The expanding utility of iron-sulfur clusters: Their functional roles in biology, synthetic small molecules, maquettes and artificial proteins, biomimetic materials, and therapeutic strategies

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal agent of coronavirus disease 2019 (COVID-19), uses an RNA-dependent RNA polymerase (RdRp) for the replication of its genome and the transcription of its genes. We found that the catalytic subunit of the RdRp, nsp12, ligates two iron-sulfur metal cofactors in sites that were modeled as zinc centers in the available cryo-electron microscopy structures of the RdRp complex. These metal binding sites are essential for replication and for interaction with the viral helicase. Oxidation of the clusters by the stable nitroxide TEMPOL caused their disassembly, potently inhibited the RdRp, and blocked SARS-CoV-2 replication in cell culture. These iron-sulfur clusters thus serve as cofactors for the SARS-CoV-2 RdRp and are targets for therapy of COVID-19.

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COVID-19: Unmasking Emerging SARS-CoV-2 Variants, Vaccines and Therapeutic Strategies

Biomolecules ◽

10.3390/biom11070993 ◽

2021 ◽

Vol 11 (7) ◽

pp. 993

Author(s):

Renuka Raman ◽

Krishna J. Patel ◽

Kishu Ranjan

Keyword(s):

Immune Response ◽

Monoclonal Antibodies ◽

Severe Acute Respiratory Syndrome ◽

Small Molecules ◽

Viral Vector ◽

Therapeutic Strategies ◽

Convincing Evidence ◽

Plasma Therapy ◽

Therapeutic Monoclonal Antibodies ◽

Increased Susceptibility

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of the coronavirus disease 2019 (COVID-19) pandemic, which has been a topic of major concern for global human health. The challenge to restrain the COVID-19 pandemic is further compounded by the emergence of several SARS-CoV-2 variants viz. B.1.1.7 (Alpha), B.1.351 (Beta), P1 (Gamma) and B.1.617.2 (Delta), which show increased transmissibility and resistance towards vaccines and therapies. Importantly, there is convincing evidence of increased susceptibility to SARS-CoV-2 infection among individuals with dysregulated immune response and comorbidities. Herein, we provide a comprehensive perspective regarding vulnerability of SARS-CoV-2 infection in patients with underlying medical comorbidities. We discuss ongoing vaccine (mRNA, protein-based, viral vector-based, etc.) and therapeutic (monoclonal antibodies, small molecules, plasma therapy, etc.) modalities designed to curb the COVID-19 pandemic. We also discuss in detail, the challenges posed by different SARS-CoV-2 variants of concern (VOC) identified across the globe and their effects on therapeutic and prophylactic interventions.

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EPR-derived structures of flavin radical and iron-sulfur clusters from Methylosinus sporium 5 reductase

Inorganic Chemistry Frontiers ◽

10.1039/d0qi01334j ◽

2021 ◽

Author(s):

Han Sol Jeong ◽

Sugyeong Hong ◽

Hee Seon Yoo ◽

Jin Kim ◽

Yujeong Kim ◽

...

Keyword(s):

Carbon Cycle ◽

Crucial Role ◽

Methane Monooxygenase ◽

Global Carbon Cycle ◽

Ambient Conditions ◽

Iron Sulfur Clusters ◽

Iron Sulfur ◽

Greenhouse Effects ◽

Global Carbon ◽

Significant Attention

Methane monooxygenase (MMO) has attracted significant attention owing to its crucial role in the global carbon cycle; it impedes greenhouse effects by converting methane to methanol under ambient conditions. The...

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EPR studies of iron-sulfur clusters in isolated subunits and subfractions of NADH-ubiquinone oxidoreductase.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)89430-3 ◽

1985 ◽

Vol 260 (5) ◽

pp. 2782-2788 ◽

Cited By ~ 1

Author(s):

T Ohnishi ◽

C I Ragan ◽

Y Hatefi

Keyword(s):

Iron Sulfur Clusters ◽

Ubiquinone Oxidoreductase ◽

Iron Sulfur ◽

Nadh Ubiquinone Oxidoreductase

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Conserved residue PsaB-Trp673 is essential for high-efficiency electron transfer between the phylloquinones and the iron-sulfur clusters in Photosystem I

Photosynthesis Research ◽

10.1007/s11120-021-00839-x ◽

2021 ◽

Author(s):

Vasily Kurashov ◽

George Milanovsky ◽

Lujun Luo ◽

Antoine Martin ◽

Alexey Yu. Semenov ◽

...

Keyword(s):

Electron Transfer ◽

Photosystem I ◽

High Efficiency ◽

Iron Sulfur Clusters ◽

Iron Sulfur ◽

Conserved Residue

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Multiple Sense and Antisense Promoters Contribute to the Regulated Expression of the isc-suf Operon for Iron-Sulfur Cluster Assembly in Rhodobacter

Microorganisms ◽

10.3390/microorganisms7120671 ◽

2019 ◽

Vol 7 (12) ◽

pp. 671 ◽

Cited By ~ 1

Author(s):

Xin Nie ◽

Bernhard Remes ◽

Gabriele Klug

Keyword(s):

Rhodobacter Sphaeroides ◽

Photosynthetic Electron Transport ◽

Regulatory Proteins ◽

Cluster Assembly ◽

Iron Sulfur Cluster ◽

Iron Sulfur Clusters ◽

Sulfur Cluster ◽

Iron Sulfur ◽

Photosynthetic Complexes ◽

The One

A multitude of biological functions relies on iron-sulfur clusters. The formation of photosynthetic complexes goes along with an additional demand for iron-sulfur clusters for bacteriochlorophyll synthesis and photosynthetic electron transport. However, photooxidative stress leads to the destruction of iron-sulfur clusters, and the released iron promotes the formation of further reactive oxygen species. A balanced regulation of iron-sulfur cluster synthesis is required to guarantee the supply of this cofactor, on the one hand, but also to limit stress, on the other hand. The phototrophic alpha-proteobacterium Rhodobacter sphaeroides harbors a large operon for iron-sulfur cluster assembly comprising the iscRS and suf genes. IscR (iron-sulfur cluster regulator) is an iron-dependent regulator of isc-suf genes and other genes with a role in iron metabolism. We applied reporter gene fusions to identify promoters of the isc-suf operon and studied their activity alone or in combination under different conditions. Gel-retardation assays showed the binding of regulatory proteins to individual promoters. Our results demonstrated that several promoters in a sense and antisense direction influenced isc-suf expression and the binding of the IscR, Irr, and OxyR regulatory proteins to individual promoters. These findings demonstrated a complex regulatory network of several promoters and regulatory proteins that helped to adjust iron-sulfur cluster assembly to changing conditions in Rhodobacter sphaeroides.

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