About

Pinghua Liu is a Professor in the Department of Chemistry at Boston University. His research is at the interface of Chemistry and Biology, focusing on mechanistic studies and the application of pharmacologically important natural products using organic, molecular biology, and biophysical methods. His work primarily investigates the chemical basis of biological clocks, including circadian rhythms, and the chemical nature of pathogen-host interactions. The Liu Group's projects include studying two metallo-proteins, IspG and IspH, in related processes, and identifying other components involved in these pathways. The group's research on biological clocks involves determining the chemical basis and signal transduction pathways of circadian rhythms, mechanistic studies of enzymes involved in histone post-translational modifications, and identifying inhibitors for clock-related enzymes for therapeutic purposes. Additionally, Liu's research on isoprenoid biosynthesis encompasses mechanistic studies of IspG and IspH, development of mechanism-based inhibitors as antibiotics and antimalarial drugs, and bioengineering approaches for isoprenoid production and activity evaluation. His expertise includes enzymology, organic synthesis, isotopically labeled probe synthesis, protein expression and purification, kinetics, inhibitor design, and mechanistic studies. The Liu Group also employs genetic techniques such as gene knockout, gene replacement, and metabolic engineering, and utilizes spectroscopic methods like EPR and Mössbauer spectroscopy for metallo-enzyme characterization. The group fosters international collaborations in Europe and China, and prepares students for careers in both Chemistry and Biology, integrating studies across these disciplines.

Research topics

• Chemistry
• Biology
• Stereochemistry
• Organic chemistry
• Medicinal chemistry
• Biochemistry
• Computational biology
• Biochemical engineering
• Engineering

Selected publications

• Ergothioneine Protects Against UV-Induced Oxidative Stress Through the PI3K/AKT/Nrf2 Signaling Pathway

  Clinical Cosmetic and Investigational Dermatology · 2024-06-01 · 18 citations

  articleOpen access

  Background: Ergothioneine (EGT) is an antioxidant, which could be detected in human tissues, and human skin cells could utilize EGT and play an anti-oxidative role in keratinocytes. And in this study we are going to elucidate whether EGT could protect the skin from photoaging by Ultraviolet (UV) exposure in mice and its molecule pathway. Methods: Histological analysis was performed for evaluating the skin structure change. Malondialdehyde (MDA) and superoxide dismutase (SOD) levels were measured with biological assay for evaluating oxidative and antioxidative ability of skin exposed to UV light. And the level of marker molecules in mouse skin were detected by hydroxyproline (Hyp) assay, immunohistochemical analysis, Western blot, and quantitative real-time PCR (qRT-PCR). The markers of skin aging and cell death were tested by cell culture and treatment, Western blot and qRT-PCR. Results: EGT decreased the levels of inflammatory factors induced by UV exposure in mouse skin. MDA and SOD activity detection showed that EGT decreased MDA levels, increased SOD activity, and upregulated PI3K/Akt/Nrf2 signals in mouse skin exposed to UV, which further activated Nrf2 in the nucleus and enhanced the expression of Nrf2 target genes. In the cell model, we revealed that EGT could inhibit the increase in senescence-associated β-galactosidase-positive cells and p16 and γ-H2A.X positive cells induced by etoposide and activate PI3K/Akt/Nrf2 signaling. Moreover, a PI3K inhibitor blocked EGT protection against etoposide-induced cell death. Conclusion: The study showed EGT may play an important protective role against cell damage or death through the PI3K/Akt/Nrf2 signaling pathway in skin.

  PublisherOA PDFDOI

• Photo-reduction facilitated stachydrine oxidative N-demethylation reaction: A case study of Rieske non-heme iron oxygenase Stc2 from Sinorhizobium meliloti

  Methods in enzymology on CD-ROM/Methods in enzymology · 2024-01-01 · 1 citations

  articleSenior authorCorresponding
  PublisherDOI

• New Frontiers in Nonheme Enzymatic Oxyferryl Species

  ChemBioChem · 2024-06-20 · 8 citations

  reviewOpen accessCorresponding

  Non-heme mononuclear iron dependent (NHM-Fe) enzymes exhibit exceedingly diverse catalytic reactivities. Despite their catalytic versatilities, the mononuclear iron centers in these enzymes show a relatively simple architecture, in which an iron atom is ligated with 2-4 amino acid residues, including histidine, aspartic or glutamic acid. In the past two decades, a common high-valent reactive iron intermediate, the S=2 oxyferryl (Fe(IV)-oxo or Fe(IV)=O) species, has been repeatedly discovered in NHM-Fe enzymes containing a 2-His-Fe or 2-His-1-carboxylate-Fe center. However, for 3-His/4-His-Fe enzymes, no common reactive intermediate has been identified. Recently, we have spectroscopically characterized the first S=1 Fe(IV) intermediate in a 3-His-Fe containing enzyme, OvoA, which catalyzes a novel oxidative carbon-sulfur bond formation. In this review, we summarize the broad reactivities demonstrated by S=2 Fe(IV)-oxo intermediates, the discovery of the first S=1 Fe(IV) intermediate in OvoA and the mechanistic implication of such a discovery, and the intrinsic reactivity differences of the S=2 and the S=1 Fe(IV)-oxo species. Finally, we postulate the possible reasons to utilize an S=1 Fe(IV) species in OvoA and their implications to other 3-His/4-His-Fe enzymes.

  PublisherOA PDFDOI

• Correspondence on “Structural Insight into the Catalytic Mechanism of the Endoperoxide Synthase FtmOx1”

  Angewandte Chemie · 2023-08-04

  articleOpen accessSenior authorCorresponding

  Abstract In their recent Angewandte Chemie publication (doi: 10.1002/anie.202112063), Cen, Wang, Zhou et al. reported the crystal structure of a ternary complex of the non‐heme iron endoperoxidase FtmOx1 (PDB entry 7ETK). The biochemical data assessed in this study were from a retracted study (doi: 10.1038/nature15519) by Zhang, Liu, Zhang et al.; no additional biochemical data were included, yet there was no discussion on the source of the biochemical data in the report by Cen, Wang, Zhou et al. Based on this new crystal structure and subsequent QM/MM‐MD calculations, Cen, Wang, Zhou et al. concluded that their work provided evidence supporting the CarC‐like mechanistic model for FtmOx1 catalysis. However, the authors did not accurately describe either the CarC‐like model or the COX‐like model, and they did not address the differences between them. Further, and contrary to their interpretations in the manuscript, the authors’ data are consistent with the COX‐like model once the details of the CarC‐like and COX‐like models have been carefully analyzed.

  PublisherOA PDFDOI

• An <i>S</i>=1 Iron(IV) Intermediate Revealed in a Non‐Heme Iron Enzyme‐Catalyzed Oxidative C−S Bond Formation

  Angewandte Chemie International Edition · 2023-08-28 · 18 citations

  articleOpen access

  Abstract Ergothioneine (ESH) and ovothiol A (OSHA) are two natural thiol‐histidine derivatives. ESH has been implicated as a longevity vitamin and OSHA inhibits the proliferation of hepatocarcinoma. The key biosynthetic step of ESH and OSHA in the aerobic pathways is the O 2 ‐dependent C−S bond formation catalyzed by non‐heme iron enzymes (e.g., OvoA in ovothiol biosynthesis), but due to the lack of identification of key reactive intermediate the mechanism of this novel reaction is unresolved. In this study, we report the identification and characterization of a kinetically competent S =1 iron(IV) intermediate supported by a four‐histidine ligand environment (three from the protein residues and one from the substrate) in enabling C−S bond formation in OvoA from Methyloversatilis thermotoleran , which represents the first experimentally observed intermediate spin iron(IV) species in non‐heme iron enzymes. Results reported in this study thus set the stage to further dissect the mechanism of enzymatic oxidative C−S bond formation in the OSHA biosynthesis pathway. They also afford new opportunities to study the structure‐function relationship of high‐valent iron intermediates supported by a histidine rich ligand environment.

  PublisherOA PDFDOI

• An <i>S</i>=1 Iron(IV) Intermediate Revealed in a Non‐Heme Iron Enzyme‐Catalyzed Oxidative C−S Bond Formation

  Angewandte Chemie · 2023-08-28 · 1 citations

  articleOpen access

  Abstract Ergothioneine (ESH) and ovothiol A (OSHA) are two natural thiol‐histidine derivatives. ESH has been implicated as a longevity vitamin and OSHA inhibits the proliferation of hepatocarcinoma. The key biosynthetic step of ESH and OSHA in the aerobic pathways is the O 2 ‐dependent C−S bond formation catalyzed by non‐heme iron enzymes (e.g., OvoA in ovothiol biosynthesis), but due to the lack of identification of key reactive intermediate the mechanism of this novel reaction is unresolved. In this study, we report the identification and characterization of a kinetically competent S =1 iron(IV) intermediate supported by a four‐histidine ligand environment (three from the protein residues and one from the substrate) in enabling C−S bond formation in OvoA from Methyloversatilis thermotoleran , which represents the first experimentally observed intermediate spin iron(IV) species in non‐heme iron enzymes. Results reported in this study thus set the stage to further dissect the mechanism of enzymatic oxidative C−S bond formation in the OSHA biosynthesis pathway. They also afford new opportunities to study the structure‐function relationship of high‐valent iron intermediates supported by a histidine rich ligand environment.

  PublisherOA PDFDOI

• Faculty Opinions recommendation of Bone marrow adipoq+ cell population controls bone mass via sclerostin in mice.

  Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · 2023-07-14

  dataset1st authorCorresponding
  PublisherDOI

• Faculty Opinions recommendation of The gut microbiota promotes distal tissue regeneration via RORγ+ regulatory T cell emissaries.

  Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · 2023-04-20

  dataset1st authorCorresponding
  PublisherDOI

• Biochemical and Structural Characterization of OvoA_<i>Th2</i>: A Mononuclear Nonheme Iron Enzyme from <i>Hydrogenimonas thermophila</i> for Ovothiol Biosynthesis

  ACS Catalysis · 2023-11-14 · 16 citations

  articleOpen accessSenior authorCorresponding

  Ovothiol A and ergothioneine are thiol-histidine derivatives with sulfur substitutions at the δ-carbon or ε-carbon of the l-histidine imidazole ring, respectively. Both ovothiol A and ergothioneine have protective effects on many aging-related diseases, and the sulfur substitution plays a key role in determining their chemical and biological properties, while factors governing sulfur incorporation regioselectivities in ovothiol and ergothioneine biosynthesis in the corresponding enzymes (OvoA, Egt1, or EgtB) are not yet known. In this study, we have successfully obtained the first OvoA crystal structure, which provides critical information to explain their C–S bond formation regioselectivity. Furthermore, OvoATh2 exhibits several additional activities: (1) ergothioneine sulfoxide synthase activity akin to Egt1 in ergothioneine biosynthesis; (2) cysteine dioxygenase activity using l-cysteine and l-histidine analogues as substrates; (3) cysteine dioxygenase activity upon mutation of an active site tyrosine residue (Y406). The structural insights and diverse chemistries demonstrated by OvoATh2 pave the way for future comprehensive structure–function correlation studies.

  PublisherDOI

• Correspondence on “Structural Insight into the Catalytic Mechanism of the Endoperoxide Synthase FtmOx1”

  Angewandte Chemie International Edition · 2023-08-04 · 2 citations

  letterOpen accessSenior authorCorresponding

  In their recent Angewandte Chemie publication (doi: 10.1002/anie.202112063), Cen, Wang, Zhou et al. reported the crystal structure of a ternary complex of the non-heme iron endoperoxidase FtmOx1 (PDB entry 7ETK). The biochemical data assessed in this study were from a retracted study (doi: 10.1038/nature15519) by Zhang, Liu, Zhang et al.; no additional biochemical data were included, yet there was no discussion on the source of the biochemical data in the report by Cen, Wang, Zhou et al. Based on this new crystal structure and subsequent QM/MM-MD calculations, Cen, Wang, Zhou et al. concluded that their work provided evidence supporting the CarC-like mechanistic model for FtmOx1 catalysis. However, the authors did not accurately describe either the CarC-like model or the COX-like model, and they did not address the differences between them. Further, and contrary to their interpretations in the manuscript, the authors' data are consistent with the COX-like model once the details of the CarC-like and COX-like models have been carefully analyzed.

  PublisherOA PDFDOI

Recent grants

• Alkaloid Biosynthetic Studies

  NIH · $1.4M · 2021–2026

• Mechanistic Studies of New C-S Bond Formation Chemistries

  NSF · $380k · 2013–2018

• CAREER: Mechanistic Studies of Phosphonate Biosynthesis and Degradation

  NSF · $570k · 2008–2013

• NIH Grant R01GM093903

  NIH · $1.5M · 2017

• Mechanistic Studies of C-X Bond Formation Chemistries

  NSF · $420k · 2020–2024

Frequent coauthors

• Youli Xiao

  Chinese Academy of Sciences

  35 shared

• Hung‐wen Liu

  The University of Texas at Austin

  28 shared

• Nathchar Naowarojna

  Sakon Nakhon Rajabhat University

  22 shared

• David Giedroc

  Indiana University Bloomington

  18 shared

• Julian L. Leibowitz

  Texas A&M University

  16 shared

• Wei‐chen Chang

  North Carolina State University

  16 shared

• Xiaoping Chen

  National Health and Family Planning Commission

  15 shared

• Caren L. Freel Meyers

  Johns Hopkins Medicine

  13 shared