Heme: emergent roles of heme in signal transduction, functional regulation and as catalytic centres

Shimizu, Tôru; Lengalova, Alzbeta; Martínek, Václav; Martínková, Markéta

doi:10.1039/c9cs00268e

Cited by 168 publications

(137 citation statements)

References 225 publications

Supporting

Mentioning

120

Contrasting

Unclassified

Order By: Relevance

“…Protoporphyrin IX is the final intermediate in the protoporphyrin IX iron complex (heme) biosynthetic pathway 17 . Heme is an important cofactor for oxygen transfer and oxygen storage 18 and is a constituent of hemoproteins which play a variety of roles in cellular metabolism . The light-activable photodynamic effect of protoporphyrin IX was used for cancer diagnosis 20 and approved by FDA for treatment of bronchial and esophageal cancers and early malignant lesions of the skin, bladder, breast, stomach, and oral cavity 21,22 .…”

Section: Discussionmentioning

confidence: 99%

Protoporphyrin IX and verteporfin prevent SARS-CoV-2 infectionin vitroand in a mouse model expressing human ACE2

Guo

et al. 2020

Preprint

View full text Add to dashboard Cite

The infection of SARS-CoV-2 has spread to more than 200 countries and regions and the numbers of infected people and deaths worldwide are expected to continue to rise.Current treatment of COVID-19 is limited and mostly supportive. At present, there is no specific therapeutics against SARS-CoV-2. In this study, we discovered that protoporphyrin IX and verteporfin, two FDA-approved drugs for treatment of human diseases, had significant antiviral effect against SARS-CoV-2, with EC50 values for the reduction of viral RNA at nanomolar concentrations. Both drugs completely inhibited the cytopathic effect (CPE) produced by SARS-CoV-2 infection at lower drug concentrations than that of remdesivir. The selection indices of protoporphyrin IX and verteporfin are 952.74 and 368.93, respectively, suggesting wide safety margins. Both drugs were able to prevent SARS-CoV-2 infection as well as suppress established SARS-CoV-2 infection. The compounds share a porphyrin ring structure. Molecular docking indicates that the compounds may interact with viral receptor ACE2 and could block the cell-cell fusion mediated by ACE2 and viral S protein. Our finding suggests that protoporphyrin IX and verteporfin might be potential antivirals against SARS-CoV-2 infection and also sheds new light on the development of a novel class of small compounds against SARS-CoV-2.

show abstract

Section: Discussionmentioning

confidence: 99%

Protoporphyrin IX and verteporfin prevent SARS-CoV-2 infectionin vitroand in a mouse model expressing human ACE2

Guo

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…In a synapse, the changes in action potential duration may influence Ca 2+ -dependent neurotransmission. For example, in dorsal root ganglia (DRG) cells containing Kv1.4 and Kv3.4 channels, a physiological consequence would be an attenuation of pain signaling [8,36].…”

Section: Discussionmentioning

confidence: 99%

Impact of intracellular hemin on N-type inactivation of voltage-gated K+ channels

Coburger

Yang

Bernert

et al. 2020

Pflugers Arch - Eur J Physiol

View full text Add to dashboard Cite

N-type inactivation of voltage-gated K + channels is conferred by the N-terminal "ball" domains of select pore-forming α subunits or of auxiliary β subunits, and influences electrical cellular excitability. Here, we show that hemin impairs inactivation of K + channels formed by Kv3.4 α subunits as well as that induced by the subunits Kvβ1.1, Kvβ1.2, and Kvβ3.1 when coexpressed with α subunits of the Kv1 subfamily. In Kvβ1.1, hemin interacts with cysteine and histidine residues in the N terminus (C7 and H10) with high affinity (EC 50 100 nM). Similarly, rapid inactivation of Kv4.2 channels induced by the dipeptidyl peptidase-like protein DPP6a is also sensitive to hemin, and the DPP6a mutation C13S eliminates this dependence. The results suggest a common mechanism for a dynamic regulation of Kv channel inactivation by heme/hemin in N-terminal ball domains of Kv α and auxiliary β subunits. Free intracellular heme therefore has the potential to regulate cellular excitability via modulation of Kv channel inactivation.

show abstract

“…Exploring the mechanistic basis of verteporfin. Because VER is a tetradentate chelating porphyrin 23 that might be involved in redox sensing, just like heme complex, and such molecules are normally sensed through thiol-based switches, we also analyzed the contribution of the single redox-active cysteine present in GraS, C227, to VER effect 24 . To do so, C227 was mutated to S or A in ∆XV Gra-RES background and transcriptional activity of dltXP in the resulting ∆XV Gra-RES S(C227-S) and ∆XV Gra-RES S(C227-A) strains was measured.…”

Section: Effect Of Verteporfin In a Murine Model Of Wound Infection mentioning

confidence: 99%

Inhibiting the two-component system GraXRS with verteporfin to combat Staphylococcus aureus infections

Prieto¹,

Rapún-Araiz

Gil

et al. 2020

Sci Rep

View full text Add to dashboard Cite

Infections caused by Staphylococcus aureus pose a serious and sometimes fatal health issue. With the aim of exploring a novel therapeutic approach, we chose GraXRS, a Two-Component System (TCS) that determines bacterial resilience against host innate immune barriers, as an alternative target to disarm S. aureus. Following a drug repurposing methodology, and taking advantage of a singular staphylococcal strain that lacks the whole TCS machinery but the target one, we screened 1.280 off-patent FDA-approved drug for GraXRS inhibition. Reinforcing the connection between this signaling pathway and redox sensing, we found that antioxidant and redox-active molecules were capable of reducing the expression of the GraXRS regulon. Among all the compounds, verteporfin (VER) was really efficient in enhancing PMN-mediated bacterial killing, while topical administration of such drug in a murine model of surgical wound infection significantly reduced the bacterial load. Experiments relying on the chemical mimicry existing between VER and heme group suggest that redox active residue C227 of GraS participates in the inhibition exerted by this FDA-approved drug. Based on these results, we propose VER as a promising candidate for sensitizing S. aureus that could be helpful to combat persistent or antibiotic-resistant infections.

show abstract

Heme: emergent roles of heme in signal transduction, functional regulation and as catalytic centres

Abstract: Molecular mechanisms of unprecedented functions of exchangeable/labile heme and heme proteins including transcription, DNA binding, protein kinase activity, K+ channel functions, cis–trans isomerization, N–N bond formation, and other functions are described.

Cited by 168 publications

References 225 publications

Protoporphyrin IX and verteporfin prevent SARS-CoV-2 infectionin vitroand in a mouse model expressing human ACE2

Protoporphyrin IX and verteporfin prevent SARS-CoV-2 infectionin vitroand in a mouse model expressing human ACE2

Impact of intracellular hemin on N-type inactivation of voltage-gated K+ channels

Inhibiting the two-component system GraXRS with verteporfin to combat Staphylococcus aureus infections

Contact Info

Product

Resources

About