β,
and γ secretases. Aβ in the form of insoluble plaques contains
up to mM amounts of Zn, Cu, and Fe ions in the neocortical region of the brain;
however, the cause/effect connection of the metallo-Aβ plaques with AD is
still under debate. Since Aβ1-42 and Aβ1-40 have been shown to
bind metal ions with high apparent affinity constants, understanding of the
metal-binding domain and its structure and chemistry may shed light on the
neuropathology of AD. We have been studying the redox chemistry of
metallo-Aβ, with particular emphasis on metal-centered oxidative
activities toward redox-sensitive compounds, including catecholamine
neurotransmitters, wherein “metallo-ROS” (i.e., metal-associated reactive
oxygen species) has been investigated to reveal the mechanisms of metalloamyloid-mediated oxidation
chemistry. As a result of our
investigation, we can safely conclude that Aβ is a rogue in the body
regardless whether it is a cause or an effect of the disease since its redox
metal complexes are always causing severe oxidative damages in the body.
Inhibition of biological oxidative stress has been extensively studied which we have also been involved. The inhibition mechanisms of vitamin B6s and a few structurally different flavonoids have been revealed. The metal-binding mode of some flavonoids have been unequivocally identified by the use of paramagnetic NMR techniques. Ongoing investigation about the inhibition of the oxidative activities of metallo-β-amyloid includes the use of an expanded list of flavonoids, curcumin and analogues, betanin from beetroots, and synthetic compounds. The preliminary results about betanin inhibition against the oxidative activities of Cu-β-amyloid were presented in the 255th National Meeting & Exposition of the American Chemical Society (ACS) and featured in the news release of the meeting, followed by citations in popular websites including Phys.org, EurekAlert!, SciNews, NewsWeek, HuffingtonPost, Alzheimer’s & Dementia Weekly, ScienceDaily, and many more, and has also been summarized in the popular magazine Today’s Geriatric Medicine.
(IV) NMR Studies of Paramagnetic Molecules
The large paramagnetism of the unpaired electrons results in significant
shortening in nuclear relaxation times (e.g. in the range of ms) and gives rise
to isotropically shifted 1H NMR
signals that can reach several hundred ppm. These signals are
attributable to the protons on the ligands and/or in the proximity of the metal
ions. Thus, paramagnetic metal ions can be used as NMR probes for the
investigation of the structure of the metal binding environment in biomolecules
and synthetic metal complexes, as well as the interactions of ligands with
paramagnetic metal centers. One- and two-dimensional NMR techniques have
been developed and applied to the study of paramagnetic compounds in our
research group as outlined below.
- Several paramagnetic lanthanide (III) ions have been used as NMR probes for the study of Ca(II) proteins, including α-lactalbumin and EF-hand proteins, and some anticancer antibiotics, including anthracyclines and streptonigrin (A summary) earlier, and recently for the investigation of metal binding of flavonoids.
- Several paramagnetic transition metal ions, including Co(II), Ni(II), and Cu(II), have been used as NMR probes for the study of the metal binding sites in metalloproteins, including several hydrolytic metalloenzymes, two heme proteins, and other metalloproteins (See below.).
- Metalloantibiotics, including anthracyclines, streptonigrin, and aureolic acids, and their interactions with DNA have been studied by means of NMR techniques. The structure and function relationship of the widely used peptide antibiotic bacitracin has also been studied by means of NMR using Co(II) as a probe. These studies will provide the molecular basis for rational drug design for the purpose of chemotherapy and for design of metal complexes for the study of DNA structure. A review about the structure and function of metalloantibiotics can be found here. Metal binding to peptidyl histatin-5 was investigated with Co(II) as a paramagnetic NMR probe and Cu(II) as an EPR probe. The Cu(II) complex of histatin-5 shows significant oxidative activity, which was implicated to be involved in its biological function.
A Book Chapter on NMR of Paramagnetic
Species
Authored "Nuclear Magnetic Resonance of Paramagnetic Metal Centers in
Proteins and Synthetic Complexes" (see table of contents) In Physical
Methods in Bioinorganic Chemistry, Spectroscopy and Magnetism, Que, L.,
Jr., Ed.; (see book information)
University Science Books; 2000.
(V) Collaborations
We have been collaborating with Dr. Alexander Angerhofer
at University of Florida on pulsed EPR studies of several Fe3+- and Cu2+-containing systems, Dr. Sanboh
Lee (李三保)
at the National Tsing Hua University in Taiwan on EPR studies of irradiated
polymers, and Dr. Andrew Terentis at Florida Altantic
University on Raman spectroscopic studies of metal centers. Collaborations with
Dr. Yufeng Zhao (Tsinghua, Xianmen,
and Zhenzhou Universities, and now at Ningbo
University, PRC), Dr.Yong Ye (Zhenzhou
University, PRC), and Dr. Le Wang (Shanghai University of Engineering Science,
PRC) on metal-binding to cyclophosphozene derivatives
have recently resulted in several publications and one was featured on the
cover of European Journal of Inorganic Chemistry.
We have also been involved in the use of 1D and 2D NMR and kinetic methods for the investigation of several metalloenzymes provided by our collaborators, including carbonic anhydrase in collaboration with Dr. David Silverman, the enzyme nitrate reductase in collaboration with Dr. Andrew Cannons (Biology), Dr. Larry Solomonson (Biochemistry), and Dr. Michael Barber (Biochemistry) of the University, with Dr. Brian Livingston at the Biology Department of the University (now at the Department of Biological Sciences of California State University at Long Beach) on molecular biology in expression of metalloproteins, prolyloligopeptidase (POP) from the hyperthermophilic Archaeon Pyrococcus furiosus with Dr. Valerie Jody Harwood of the University (Biology), the heme-based oxygen sensor FixL kinase in nitrogenase synthesis in collaboration with Dr. Marie Alda Gonzalez of Ohio State University (now at University of Texas Southwestern Medical Center at Dallas), the urease accessory protein UreE in collaboration with Dr. Robert Hausinger of Michigan State University, and CuCu-aminopeptidase with Dr. Richard Holz at Utah State University, and metallo-dendrimers in collaboration with Dr. George Newkome of the Department (now at the University of Akron).
USF Summer Program on BioMedical and Life Science for High School Students
CHM2030 General, Organic, and Biological Chemistry: Course information
Co(II)-bacitracin complex
determined by means of NMR
Molecular modling of Pyrococcus POP (green) on porcine POP (red)
Other than science
What about crayfish outside the lab? (Hmm!)
Anything else, like pets or flowers? (Tell me!)
For questions about the graduate research in bioinorganic chemistry at USF
Email Dr. Li-June Ming at: ming@usf.edu
Updated Spring, 2024