In This Issue Cite This: ACS Chem. Biol. 2018, 13, 1699−1699
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A COPPER SENSOR FOR CELLS
RES, 4-hydroxynonenal (HNE), and use circular dichroism to show that the modification alters the β-sheet character of the protein. The researchers confirm that the human homologue can also be modified with HNE since it carries the conserved cysteine residue. A known cancer mutation proximal to the cysteine is also tested and shows a profound reduction in HNEylation. Taken together, the results point toward a new role for this heart-expressed heat shock protein as a cellular sensor for reactive electrophiles.
Copper is an essential element, positioned at the active site of numerous enzymes and acting as a cofactor for a variety of cellular proteins. The redox capacity of copper makes it an effective metal ion for biological reactions, but with this power comes potential hazards. Free copper can lead to reactive oxygen species which can damage macromolecules. As a consequence, organisms have evolved regulatory mechanisms to monitor and control copper levels in the cell. Defects in this cellular rheostat can result in disease states, and elevated cellular copper levels have been observed in multiple cancer types. In this issue, Jia et al. (DOI: 10.1021/acschembio.7b00748) introduce a new set of sensitive imaging compounds that allow measurement of free copper in living cells. After measuring copper binding affinities in the low picomolar range and a copper dose-dependent increase in fluorescence, they move into cellular assays to measure the copper pool in human cell lines, including a disease model for Menkes disease, a defect in a copper transporter protein. Finally, the utility of these new dyes for simultaneous measurements is demonstrated using a second dye to measure intracellular calcium.
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Solid tumors can be highly heterogeneous in nature, exhibiting microenvironments of cells with different proliferative potential. One contributor to this phenomenon is each cell’s access to nutrients and oxygen. Hypoxia is the state of low oxygen, and this can induce transcriptional changes to cope with the stressful environment. Current methods for measuring hypoxia involve invasive procedures and lack the ability to look deep inside the tumor. A promising advance in noninvasive detection is photoacoustic (PA) imaging, and here Knox et al. (DOI: 10.1021/ acschembio.8b00099) improve upon a previously developed PA probe for hypoxia by incorporating an internal standard. Their prior probe, HyP-1, had an N-oxide functional group that was reduced in response to hypoxia, yielding an absorbance shift that could be visualized by PA. The caveat was that an absence of signal in some areas of a tumor could be attributed to normoxia or simply a lack of sufficient probe concentration in that region. The new probes, which they dub ratiometic Hyp-1s, or rHyp-1s, yield a PA signal under normoxia and an additional signal, shifted in wavelength, under hypoxia conditions. They test the new compounds for PA imaging of solid tumors in mice, demonstrating that tumor hypoxic zones can be 3D reconstructed at high spatial resolution.
HEAT SHOCK MEETS ELECTROPHILE AVENUE
Reactive electrophilic species (RES) such as small unsaturated lipids can elicit powerful cellular responses, including the upregulation of stress response programs. Nucleophilic cysteine side chains are the target for RES, and adduct formation can modulate a variety of the sensor protein’s properties such as local structure or affinity for a partner. Searching for new sensor proteins has been carried out with mass spectrometry using synthetic RES that harbor a chemical handle, but many cellular targets remain unidentified. Now, Surya et al. (DOI: 10.1021/acschembio.7b00925) unveil a new target for RES, the zebrafish small heat shock protein Hspb7, identified during a screen for kinetically privileged sensor proteins. They go on to characterize the two candidate Hspb7 cysteines for sensing of an endogenous © 2018 American Chemical Society
PEERING INSIDE TUMORS WITH A HYPOXIA PROBE
Special Issue: Sensors Published: July 20, 2018 1699
DOI: 10.1021/acschembio.8b00612 ACS Chem. Biol. 2018, 13, 1699−1699
