Class of 1942 Chair and Professor of Biochemistry, Biophysics and Structural Biology*
*And of Chemistry
Chemical Biology: Imaging and Proteomics to Decipher and Drug Novel Metal and Redox Disease Vulnerabilities
Our laboratory studies the chemistry of biology and energy, where we advance new concepts in imaging, proteomics, drug discovery, and catalysis. Our work draws from core disciplines of chemistry, biochemistry, and molecular biology and features a diverse range of elements across the periodic table of life. We have developed activity-based sensing (ABS) as a general platform for biology and medicine, enabling broad applications of this technology to imaging, proteomics, and drug discovery. These chemical tools have identified copper, hydrogen peroxide, and formaldehyde as signals for allosteric regulation of protein function to open new fields of transition metal signaling, metalloallostery, and single-atom signaling, impacting areas of health and disease spanning neural activity and neurodegeneration to cancer, obesity, and metabolic diseases. Our work in artificial photosynthesis uses design concepts from biology to develop new molecular and hybrid catalysts for sustainable electrosynthesis applied to global challenges in carbon dioxide capture and conversion and nitrogen/phosphorus cycles. Representative project areas are summarized below.
The Chang Lab, 2020
Transition Metal Signaling: From Metalloallostery to Metalloplasia in the Brain and Beyond. We are advancing a new paradigm of transition metal signaling, where essential nutrients like copper and iron can serve as dynamic signaling messengers to regulate protein function beyond their traditional roles as static active site cofactors. We develop activity-based sensing fluorescent probes for imaging mobile transition metal pools and activity-based proteomics probes for discovery and characterization of enzymes regulated by metalloallostery. These chemical tools enable us to decipher complex biology such as sleep behavior and fat metabolism at a molecular and systems level. Working across cell, zebrafish, and mouse models, we identify disease vulnerabilities to metal nutrients to develop new modalities for drug discovery, such as targeting metalloplasias that rely on metal-dependent cell proliferation in cancer, neurodegenerative diseases, and metabolic liver diseases.
Activity-Based Sensing: Imaging Redox and One-Carbon Signaling. We are advancing the field of activity-based sensing, which exploits molecular reactivity, rather than molecular recognition with conventional lock-and-key binding, to design chemical sensors for biological discovery that achieve high specificity and spatiotemporal resolution. We create activity-based sensing probes to visualize fluxes of transient reactive oxygen species and one-carbon metabolites using fluorescence and other imaging modalities. We apply these chemical tools in profiling assays at the single-cell, tissue, and animal level to identify and elucidate principles of redox and one-carbon biology, including sources and scavengers of reactive molecular signals.
Activity-Based Proteomics: From Single-Atom Signaling to Redox Drug Discovery. We are advancing the concept of single-atom signaling, deciphering how site-specific allosteric modification of a protein with just a single element can regulate its function. We focus on the reversible redox cycling between methionine and methionine sulfoxide and the writers and erasers that install and remove these one-oxygen post-translational modifications. We develop synthetic methods for bioconjugation to native amino acids for use from proteins to proteomes, enabling platforms such as activity-based protein profiling to find novel sites for allosteric protein regulation. In turn, we translate our findings to target these newly-discovered druggable hotspots in cancer and other diseases using small-molecule covalent ligand libraries, antibody-drug conjugates, and related therapeutic modalities.
Artificial Photosynthesis: Catalyzing Sustainable Electrosynthesis. We develop catalysts for sustainable electrosynthesis to address changing climate and rising global energy demands. Inspired by natural photosynthesis, which catalyzes conversion of the abundant chemical resources of light, water, and carbon dioxide to produce the value-added products needed to sustain life, we are taking a unified approach to this small-molecule activation problem by creating molecular electrocatalysts for carbon dioxide capture and conversion as well as nitrogen/phosphorus cycling that draw on design principles from molecular, materials, and biological catalysis and operate in water.
1. "Searching for Harmony in Transition-Metal Signaling", Chang, C. J. Nature Chem. Biol. 2015, 111, 744-747.
2. "Connecting copper and cancer: from transition metal signalling to metalloplasia", Ge, E. J.; Bush, A. I.; Casini, A.; Cobine, P. A.; Cross, J. R.; DeNicola, G. M.; Dou, Q. P.; Franz, K. J.; Gohil, V. M.; Gupta, S.; Kaler, S. G.; Lutsenko, S.; Mittal, V.; Petris, M. J.; Polishchuk, R.; Ralle, M.; Schilsky, M. L.; Tonks, N. K.; Vahdat, L. T.; Aelst, L. V.; Xi, D.; Yuan, P.; Brady, D. C.; Chang, C. J.. Nature Rev. Cancer 2021, 61, in press.
3. "Copper regulates cyclic-AMP-dependent lipolysis", Krishnamoorthy, L.; Cotruvo Jr., J. A.; Chan, J.; Kaluarachchi, H.; Muchenditsi, A.; Pendyala, V. S.; Jia, S.; Aron, A. T.; Ackerman, C. M.; Wander Wal, M. N.; Guan, T.; Smaga, L. P.; Farhi, S. L.; New, E. J.; Lutsenko, S.; Chang, C. J. Nature Chem. Biol. 2016, 12, 586-593.
4. "Redox-based reagents for chemoselective methionine bioconjugation", Lin, S.; Yang, X.; Jia, S.; Weeks, A. M.; Hornsby, M.; Lee, P. S.; Nichiporuk, R. V.; Iavarone, A. T.; Wells, J. A.; Toste, F. D.; Chang, C. J. Science 2017, 355, 597-602.
5. "Copper regulates rest-activity cycles through the locus coeruleus-norepinephrine system", Xiao, T.; Ackerman, C. M.; Carroll, E. C.; Jia, S.; Hoagland, A.; Chan, J.; Thai. B.; Liu, C. S.; Isacoff, E. Y.; Chang, C. J. Nature Chem. Biol. 2018, 14, 655-663.
Last Updated 2022-01-15