| Abstract
| - We have designed, synthesized, and characterized a metal chelating compound based on the structure of cholesterol that contains the high affinity metal chelating group, lysine nitrilotriacetic acid (Lys-NTA). Using the enzyme isoprenylcysteine carboxyl methyltransferase (Icmt) as a model integral membrane metalloenzyme, this agent potently inhibits Icmt activity. We propose that the rigid hydrophobic cholesterol moiety promotes partitioning into the membrane, enabling the NTA groups to inactivate the enzyme by metal chelation.
- We have designed, synthesized, and characterized a metal chelating compound that is based on thestructure of cholesterol and contains the high affinity metal chelating group, lysine nitrilotriaceticacid (Lys-NTA). Using the enzyme isoprenylcysteine carboxylmethyltransferase (Icmt) from yeast asa model integral membrane metalloenzyme, we find that this agent potently inhibits Icmt activitywith an IC50 value between 35 and 75 μM, which is at least 40 times more potent than the best knownIcmt metal chelating inhibitor, Zincon. We propose that the rigid hydrophobic cholesterol moietypromotes partitioning into the membrane, enabling the metal-binding NTA group(s) to inactivate theenzyme by metal chelation. Because this compound is based on a naturally occurring membrane lipidand appears to chelate metals buried deeply within water insoluble environments, this agent mayalso be useful as a general tool for identifying previously unappreciated metal dependencies of otherclasses of membrane proteins.
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