Abstract
Cellular protective mechanisms exist to ensure survival of the cells and are a fundamental feature of all cells that is necessary for adapting to changes in the environment. Indeed, evolution has ensured that each cell is equipped with multiple overlapping families of genes that safeguard against pathogens, injury, stress, and dysfunctional metabolic processes. Two of the better-known enzymatic systems, conserved through all species, include the heme oxygenases (HO-1/HO-2), and the ectonucleotidases (CD39/73). Each of these systems generates critical bioactive products that regulate the cellular response to a stressor. Absence of these molecules results in the cell being extremely predisposed to collapse and, in most cases, results in the death of the cell. Recent reports have begun to link these two metabolic pathways, and what were once exclusively stand-alone are now being found to be intimately interrelated and do so through their innate ability to generate bioactive products including adenosine, carbon monoxide, and bilirubin. These simple small molecules elicit profound cellular physiologic responses that impact a number of innate immune responses, and participate in the regulation of inflammation and tissue repair. Collectively these enzymes are linked not only because of the mitochondria being the source of their substrates, but perhaps more importantly, because of the impact of their products on specific cellular responses. This review will provide a synopsis of the current state of the field regarding how these systems are linked and how they are now being leveraged as therapeutic modalities in the clinic.
Highlights
Metabolism requires complex relationships among substrates, the enzymes that catalyze their transformation and the products that are generated, to maintain cellular physiological functions
Fe2+, which is acquired from the diet or recycled from senescent erythrocytes that have been engulfed by macrophages, a process known as erythrophagocytosis, is inserted into protoporphyrin IX by the enzyme ferrochelatase forming the final heme tetrapyrol configuration (Figure 1) [3, 4]
Heme turnover is a key component of cell survival both as an active component of numerous proteins, and as it is metabolically deconstructed by heme oxygenases (HO)-1 into powerful products with effective signaling mechanisms that regulate important cellular functions
Summary
Metabolism requires complex relationships among substrates, the enzymes that catalyze their transformation and the products that are generated, to maintain cellular physiological functions. This is perhaps best illustrated by the intricacies of glycolysis and the Krebs cycle where glucose is converted to energy to fuel all cellular activities. Such pathways and cycles are intimately interrelated with others and in many instances cooperate to promote efficiency ensuring survival of the cell and organism. Exogenous supplementation of each product results in powerful protection of the cellular and tissue realm
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