SARS-CoV-2 Proteins Bind to Hemoglobin and Its Metabolites

Lechuga, Guilherme Curty; Souza-Silva, Franklin; Sacramento, Carolina Q; Trugilho, Monique Ramos de Oliveira; Valente, Richard H.; Napoleão-Pêgo, Paloma; Dias, Suelen da Silva Gomes; Fintelman-Rodrigues, Natália; Temerozo, Jairo R.; Carels, Nicolas; Alves, Carlos Roberto; Pereira, Mirian Cláudia de Souza; Provance, David William; Souza, Thiago Moreno L.; De-Simone, Salvatore Giovanni

doi:10.3390/ijms22169035

Cited by 53 publications

(60 citation statements)

References 71 publications

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“…In consistent with our analysis, a recent interatomics study shows that SARS-CoV-2 proteins interacts with ubiquitin ligases, kinases, lipid modifications, as well as proteins contain zinc finger, SH2, SH3, and PDZ domains [28], Supplementary Table S10. Additionally, PDZ-binding motifs (PBM) is crucial during SARS-CoV infection.…”

Section: Discussionsupporting

confidence: 91%

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The Potential Functions of Protein Domains during COVID Infection: An Analysis and a Review

Sobhy

2021

COVID

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Coronaviruses (CoVs) are a large viral family that can evolve rapidly emerging new strains that cause outbreaks and life-loss, including SARS-CoV, MERS-CoV, and SARS-CoV-2 (COVID-19). CoVs encode a diverse number of proteins, ranging from 5 proteins in bat CoV, to 14 in SARS CoV, which could have implication on viral tropism and pathogenicity. Here, we highlight the functional protein motifs (domains) that could contribute in the coronavirus infection and severity, including SARS-CoV-2. For this role, we used the experimentally validated domain (motif) datasets that are known to be crucial for viral infection. Then, we highlight the potential molecular pathways and interactions of SARS-CoV-2 proteins within human cells. Interestingly, the C-terminal of SARS-COV-2 nsp1 protein encodes MREL motif, which a signature motif of the tubulin superfamily, and regulate tubulin expression. The C-terminal region of nsp1 protein can bind to ribosome and regulation viral RNA translation.

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Section: Discussionsupporting

confidence: 91%

“…(E) The sequence logo and consensus sequences of nsp1 C-terminus of coronaviruses. The figures(A-C) adopted from[28][29][30][31][32]; (D-E) from EBI portal (https://www.ebi.ac.uk/thornton-srv/ databases/cgi-bin/VarSite/GetPage.pl?home=TRUE, last accessed on 30 August 2021, UniProt ID: P0DTD1_1).…”

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confidence: 99%

The Potential Functions of Protein Domains during COVID Infection: An Analysis and a Review

Sobhy

2021

COVID

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“…SARS-CoV-2, is the novel beta coronavirus of the Coronaviridae family whose genome is composed of a single stranded RNA molecule [ 173 ]. It has been shown that hemin, hemoglobin and protoporphyrin IX bind to SARS-CoV-2 proteins, blocking its adsorption and replication independently from HO-1 induction [ 174 ]. However, the current literature regarding HO-1′s antiviral effect against SARS-CoV-2 remains unclear.…”

Section: Unveiling How Ho-1 Promotes Viral Clearancementioning

confidence: 99%

A Journey into the Clinical Relevance of Heme Oxygenase 1 for Human Inflammatory Disease and Viral Clearance: Why Does It Matter on the COVID-19 Scene?

et al. 2022

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Heme oxygenase 1 (HO-1), the rate-limiting enzyme in heme degradation, is involved in the maintenance of cellular homeostasis, exerting a cytoprotective role by its antioxidative and anti-inflammatory functions. HO-1 and its end products, biliverdin, carbon monoxide and free iron (Fe2+), confer cytoprotection against inflammatory and oxidative injury. Additionally, HO-1 exerts antiviral properties against a diverse range of viral infections by interfering with replication or activating the interferon (IFN) pathway. Severe cases of coronavirus disease 2019 (COVID-19), an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are characterized by systemic hyperinflammation, which, in some cases, leads to severe or fatal symptoms as a consequence of respiratory failure, lung and heart damage, kidney failure, and nervous system complications. This review summarizes the current research on the protective role of HO-1 in inflammatory diseases and against a wide range of viral infections, positioning HO-1 as an attractive target to ameliorate clinical manifestations during COVID-19.

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“…[235][236][237] A long series of publications have regarded the possible SARS-CoV-2 interaction with erythrocytes and the consequent hemoglobin dysfunction, with release of free circulating hemoglobin/heme. 21,22,126,130,238,239 More importantly, a few researchers highlighted clear erythrocyte membrane alterations in COVID-19 patients. 4 These and previous data seem to demonstrate furthermore the CD147/SA-based interaction of SARS-CoV-2 with RBC which, at least partially, explains the consequent hemoglobin/iron cycle alteration.…”

Section: A) Sialic Acidmentioning

confidence: 99%

“…Nearly 75% of human iron is contained in hemoglobin; in view of the iron deranged metabolism in COVID-19, a number of articles have investigated a possible hemoglobin denaturation in these patients 1,3,22,61,124,[126][127][128] Though no sound evidence of a direct hemoglobin viral attack has been documented so far, free circulating heme has been described in a few papers 130,238,239 ; moreover, some recruitment of hemoglobin and its metabolites (hemin and protoporphyrin IX) by a few SARS-CoV-2 proteins was documented in a computational biology study. 239 An analogue scientific debate is underway about the alteration of the dissociation curves of hemoglobin in these patients, regardless of whether hypoxia may not be regarded as solely generated by pneumolysis/lung disease. [143][144][145]305 h) Potential environmental, genetic and microbiome susceptibility factors Beside AB0 group and sickle cell conformation, several other factors may predispose to SARS-CoV-2 pathogenicity.…”

Section: G) Hemoglobin Hemementioning

confidence: 99%

COVID-19, Cation Dysmetabolism, Sialic Acid, CD147, ACE2, Viroporins, Hepcidin and Ferroptosis: A Possible Unifying Hypothesis

et al. 2022

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Background: iron and calcium dysmetabolism, with hyperferritinemia, hypoferremia, hypocalcemia and anemia have been documented in the majority of COVID-19 patients at later/worse stages. Furthermore, complementary to ACE2, both sialic acid (SA) molecules and CD147 proved relevant host receptors for SARS-CoV-2 entry, which explains the viral attack to multiple types of cells, including erythrocytes, endothelium and neural tissue. Several authors advocated that cell ferroptosis may be the core and final cell degenerative mechanism. Methods: a literature research was performed in several scientific search engines, such as PubMed Central, Cochrane Library, Chemical Abstract Service. More than 500 articles were retrieved until mid-December 2021, to highlight the available evidence about the investigated issues. Results: based on COVID-19 literature data, we have highlighted a few pathophysiological mechanisms, associated with virus-based cation dysmetabolism, multi-organ attack, mitochondria degeneration and ferroptosis. Our suggested elucidated pathological sequence is: a) spike protein subunit S1 docking with sialylated membrane glycoproteins/receptors (ACE2, CD147), and S2 subunit fusion with the lipid layer; b) cell membrane morpho-functional changes due to the consequent electro-chemical variations and viroporin action, which induce an altered ion channel function and intracellular cation accumulation; c) additional intracellular iron concentration due to a deregulated hepcidin-ferroportin axis, with higher hepcidin levels. Viral invasion may also affect erythrocytes/erythroid precursors, endothelial cells and macrophages, through SA and CD147 receptors, with relative hemoglobin and iron/calcium dysmetabolism. AB0 blood group, hemochromatosis, or environmental elements may represent possible factors which affect individual susceptibility to COVID-19. Conclusions: our literature analysis confirms the combined role of SA molecules, ACE2, CD147, viroporins and hepcidin in determining the cation dysmetabolism and final ferroptosis in the cells infected by SARS-CoV-2. The altered ion channels and electrochemical gradients of the cell membrane have a pivotal role in the virus entry and cell dysmetabolism, with subsequent multi-organ immune-inflammatory degeneration and erythrocyte/hemoglobin alterations.

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SARS-CoV-2 Proteins Bind to Hemoglobin and Its Metabolites

Cited by 53 publications

References 71 publications

The Potential Functions of Protein Domains during COVID Infection: An Analysis and a Review

The Potential Functions of Protein Domains during COVID Infection: An Analysis and a Review

A Journey into the Clinical Relevance of Heme Oxygenase 1 for Human Inflammatory Disease and Viral Clearance: Why Does It Matter on the COVID-19 Scene?

COVID-19, Cation Dysmetabolism, Sialic Acid, CD147, ACE2, Viroporins, Hepcidin and Ferroptosis: A Possible Unifying Hypothesis

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