Interaction of Carbon Monoxide with Transition Metals: Evolutionary Insights into Drug Target Discovery

Roberta      Foresti; Roberto      Motterlini

Abstract

The perception that carbon monoxide (CO) is poisonous and life-threatening for mammalian organisms stems from its intrinsic propensity to bind iron in hemoglobin, a reaction that ultimately leads to impaired oxygen delivery to tissues. From evolutionary and chemical perspectives, however, CO is one of the most essential molecules in the formation of biological components and its interaction with transition metals is at the origin of primordial cell signaling. Not surprisingly, mammals have gradually evolved systems to finely control the synthesis and the sensing of this gaseous molecule. Cells are indeed continuously exposed to small quantities of CO produced endogenously during the degradation of heme by constitutive and inducible heme oxygenase enzymes. We have gradually learnt that heme oxygenase-derived carbon monoxide (CO) serves as a ubiquitous signaling mediator which could be exploited for therapeutic purposes. The development of transition metal carbonyls as prototypic carbon monoxide-releasing molecules (CO-RMs) represents a novel stratagem for a safer delivery of CO-based pharmaceuticals in the treatment of various pathological disorders. This review looks back at evolution to analyze and argue that a dynamic interaction of CO with specific intracellular metal centers is the common denominator for the diversified beneficial effects mediated by this gaseous molecule.

Keywords: Carbon monoxide, transition metals, carbon monoxide-releasing molecules, hemoglobin, mitochondria, ubiquitous signaling mediator, carbon monoxide-releasing molecules (CO-RMs), protoporphyrins, methane (CH4), ammonia (NH4), hydrothermal vents, cluster of iron (FeS), nickel sulfide (NiS), molecular oxygen (O2), cyanobacteria, phototropic bacterium, CO-dehydrogenase (CODH), Rhodospirillum rubrum, acetyl coenzyme A synthase (ACS), carbon monoxy hemoglobin (HbCO), pulmonary disease, red blood cells (RBCs), hemorrhagic shock, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, adenosine triphosphate (ATP), cellular respiration, nicotinamide adenine dinucleotide (NADH), myoglobin, hemoproteins, apoptotic stimulus, cytochrome, cardiolipin, reactive oxygen species (ROS), neurodegenerative diseases, mitochondrial biogenesis, transition metal carbonyl, CO-releasing molecules” (CO-RMs), boranocarbonate (CORM-A1), carbon monoxy myoglobin (MbCO), cardiomyopathy, nephrotoxicity, bacteriostatic effect, molybdenum (Mo), Guanylate cyclase, xanthine oxidase, molybdenum, superoxide dismutases, alcohol dehydrogenase, Desulfovibrio vulgaris