Inhibition of the carnitine acylcarnitine carrier by carbon monoxide reveals a novel mechanism of action with non-metal-containing proteins

Free Radic Biol Med. 2022 Jul 2:S0891-5849(22)00471-3. doi: 10.1016/j.freeradbiomed.2022.06.244. Online ahead of print.ABSTRACTBoth toxic and physiological effects of CO are mostly caused by well described interactions with heme-groups of proteins. Interactions of CO with non-heme proteins have also been unveiled. Besides interaction of CO with mitochondrial heme containing respiratory complexes, a BK channel and the phosphate carrier which do not contain metal cofactors, have been identified as CO targets. However, the molecular mechanisms of interaction with non-metal-containing proteins are not understood. We show in this work the effect of CO on the mitochondrial carnitine carrier (SLC25A20) using CORM-3, a widely recognized CO releasing compound. CO exerts an inhibitory effect at the micromolar concentration on the transport function of the transporter extracted from treated mitochondria. The effect is due to a single Cys residue, C136 as revealed by mass spectrometry analysis. A computational approach predicted the need for vicinal Asp and Lys residues for the C136 carbonylation to occur. These data demonstrate a novel mechanism of interaction of CO with a protein not containing metal atoms and will enable the prediction of CO targets.PMID:35792242 | DOI:10.1016/j.freeradbiomed.2022.06.244

Source: Free Radical Biology and Medicine - July 6, 2022 Category: Biology Authors: Annamaria Tonazzi Nicola Giangregorio Lara Console Cosima Damiana Calvano Mario Prejan ò Mariafrancesca Scalise Giovanna Incampo Tiziana Marino Nino Russo Tommaso R I Cataldi Cesare Indiveri Source Type: research