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Abstract
Heme is not only a prosthetic group of hemoproteins, but also a potent effector molecule. This regulatory heme can bind to short nonapeptide sequences, i.e. heme-regulatory motifs (HRMs), on the protein surface. We studied >300 HRMs in detail employing peptides and proteins as well as a plethora of spectroscopic and bioinformatics methods. Apart from knowledge acquired for the physiological role of transient heme binding to proteins, its pathophysiological impact is still not completely understood. However, a considerable amount of heme is released under hemolytic conditions and causes pathological states such as thrombosis. On the other hand, the SARS-CoV2-triggered respiratory tract disease COVID-19 has been shown to lead to serious changes in clinical biomarkers like hemoglobin and interleukins, parameters, which are also altered during hemolysis. With various computational-experimental basic and advanced studies, we aimed at analyzing a potential link between heme-related and COVID-19 pathophysiologies. We performed a detailed analysis of the common pathways induced by heme and SARS-CoV-2 by superimposition of knowledge graphs covering heme biology (Heme-KG) and COVID-19 pathophysiology. Thereby, focus was laid on inflammatory pathways and distinct biomarkers as the linking elements. In a subsequent approach, four COVID-19-related proteins, the host cell proteins ACE2 and TMPRSS2 as well as the viral protein 7a and protein S as well as HRM-peptides derived thereof, were experimentally and computationally analyzed as potential heme-binding proteins. The results contribute to our understanding of the progression heme-related diseases in the context of infections in patients with different clinical backgrounds and may allow for a more individual diagnosis and therapy in the future.
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