SCIENCE & TECHNOLOGY
ONE SCAFFOLD, TWO SOLUTIONS Both natural and synthetic porphyrins bind to potassium channels—but in different ways AMANDA YARNELL, C&EN WASHINGTON
His team is currendy trying to test whether these channels are tagged with heme after cellular injury Dirk Trauner, an assistant professor of chemistry at the University of California, Berkeley is also interested in the interaction of hemelike molecules withpotassium channels. Trauner believes man-made, symmetric porphyrins are a promising start toward designing drugs for autoimmune diseases, epilepsy, cardiac arrythmia, and diabetes. "We were prompted to develop our ligands by analyzing X-ray structures of potassium channels and their interactions with naturally occurring peptide toxins," Trauner says. In these channels, the pore that potassi-
enzymes that metabolize drugs in the body porphyrin molecules—nitroBut free-floating heme may also play an gen-containing macrocycles important biological role, according to a that often coordinate iron or new study led by associate professor ofphysother metals—are capable of iology Tbshinori Hoshi of the University of binding potassium channel proteins in at Pennsylvania. Hoshi, staff scientist Xiang SYNTHETIC Trauner expects his least two very different ways. The findings Dong Tang, and coworkers recently symmetric tetraphenylporphyrin suggest that heme, which is a natural iron- showed thatfreeheme can bind to and Ugands (purple) to bind to the coordinating porphyrin that functions as inhibit the action ofa calcium-defSlV^ extracellular side of a catalytic center in many enzymes, might pendent potassium channel [Napotassium channels (gray). also play a solo role as a cell-signaling mol- ture, 425,531 (2003)]. ecule. And they point to artificial symurn ions go through is loHoshi's team began to metric porphyrins as a promising start to- investigate the interac^ cated at the center of ward designing clinically important tion of heme with this Y^ **»k symmetry offouridenpotassium channel inhibitors. *' ** tical protein subunits. channel after an analySo Trauner settled on Heme (otherwise known as iron proto- sis of its amino acid setetraphenylporphyrins porphyrin IX) is a key biological cofactor. quence turned up a in the hopes that the fourHemoglobin, the protein that carries oxy- known heme-binding mofold symmetrical molecules gen through the blood, binds oxygen via tif. This motif, which conmight interact with all four subits four heme cofactors. And heme acts as tains two cysteines and a histidine, units simultaneously Such polythe catalytic center in a variety of enzymes, is located in the portion of the valent ligands should bind to the exincluding the various cytochrome P450 potassium channel that protrudes into the cytoplasm between the domains that tracellular side of the channel with high affinity, he tells C&EN. are thought to regulate channel opening. In fact, the water-soluble tetraphenylSure enough, Hoshi's team found that heme does bind to this motif. Electron porphyrins that Trauner, graduate student paramagnetic resonance and UV-visible Stefan N. Gradl, and their coworkers synspectra of heme bound to a 23-residue thesized bind to voltage-gated potassium peptide fragment encompassing the mo- ion channels with nanomolar affinities \J. tif suggest that the histidine side chain co- Am. Chem. Soc, 125,12668 (2003)}. Porordinates to the heme's iron center. This phyrins that bear phenyl groups with mode of heme coordination is similar to positively charged substituents are particularly good inhibitors ofchannel function— that seen in cytochrome proteins. Using electrophysiological techniques although none of the derivatives Trainer's to monitor the ability of single channels to team has tested completely blocks potastransport potassium ions across mem- sium ion flow across the membrane. 'The modular composition ofour ligands branes, Hoshi's team has shown that heme binding inhibits the channel's function by allows easy modifications and should prodecreasing the frequency of channel open- vide a large set of synthetic probes that ings. In vivo, free heme—high concentra- discriminate among different potassium tions of which are released after strokes, channels," the authors write. Trauner is parALL NATURAL Hoshi'steam ticularly interested in making metalloporheart attacks, and other severe injuries— suggests that heme binds the cytoplasmic side of a calcium-dependent may block this potassium channel, pre- phyrins and fluorescent porphyrins with potassium channel in a manner venting itfromcarrying out its normal cell- larger substituents. According to Maria L. similar to that seen in cytochrome c' Garcia, a distinguished senior investigator protective duties, Hoshi suggests. (shown). The iron (red ball) of heme Nobody expected that free heme might inMerck Research Laboratory's department (green = carbon, blue = nitrogen, red = play such a role, Hoshi says. But "now that of ion channels and a coauthor on both paoxygen) is coordinated by a histidine we have provided the first example of a pers, these ligands could be used to "dial in" side chain (yellow). Cysteine side fast heme-signaling system, other exam- channel specificity to selectively modulate chains are shown in white. ples are likely to follow," he tells C&EN. the action of specific channels in vivo. •
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