Redox reactions play important roles in almost all biological processes, including photosynthesis and respiration, which are two essential energy processes that sustain all life on earth. It is thus not surprising that biology employs redox-active metal ions in these processes. It is largely the redox activity that makes metal ions uniquely qualified as biological cofactors and makes bioinorganic enzymology both fun to explore and challenging to study.

Even though most metal ions are redox active, biology employs a surprisingly limited number of them for electron transfer (ET) processes. Prominent members of redox centers involved in ET processes include cytochromes, iron–sulfur clusters, and cupredoxins. Together these centers cover the whole range of reduction potentials in biology (Figure ​(Figure1).1). Because of their importance, general reviews about redox centers1−77 and specific reviews about cytochromes,8,24,78−90 iron–sulfur proteins,91−93 and cupredoxins94−104 have appeared in the literature. In this review, we provide both classification and description of each member of the above redox centers, including both native and designed proteins, as well as those proteins that contain a combination of these redox centers. Through this review, we examine structural features responsible for their redox properties, including knowledge gained from recent progress in fine-tuning the redox centers. Computational studies such as DFT calculations become more and more important in understanding the structure–function relationship and facilitating the fine-tuning of the ET properties and reduction potentials of metallocofactors in proteins. Since this aspect has been reviewed extensively before,105−110 and by other reviews in this thematic issue,2000,2001,2002 it will not be covered here.






Open in a separate window


Figure 1


Reduction potential range of redox centers in electron transfer processes.

Metalloproteins containing cytochrome, iron-sulfur, or copper redox centers.

The mitochondrial oxidative phosphorylation system is central to cellular metabolism. It comprises five enzymatic complexes and two mobile electron carriers that work in a mitochondrial respiratory chain. By coupling the oxidation of reducing equivalents coming into mitochondria to the generation and subsequent dissipation of a proton gradient across the inner mitochondrial membrane, this electron transport chain drives the production of ATP, which is then used as a primary energy carrier in virtually all cellular processes. Minimal perturbations of the respiratory chain activity are linked to diseases; therefore, it is necessary to understand how these complexes are assembled and regulated and how they function. In this Review, we outline the latest assembly models for each individual complex, and we also highlight the recent discoveries indicating that the formation of larger assemblies, known as respiratory supercomplexes, originates from the association of the intermediates of individual complexes. We then discuss how recent cryo-electron microscopy structures have been key to answering open questions on the function of the electron transport chain in mitochondrial respiration and how supercomplexes and other factors, including metabolites, can regulate the activity of the single complexes. When relevant, we discuss how these mechanisms contribute to physiology and outline their deregulation in human diseases. Mitochondrial respiration relies on five enzymatic complexes that couple electron transport with proton pumping, leading to ATP synthesis. Recent studies have shed new light on the organization, assembly and mechanisms of the respiratory complexes, including the formation of their larger assemblies — respiratory supercomplexes — and their roles in physiology.

The assembly, regulation and function of the mitochondrial respiratory chain.

The new broad-spectrum fungicides from the succinate dehydrogenase inhibitor (SDHI) class have been quickly adopted by the market, which may lead to a high selection pressure on various pathogens. Cases of resistance have been observed in 14 fungal pathogens to date and are caused by different mutations in genes encoding the molecular target of SDHIs, which is the mitochondrial succinate dehydrogenase (SDH) enzyme. All of the 17 marketed SDHI fungicides bind to the same ubiquinone binding site of the SDH enzyme. Their primary biochemical mode of action is the blockage of the TCA cycle at the level of succinate to fumarate oxidation, leading to an inhibition of respiration. Homology models and docking simulations explain binding behaviors and some peculiarities of the cross-resistance profiles displayed by different members of this class of fungicides. Furthermore, cross-resistance patterns among SDHIs is complex because many mutations confer full cross resistance while others do not. The nature of the mutations found in pathogen populations varies with species and the selection compound used but cross resistance between all SDHIs has to be assumed at the population level. In most of the cases where resistance has been reported, the frequency is still too low to impact field performance. However, the Fungicide Resistance Action Committee has developed resistance management recommendations for pathogens of different crops in order to reduce the risk for resistance development to this class of fungicides. These recommendations include preventative usage, mixture with partner fungicides active against the current pathogen population, alternation in the mode of action of products used in a spray program, and limitations in the total number of applications per season or per crop.

https://apsjournals.apsnet.org/doi/pdfplus/10.1094/PHYTO-01-13-0009-RVW

A review of current knowledge of resistance aspects for the next-generation succinate dehydrogenase inhibitor fungicides.

The pathogenesis of Alzheimer's disease is highly complex. While several pathologies characterize this disease, amyloid plaques, composed of the β-amyloid peptide are hallmark neuropathological lesions in Alzheimer's disease brain. Indeed, a wealth of evidence suggests that β-amyloid is central to the pathophysiology of AD and is likely to play an early role in this intractable neurodegenerative disorder. The BACE1 enzyme is essential for the generation of β-amyloid. BACE1 knockout mice do not produce β-amyloid and are free from Alzheimer's associated pathologies including neuronal loss and certain memory deficits. The fact that BACE1 initiates the formation of β-amyloid, and the observation that BACE1 levels are elevated in this disease provide direct and compelling reasons to develop therapies directed at BACE1 inhibition thus reducing β-amyloid and its associated toxicities. However, new data indicates that complete abolishment of BACE1 may be associated with specific behavioral and physiological alterations. Recently a number of non-APP BACE1 substrates have been identified. It is plausible that failure to process certain BACE1 substrates may underlie some of the reported abnormalities in the BACE1-deficient mice. Here we review BACE1 biology, covering aspects ranging from the initial identification and characterization of this enzyme to recent data detailing the apparent dysregulation of BACE1 in Alzheimer's disease. We pay special attention to the putative function of BACE1 during healthy conditions and discuss in detail the relationship that exists between key risk factors for AD, such as vascular disease (and downstream cellular consequences), and the pathogenic alterations in BACE1 that are observed in the diseased state.

/pdf/the-alzheimer-s-disease-b-secretase-enzyme-bace1-2xtxoz4s2v.pdf

The Alzheimer's disease β-secretase enzyme, BACE1

https://www.ndsu.edu/fileadmin/potatopathology/Alternia_SHHI_fungicides.pdf

Progress in understanding molecular mechanisms and evolution of resistance to succinate dehydrogenase inhibiting (SDHI) fungicides in phytopathogenic fungi

https://escholarship.org/content/qt49p301zw/qt49p301zw.pdf?t=lnqzc4

3-Nitropropionic Acid Is a Suicide Inhibitor of Mitochondrial Respiration That, upon Oxidation by Complex II, Forms a Covalent Adduct with a Catalytic Base Arginine in the Active Site of the Enzyme

3-NITROPROPIONIC ACID IS A SUICIDE INHIBITOR OF MITOCHONDRIAL RESPIRATION THAT, UPON OXIDATION BY COMPLEX II, FORMS A COVALENT ADDUCT WITH A CATALYTIC-BASE ARGININE IN THE ACTIVE SITE OF THE ENZYME*. Li-shar Huang 1 , Gang Sun 2± , David Cobessi 1§ , Andy Wang 1 , John T. Shen 1 , Eric Y. Tung 1 , Vernon E. Anderson 2 , and Edward A. Berry 1 From Lawrence Berkeley National Laboratory, Berkeley, CA; and , 2 Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH Running title: Structure of 3-nitropropionate - inactivated Complex II Address correspondence regarding the crystallographic work to EAB (EABerry@LBL.gov; telephone 1-510-486-4335), and correspondence regarding characterization of the tryptic fragments and 3-NP adduct to VEA (vea@cwru.edu). Current address: Div. of Bioorganic Chemistry and Mol. Pharm., Dept. of Int. Medicine, Wash. Univ. School of Medicine, Campus Box 8020, 660 South Euclid Avenue, St. Louis, MO 63110 Current address: Ecole Superieure de Biotechnologie de Strasbourg, UMR7100 CNRS, Boulevard Sebastien Brant, BP 10413, 67412 Illkirch, France We report three new structures of mitochondrial respiratory Complex II (succinate ubiquinone oxidoreductase, E.C. 1.3.5.1) at up to 2.1 A resolution, with various inhibitors. The structures define the conformation of the bound inhibitors and suggest the residues involved in substrate binding and catalysis at the dicarboxylate site. In particular they support the role of Arg297 as a general base catalyst accepting a proton in the dehydrogenation of succinate. The dicarboxylate ligand in oxaloacetate-containing crystals appears to be the same as that reported for Shewanella flavocytochrome c treated with fumarate. The plant and fungal toxin 3-nitropropionic acid, an irreversible inactivator of succinate dehydrogenase, forms a covalent adduct with the side chain of Arg297. The modification eliminates a trypsin cleavage site in the flavoprotein, and tandem mass spectroscopic analysis of the new fragment shows the mass of Arg 297 to be increased by 83 Da and to have potential of losing 44 Da, consistent with decarboxylation, during fragmentation. The toxin 3-nitropropionic acid (3-NP 1 ) is produced by certain plants and fungi. It is a specific inhibitor of mitochondrial respiratory complex II. Fatalities after eating moldy sugarcane have been linked to 3-NP toxicity(1,2). Ruminants grazing in regions with 3-NP-producing plants acquire resistance due to reduction of the nitro group to an amine by ruminal bacteria(3). The effectiveness of 3-NP in vivo after injection or oral administration has made it useful in studies involving tissues or whole animals. Ingestion of 3-NP results in neurodegeneration with symptoms resembling those of Huntington's disease(4), and conversely Huntington's disease results in loss of complex II activity(5), thus 3-NP has been used to produce an animal model for study of Huntington's(6,7). Symptoms also include convulsions, and 3-NP is being looked at for inducing a model of epilepsy(8). Prior sub- acute 3-NP poisoning seems to provide resistance to ischemic damage to nervous tissue by a preconditioning effect(9) similar to that resulting from mild ischemia. The target of 3-NP is Complex II, which is both a member of the Krebs tricarboxylic acid cycle (oxidizing succinate to fumarate) and an entry-point for electrons into the respiratory chain at the level of ubiquinol. It consists of a large flavoprotein subunit (FP) containing covalently bound FAD, an iron-sulfur protein (IP) with three different iron-sulfur clusters, and two small membrane anchor subunits (chains C and D) ligating a single low-spin heme of type B. Human genetic defects in the IP subunits or chains C or D lead to

3-Nitropropionic Acid is a Suicide Inhibitor of Mitochondrial Respiration that, Upon Oxidation by Complex II, Forms a Covalent Adduct With a Catalytic Base Arginine in the Active Site of the Enzyme

Crystallographic studies of the binding of ligands to the dicarboxylate site of Complex II, and the identity of the ligand in the “oxaloacetate-inhibited” state

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

Andy C. Wang

Author Tools

Chat about Author

Papers

3-Nitropropionic Acid Is a Suicide Inhibitor of Mitochondrial Respiration That, upon Oxidation by Complex II, Forms a Covalent Adduct with a Catalytic Base Arginine in the Active Site of the Enzyme

3-Nitropropionic Acid is a Suicide Inhibitor of Mitochondrial Respiration that, Upon Oxidation by Complex II, Forms a Covalent Adduct With a Catalytic Base Arginine in the Active Site of the Enzyme

Crystallographic studies of the binding of ligands to the dicarboxylate site of Complex II, and the identity of the ligand in the “oxaloacetate-inhibited” state