Transition Metal Signaling

Transition Metal Signaling and Metalloallostery

Bioinorganic Chemistry Beyond Active Sites

We are advancing a new paradigm of transition metal signaling, where metal nutrients like copper and iron can serve as dynamic signals to regulate protein function by metalloallostery, going beyond their traditional roles as static active site cofactors. We develop activity-based sensing probes for imaging mobile transition metal pools and activity-based proteomics probes for identifying allosteric metal sites in proteins. These chemical tools enable us to decipher the complex biology of sleep, cognition, and obesity in cell, zebrafish, and mouse models. We also develop medicines to target metals as disease vulnerabilities in cancer, neurodegeneration, and metabolic liver disorders. These drug discovery efforts focus on cuproplasia and cuproptosis, newly recognized forms of copper-dependent cell proliferation and cell death, respectively.

Related Publications

• Reviews
• Representative Copper Papers
• Representative Iron Papers

Reviews

• 

  Metalloallostery and Transition Metal Signalling: Bioinorganic Copper Chemistry Beyond Active Sites

  237

  Pham, V. N.; Chang, C. J.

  Angew. Chem. Int. Ed. 2023, 62, e202213644

• 

  Connecting copper and cancer: from transition metal signalling to metalloplasia

  224

  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. 2022, 22, 102–113

• 

  Bioinorganic Life and Neural Activity: Toward a Chemistry of Consciousness?

  163

  Chang, C. J.

  Acc. Chem. Res. 2017, 50, 535-538

• 

  Analytical Methods for Imaging Metals in Biology: From Transition Metal Metabolism to Transition Metal Signaling

  161

  Ackerman, C. M.; Lee, S.; Chang, C. J.

  Anal. Chem. 2017, 89, 22-41

• 

  Searching for Harmony in Transition-Metal Signaling

  145

  Chang, C. J.

  Nature Chem. Biol. 2015, 111, 744-747

• 

  Recognition- and Reactivity-Based Fluorescent Probes for Studying Transition Metal Signaling in Living Systems

  141

  Aron, A. T.; Ramos-Torres, K. M.; Cotruvo, Jr., J. A.; Chang, C. J.

  Acc. Chem. Res. 2015, 48, 2434-2442

Representative Copper Papers

• 

  ATPase copper transporting beta (ATP7B) is a novel target for improving the therapeutic efficacy of docetaxel by disulfiram/copper in human prostate cancer

  253

  Song, L., Nguyen, V., Xie, J., Jia, S., Chang, C. J., Uchio, E., & Zi, Xiaolin.

  Mol Cancer Ther. 2024, 23, 1-30.

• 

  Dysfunction in atox-1 and ceruloplasmin alters labile Cu levels and consequently Cu homeostasis in C. elegans

  252

  Weishaupt, A. K., Lamann, K., Tallarek, E., Pezacki, A. T., Matier, C. D., Schwerdtle, T., Aschner, M., Chang, C. J., Stürzenbaum, S. R., & Bornhorst, J.

  Front Mol Biosci. 2024, 11, 1-12.

• 

  Oxidation state-specific fluorescent copper sensors reveal oncogene-driven redox changes that regulate labile copper(II) pools

  234

  Pezacki, A. T.; Matier, C. D.; Gu, X.; Kummelstedt, E.; Bond, S. E.; Torrente, L; Jordan-Sciutto, K. L.; DeNicola, G. M.; Su, T. A.; Brady, D. C.; Chang, C. J.

  Proc. Natl. Acad. Sci. U.S.A. 2022, 119, e2202736119

• 

  Activity-Based Sensing with a Metal-Directed Acyl Imidazole Strategy Reveals Cell Type-Dependent Pools of Labile Brain Copper

  208

  Lee, S.; Chung, C. Y.-S.; Liu, P., Craciun, L; Nishikawa, Y.; Bruemmer, K. J.; Hamachi, I.; Saijo, K.; Miller, E. W.; Chang, C. J.

  J. Am. Chem. Soc. 2020, 142, 14993–15003

• 

  Activity-based ratiometric FRET probe reveals oncogene-driven changes in labile copper pools induced by altered glutathione metabolism

  192

  Chung, C. Y.; Posimo, J. M.; Lee, S.;, Tsang, T.; Davis, J. M.; Brady, D. C.; Chang, C. J.

  Proc. Natl. Acad. Sci. USA 2019, 116, 18285-18294

• 

  Copper regulates rest-activity cycles through the locus coeruleus-norepinephrine system

  180

  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

• 

  In vivo bioluminescence imaging reveals copper deficiency in a murine model of nonalcoholic fatty liver disease

  160

  Heffern, M. C.; Park, H. M.; Au-Yeung, H. Y.; Van de Bittner, G. C.; Ackerman, C. M.; Stahl, A. Chang, C. J.

  Proc. Natl. Acad. Sci. USA 2016, 113, 14219-14224

• 

  Copper Capture in a Thioether-Functionalized Porous Polymer Applied to the Detection of Wilson’s Disease

  151

  Lee, S.; Barin, G.; Ackerman, C. M.; Muchenditsi, A.; Xu, J.; Reimer, J. A.; Lutsenko, S.; Long, J. R.; Chang, C. J.

  J. Am. Chem. Soc. 2016, 138, 7603-7609

• 

  Copper regulates cyclic-AMP-dependent lipolysis

  150

  Krishnamoorthy, L.; Cotruvo, Jr., J. A.; Chan, J.; Kaluarachchi, H.; Muchenditsi, A.; Pendyala, V. S.; Jia, S.; Aron, A. T.; Ackerman, C. M.; Vander Wal, M. N.; Guan, T.; Smaga, L. P.; Farhi, S. L.; New, E. J.; Lutsenko, S.; Chang, C. J.

  Nature Chem. Biol. 2016, 12, 586-592

• 

  Calcium-dependent copper redistributions in neuronal cells revealed by a fluorescent copper sensor and X-ray fluorescence microscopy

  72

  Dodani, S. C.; Domaille, D. W.; Nam, C. I.; Miller, E. W.; Finney, L. A.; Vogt, S.; Chang, C. J.

  Proc. Natl. Acad. Sci. USA 2011, 108, 5980-5985

Representative Iron Papers

• 

  In vivo bioluminescence imaging of labile iron accumulation in a murine model of Acinetobacter baumannii infection

  169

  Aron, A. T.; Heffern, M. C.; Lonergan, Z. R.*; Vander Wal, M. N.; Blank, B. R.; Spangler, B.; Zhang, Y.; Park, H. M.; Stahl, A.; Renslo, A. R.; Skaar, E. P.; Chang, C. J.

  Proc. Natl. Acad. Sci. USA 2017, 114, 12669–12674

• 

  An Endoperoxide Reactivity-Based FRET Probe for Ratiometric Fluorescence Imaging of Labile Iron Pools in Living Cells

  158

  Aron, A. T.; Loehr, M. O.; Bogena, J.; Chang, C. J.

  J. Am. Chem. Soc. 2016, 138, 14338-14346

• 

  Molecular Imaging of Labile Iron(II) Pools in Living Cells with a Turn-On Fluorescent Probe

  116

  Au-Yeung, H. Y.; Chan, J.; Chantarojsiri, T.; Chang, C. J.

  J. Am. Chem. Soc. 2013, 135, 15165-15173