A computational approach for mapping heme biology in the context of hemolytic disorders

Abstract

Heme is an iron ion-containing molecule found within hemoproteins such as hemoglobin and cytochromes that participates in diverse biological processes. While its unlimited supply has been implicated in deleterious processes in several diseases including malaria, sepsis, ischemia-reperfusion, and disseminated intravascular coagulation, little is known about its regulatory and signaling functions. A majority of the computational research to elucidate these functions has been purely data-driven due to the absence of curated pathway resources, which have proven useful in the computational study in other indications. Here, we present two resources aimed to exploit this unexplored information to model heme biology. The first resource is an ontology covering heme-specific terms not yet included in standard controlled vocabularies. Using this ontology, we curated and modeled a corpus of 46 scientific articles to generate a mechanistic knowledge graph representing the hemes interactome for that particular literature. Finally, we demonstrated the utility of these resources by investigating the role of heme in the Toll-like receptor signaling pathway. Our analysis proposed a series of crosstalk events that could explain the role of heme in activating the TLR4 signaling pathway. In summary, the presented work opens the door for the scientific community to explore in more detail the published knowledge on heme biology.