Plenary Speakers

A diverse line up of exceptional experts shaping the forefront of metallomics.

Prof. Hongzhe SUN

Hongzhe SUN is the Norman & Cecilia Yip Professor in Bioinorganic Chemistry at the University of Hong Kong. As a leading expert in the field of biological inorganic chemistry and metallomics, his research interests lie in the frontier of metalloproteomics and metallomics, discovery of antimicrobial and antiviral agents, and inorganic chemical biology. His seminal contributions to the field of metallomics/metalloproteomics have garnered significant recognition.

For his pioneering work uncovering potential metallodrug binding proteins in pathogens, he was recently awarded the Dalton Horizon Prize (RSC, 2023), given to teams and collaborations that open new directions in contemporary chemical science through groundbreaking scientific developments.

His recent interest lies in integrative metallomic approaches for overcoming emerging infectious diseases. He has published over 230 papers, and edited a book entitled “biological chemistry of arsenic, antimony and bismuth” (John Wiley, 2011). He is the recipient of the AsBIC Outstanding Achievement Award (2022), UC Berkeley Muetterties Lectureship (2018) and WuXi AppTech Life Chemistry Research Award (2016). He is an editor of the Journal of Biological Inorganic Chemistry (Springer) and was a series editor of Metallobiology (RSC).

Abstract

TWENTY YEARS OF METALLOMICS AND METALLOPROTEOMICS: FROM INORGANIC CHEMICAL BIOLOGY TO MEDICINAL APPLICATIONS

H. Sun1, H. Li1, Y. Zhou1, X. Wei1,2, C. Wang1, S. Yuan2

1Department of Chemistry and CAS-HKU Joint Laboratory of Metallomics on Health & Environment
2Department of Microbiology and State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Pokfulam Road, Hong Kong SAR, China

Metals are essential for all lives, and certain metal compounds have long been used in medicine (for diagnosis and therapy) and healthcare. The concentration and speciation of certain metal ions (e.g. transition metal ions) are tightly regulated. It is important to identify metal-protein interactions at a proteome-wide scale which are challenging due to diversity of metal-protein interactions [1,2]. Metallomics/metalloproteomics was evolved over 20 years ago and complements genomics, proteomes and metabolomics. We have integrated metallomics with metabolomics, trans-criptomics and deep learning (DL) to examine multiple cellular changes to the numerous intracellular process affected [3] and to quantify the metals for metallome/proteome-wide profiling of metal-binding proteins.

Based on our integrative metallomic/ metalloproteomic approach, we have found that metallo-agents (e.g., Bi(III) and Au(I)) interfere with Zn(II) biochemistry in microbials, and propose to use Bi(III) complexes to inhibit Zn(II) enzymes in superbugs (metallo-β-lactamases (MBLs)) and coronaviruses [4-6]. We show that bismuth drugs related Bi(III) complexes irreversibly inhibit different types of MBLs and have demonstrated a high potential of Bi(III) compounds as the first broad-spectrum MBL inhibitors to treat MBL producing bacterial infection in combined use with existing carbapenems [5]. We then showed that auranofin serves as a dual inhibitor to resensitize carbapenem- and colistin-resistant bacteria to antibiotics [6]. Very recently, we have demonstrated that Bi(III) drugs effectively suppress SARS-CoV-2 replication and relieves virus-associated pneumonia in Syrian hamsters [6]. The metallodrug may inhibit multiple viral Zn(II) enzymes including helicase (nsp13) and ExoN/MTase (nsp14).

By integrating a home-made fluorescence imaging with a proteomic approach, we visualized the Cr(III) proteome being mainly localized in the mitochondria, and subsequently show that Cr(III) binds to ATP synthase at its beta-subunit [3]. Such a long-standing question of how Cr(III) ameliorates hyperglycaemia stress opens a new avenue for the pharmacological effects of Cr(III).

We have also built up a metal-coding assisted systematic multi-omic platform, i.e. serological metallome, immunoproteome integrated with single-cell proteome. We constructed a correlation network between the host Metallome/ Metalloproteome−Immunoproteomes, providing a holistic view of the links between the host metallome and immunity of COVID-19. Our integrative metallomic approach can be readily extended to other essential biometals, opening a new horizon for metallobiology, inorganic chemical biology and precision medicine.

We thank the RGC (SRFS2122-7S04, C7034-20E, R7070-18, 17306323, T11-709/21N, 17318322) of HK SAR; and the University of Hong Kong (URC and Norman & Cecilia Yip Foundation) for support.

  1. K. J. Waldron, J. C. Rutherford, D. Ford, N. J. Robinson. Nature, 2009, 460, 823-830.
  2. Y. Zhou, H. Li, H. Sun. Ann. Rev. Biochem., 2022, 91, 449-473.
  3. H. B. Wang, L. G. Hu, H. Li, Y.-T. Lai, X. Wei, X. Xu, Z. Cao, H. Cao, Q. Wan, Y.-Y. Chang, A. Xu, Q. Zhou, G. Jiang, M. He, H. Sun. Nat. Commun., 2023, 14, 1738.
  4. H. Li, H. Sun. Nat. Chem., 2022, 14, 608.
  5. R. M. Wang, T. P. Lai, P. L. Ho, P. C. Woo, R. G. Ma, Y. Kao, H. Li, H. Sun. Nat. Commun., 2018, 9, 439.
  6. S. Yuan, R. M. Wang, J. F. W. Chan, A. J. Zhang, T. F. Cheng, K. K. H. Chik, Z. W. Ye, S. Y. Wang, A. C. Lee, L. J. Jin, H. Y. Li, D. Y. Jin, K. Y. Yuen, H. Sun. Nat. Microbiol., 2020, 5, 1439-1448.

Dr. Mak Saito

Dr. Mak Saito is a Senior Scientist in the Marine Chemistry and Geochemistry Department of the Woods Hole Oceanographic Institution (WHOI) in Massachusetts USA. He received his PhD from the Massachusetts Institute of Technology-WHOI Joint Program and did postdoctoral research at Princeton University.

The Saito laboratory studies the nutritional role of metals in marine microorganisms and their role on global biogeochemical cycling. With human economies now large enough to impinge upon many of these cycles, obtaining an understanding of the mechanisms that create and maintain these biogeochemical cycles is critical in achieving sustainable economies.

His team has participated in over 30 oceanographic expeditions to remote environments from Antarctica to Arctic Ocean and applies a variety of proteomic and analytical chemistry techniques. His group’s research has examined the roles of zinc, cobalt (including vitamin B12), iron, nickel, and other metals in the sustenance of marine phytoplankton, bacteria, and Archaea. He is the lead PI for the Ocean Protein Portal Project and the Biological Chemical Oceanographic Data Management Office (BCO-DMO).

Abstract

THE ADAPTIVE CAPABILITIES OF PHYTOPLANKTON AND MICROBIAL METALLOMES IN A CHANGING OCEAN

M. Saito

Marine Chemistry and Geochemistry Department, Woods Hole Oceanographic Institution, Woods Hole, USA

The essential metal use within microorganisms is shaped by cellular processes of transport and metalloprotein biosynthesis against the backdrop of environmental availability. Moreover, the choice of metal is driven by the chemical properties of each element, with some elements able to substitute for one another when their properties overlap. Alternate isoforms of enzymes can also occur with different metal usage and kinetic properties. This adaptive biochemistry then interacts with both the chemical speciation of micronutrients (and resulting bioavailability) and the ecology of organisms deploying these biochemical systems to determine the fitness of microbes and their biogeochemical functionalities. The development and deployment of proteomic methods can now contribute to the mechanistic understanding of (micro)nutritional stress and allow a characterization of the major metalloprotein that comprise the cellular metal inventory, respectively.

Changes in metal nutritional controls of phytoplankton in coastal Antarctic and Southern Ocean environments will be described, where increased iron inputs due to subglacial melting are inducing the emergence of new limitations for vitamin B12 and zinc. Recently discovered zinc and B12 responsive proteins in marine organisms and their role in transport and sparing will be described. With the oceans experiencing an array of anthropogenic challenges, characterizing the metallomic mechanisms such as these that underlie microbial biogeochemical cycles will contribute to understanding the damage incurred and the paths towards sustainability.

Prof. Ute Krämer

Ute Krämer is a Full Professor at the Ruhr University Bochum, Germany, where she holds the Chair of Molecular Genetics and Physiology of Plants. She received a D.Phil. at the University of Oxford, UK, and did postdoctoral research at Rutgers University, NJ, USA. Renowned for her ground-breaking work on metal hyperaccumulation in plants, she has deciphered how certain plants flourish in heavy metal-laden soils, surviving at concentrations toxic to most.

The Krämer lab’s investigations dissect the complex interactions between plants and soil, particularly the uptake and management of both essential nutrients and non-essential heavy metals. Her team adeptly combines physiology, molecular and cell biology, biochemistry, genetics, genomics, and field studies to elucidate the integration of metal homeostasis with plant metabolism, growth, and development. This multifaceted approach shines a light on the intersection of molecular mechanisms with evolutionary ecology, especially in the metal hyperaccumulator Arabidopsis halleri.

Ute Krämer is a member of the prestigious German Academy of Sciences Leopoldina and was awarded an Advanced Grant of the European Research Council in 2018.

Abstract

METAL-RELATED EVOLUTIONARY ADAPTATIONS IN THE EXTREMOPHILE MODEL PLANT ARABIDOPSIS HALLERI

V. Kumar, N. Wozniak, M. Zhao, B. Pietzenuk, U. Kramer

Molecular Genetics and Physiology of Plants, Ruhr University Bochum, Bochum, Germany

Environmental pollution threatens human and environmental health globally. Uptake by land plants is a major source of both contaminant and essential micronutrient trace elements in the food web. Our research objective is to understand the genetic and physiological mechanisms underlying metal handling by land plants in an ecological and evolutionary context.

Among the sister species of the genetic model plant Arabidopsis thaliana in the Brassicaceae family, Arabidopsis halleri accumulates extraordinarily high concentrations of zinc (Zn) and cadmium (Cd) in above-ground organs. Although the majority of populations of A. halleri are found on normal soils, the species has naturally colonized extreme heavy metal-contaminated habitats in multiple instances. Thus, in contrast to A. thaliana, natural populations of A. halleri can be found among the specialists on so-called calamine metalliferous soils containing high levels of Zn, Cd, lead (Pb), and sometimes copper (Cu). Orders of magnitude higher than in ordinary plants, hyperaccumulator levels of Zn above 3,000 µg g-1 leaf dry biomass are found in all natural populations of Arabidopsis halleri, and Cd hyperaccumulation above 100 µg g-1 leaf dry biomass is reached in part of the populations on both metalliferous and non-metalliferous pristine soils.

We use transcriptomic, reverse genetic and population genomic approaches to uncover the genetic basis of the extremely large differences in metal accumulation and metal tolerance between A. halleri and A. thaliana. In addition, we combine genetic and genomic approaches to address variation within the species A. halleri. Based on short-read re-sequencing of about 900 Arabidopsis halleri individuals, genome-wide association studies provide insights into the genetic architecture of within-species variation in metal-related extreme physiological traits in A. halleri.

Moreover, Quantitative Trait Locus (QTL) mapping in targeted crosses suggests the contribution of only few major loci to enhanced metal hypertolerance in A. halleri originating from a particularly highly Cd-contaminated site. Our results highlight the importance of structural genomic variants in metal-related extreme traits. This work will allow advances in the development of phytoremediation and phytomining technologies and provide insights into the ecological role and evolution of trace element-related physiological traits in plants.

Prof. Louise Horsfall

Louise Horsfall is a Professor of Sustainable Biotechnology at The University of Edinburgh. She earned her MChem from Oxford and a PhD in Biochemistry from Université de Liège. After roles at Leeds and Glasgow Universities, she joined Edinburgh in 2012. A founding member of the European Federation of Biotechnology’s (EFB) Bioengineering Division, she is interested in multidisciplinary challenges utilising Biotechnology and Synthetic Biology towards a sustainable, circular economy.

The Horsfall group is renowned for developing the most advanced bio-based lithium-ion battery recycling process to date and contributing to the roadmap for sustainable circular economy in lithium-ion and future battery technologies. Their innovative research merges biosynthesised nanoparticles with green chemistry for enhanced catalysis.

Prof. Horsfall serves on the EFB’s Executive Board and holds memberships in European Synthetic Biology Society, SynBioUK Advisory Boards, EPSRC’s Strategic Advisory Team for manufacturing and circular economy, BBSRC Strategy Advisory Panel for advanced manufacturing and clean growth, the Carbon Technology Research Foundation Advisory Council, the Scottish Universities Life Sciences Alliance strategic group and the Scottish Science Advisory Council – providing independent advice and recommendations on science strategy, policy and priorities to the Scottish Government.

Abstract

ENGINEERING A BIO-ENABLED CIRCULAR ECONOMY FOR TECHNOLOGY CRITICAL METALS

L. Horsfall

School of Biological Sciences, University of Edinburgh, Edinburgh, UK

Metals have a finite supply and are resource intensive to obtain but with advanced recycling technologies they could be used within a circular economy for centuries.

Certain microorganisms have the potential to manufacture metallic nanoparticles, irrespective of the source of metal ions, and provide us with new particles with novel functions. To exploit this, we have been studying the interaction between bacteria and technology critical metals, such as platinum, palladium, cobalt and nickel. We are identifying and optimising genetic elements with an aim to increase nanoparticle production and control nanoparticle size and homogeneity; in effect standardising nanoparticle samples by using biology. While developing this process we are exploring its use for the treatment of contaminated waste, water and land, and examining applications for the resultant biogenic nanoparticles.

Our ultimate aim is to produce engineered microbes with the ability to upcycle technology critical metals from waste streams into high value nanoparticles with exciting applications in the green technology sector ranging from batteries to catalysts. This area is rapidly growing in importance, as society’s dependency on metals only increases in our transition away from using fossil resources.

Prof. Pernilla Wittung-Stafshede

Pernilla Wittung-Stafshede is a Professor at the Life Sciences Department at Chalmers University of Technology in Gothenburg, Sweden. She launched her independent research career at Tulane University in 1999, following a PhD in physical chemistry and a postdoc at the California Institute of Technology. Prof. Wittung-Stafshede continued her impactful career at Rice University, and Umeå University, ultimately moving to Chalmers University’s newly established Life Sciences Department in 2015.

Having pioneered discoveries concerning metals in protein folding, macromolecular crowding effects on folding reactions, and the mechanisms of copper-transport proteins, Prof. Wittung-Stafshede’s current research focuses on elucidating the roles of copper transport proteins in cancer processes and exploring the cross-reactivity between amyloidogenic proteins and metals in neurodegenerative diseases.

Prof. Wittung-Stafshede, a member of the Royal Swedish Academies of the Sciences and the Engineering Sciences, joined the 2020 Nobel Prize in Chemistry committee and has been lauded with numerous awards throughout her career, publishing over 265 scientific articles and 50 popular texts. In 2019, she spearheaded “Genie,” a substantial gender equality program at her university, further establishing herself as an international spokesperson for gender equality in science.

Abstract

FROM COPPER-PROTEIN BIOPHYSICS TO HUMAN-DISEASE MECHANISMS

P. Wittung-Stafshede

Department of Life Sciences, Chalmers University of Technology, Gothenburg, Sweden

Mechanistic information of (dys)functional interactions between proteins and metals is important for the understanding of basic biology, and to combat human diseases where metals are involved. Here I will describe some of our biophysical research on copper (Cu) transport proteins that provides new information on cancer metastasis mechanisms and protein amyloid formation, the latter which is linked to neurodegenerative disorders such as Parkinson’s disease (PD).

Cu is an essential metal ion acting as a reactive cofactor in many key enzymes. To avoid toxicity of free Cu, human cells harbor dedicated Cu transport proteins that facilitate safe delivery to target proteins. Since many proteins depend on Cu for functionality, it is not surprising that cancer cells have a high demand for Cu. Using in vitro experiments with purified proteins in combination with cell culture studies, we have discovered that the cytoplasmic Cu chaperone Atox1 plays a promoting role in cancer cell migration, and we identified underlying principles. We also discovered that a known cancer-promoting protein, Memo1, in fact can scavenge Cu ions and thereby limits formation of (otherwise) damaging reactive oxygen species.

Disturbances of Cu homeostasis also appear to play roles in neurodegenerative disorders. In PD, the aggregation of the Cu-binding protein α-synuclein into amyloid fibers contributes to neuronal cell death. We have unravelled that α-synuclein amyloid formation is blocked by Cu-dependent Atox1 interactions in vitro and in neuronal cells. We also discovered that free Cu ions are readily incorporated into α-synuclein amyloids, and this affects both the resulting amyloid structure and the metal’s chemical properties. Molecular knowledge of protein-copper cross-reactivity, as described here for cancer and PD processes, may act as the basis for new drug discovery efforts towards devastating human diseases.

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