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

Abstract

Transition metal chemistry is essential to life, where metal binding to DNA, RNA, and proteins underpins all facets of the central dogma of biology. In this context, metals in proteins are typically studied as static active site cofactors. However, the emergence of transition metal signaling, where mobile metal pools can transiently bind to biological targets beyond active sites, is expanding this conventional view of bioinorganic chemistry. This Minireview focuses on the concept of metalloallostery, using copper as a canonical example of how metals can regulate protein function by binding to remote allosteric sites (e.g., exosites). We summarize advances in and prospects for the field, including imaging dynamic transition metal signaling pools, allosteric inhibition or activation of protein targets by metal binding, and metal‐dependent signaling pathways that underlie nutrient vulnerabilities in diseases spanning obesity, fatty liver disease, cancer, and neurodegeneration.

Combining Copper and Zinc into a Biosensor for Anti-Chemoresistance and Achieving Osteosarcoma Therapeutic Efficacy

“…However, the chelating mechanisms of copper (I) and copper (II) are complex and intertwined [107]. For instance, the 6-transmembrane epithelial antigen of prostate reductase (STEAP) converts copper into copper (I) in serum [25]. In the tissue cell copper uptake mechanism, CTR1 transports copper (I) but not copper (II) [111].…”

“…These protein kinases with copper-binding activity induce cell proliferation [192]. However, these copper-binding activities will decrease copper availability, resulting in copper deficiency [25]. Conversely, the increase in copper availability will enhance ULK1/2 activities and autophagy functions [189].…”

Combining Copper and Zinc into a Biosensor for Anti-Chemoresistance and Achieving Osteosarcoma Therapeutic Efficacy

“…However, the chelating mechanisms of copper(I) and copper(II) are complex and intertwined [ 102 ]. For instance, the 6-transmembrane epithelial antigen of prostate reductase (STEAP) converts copper into copper(I) in serum [ 25 ]. In the tissue cell copper uptake mechanism, CTR1 transports copper(I) but not copper(II) [ 106 ].…”

“…These protein kinases with copper-binding activity induce cell proliferation [ 193 ]. However, these copper-binding activities will decrease copper availability, resulting in copper deficiency [ 25 ]. Conversely, the increase in copper availability will enhance ULK1/2 activities and autophagy functions [ 190 ].…”

“…This will alter MBD’s perspectives and generate new drug discovery insight maps [ 21 ]. In modern medicine, the understanding of metal-ion functions [ 22 ] and diagnosis at the molecular level [ 23 ] have become inevitable consequences of delivering new MBD in medicinal bioinorganic chemistry [ 24 , 25 ]. There is still inadequate effort devoted at mechanistic levels [ 26 ] towards providing an alternative, targeted, and rational approach [ 27 ] to supplement screening of novel chemical entities for biological activity [ 21 ].…”