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Future Med Chem 2021 Apr 13. Epub 2021 Apr 13.

Auckland Cancer Society Research Centre, School of Medical Sciences, Private Bag 92019, Auckland, 1142, New Zealand.

The spectacular success of the mycobacterial FF-ATP synthase inhibitor bedaquiline for the treatment of drug-resistant tuberculosis has generated wide interest in the development of other inhibitors of this enzyme. Work in this realm has included close analogues of bedaquiline with better safety profiles and 'bedaquiline-like' compounds, some of which show potent antibacterial activity although none have yet progressed to clinical trials. The search has lately extended to a range of new scaffolds as potential inhibitors, including squaramides, diaminoquinazolines, chloroquinolines, dihydropyrazolo[1,5-a]pyrazin-4-ones, thiazolidinediones, diaminopyrimidines and tetrahydroquinolines. Read More

Proteome Sci 2021 Jan 12;19(1). Epub 2021 Jan 12.

College of Food Science and Technology, Yunnan Agricultural University, Kunming, 650201, Yunnan, China.

Background: Protein lysine malonylation, a novel post-translational modification (PTM), has been recently linked with energy metabolism in bacteria. Staphylococcus aureus is the third most important foodborne pathogen worldwide. Nonetheless, substrates and biological roles of malonylation are still poorly understood in this pathogen. Read More

Cell Mol Life Sci 2021 Mar 22;78(6):2839-2856. Epub 2020 Oct 22.

Department of Genetics and Cell Biology, Faculty of Health, Medicine and Life Sciences, Maastricht University Medical Center+, 6200 MD, Maastricht, The Netherlands.

In the diabetic heart, long-chain fatty acid (LCFA) uptake is increased at the expense of glucose uptake. This metabolic shift ultimately leads to insulin resistance and a reduced cardiac function. Therefore, signaling kinases that mediate glucose uptake without simultaneously stimulating LCFA uptake could be considered attractive anti-diabetic targets. Read More

Biochim Biophys Acta Gen Subj 2021 01 15;1865(1):129766. Epub 2020 Oct 15.

Delft University of Technology, Department of Biotechnology, Van der Maasweg 9, Delft 2629HZ, the Netherlands. Electronic address:

Background: Prediction of ligand binding and design of new function in enzymes is a time-consuming and expensive process. Crystallography gives the impression that proteins adopt a fixed shape, yet enzymes are functionally dynamic. Molecular dynamics offers the possibility of probing protein movement while predicting ligand binding. Read More

Sci Rep 2020 10 16;10(1):17589. Epub 2020 Oct 16.

Department of Biological Sciences, The University of Texas at Dallas, 800 west Campbell Rd, Richardson, TX, 75080, USA.

Dendritic spine injury underlies synaptic failure in many neurological disorders. Mounting evidence suggests a mitochondrial pathway of local nonapoptotic caspase signaling in mediating spine pruning. However, it remains unclear whether this caspase signaling plays a key role in spine loss when severe mitochondrial functional defects are present. Read More

J Plant Physiol 2020 Nov 22;254:153264. Epub 2020 Sep 22.

Laboratory of Germplasm Innovation and Molecular Breeding, Institute of Vegetable Science, Zhejiang University, Hangzhou, 310058, China.

Mitochondrial FF-ATP synthase (FF-ATPase) inhibitor factor 1 (IF1) has been extensively characterized as an endogenous inhibitor that prevents the hydrolysis of adenosine-5'-triphosphate (ATP) by mitochondrial ATPases in mammals and yeasts; however, IF1's functions in plants remain unclear. Here, a comprehensive bioinformatic analysis was performed to identify plant mitochondrial FF-ATPase IF1 orthologs. Plant IF1s contain a conserved FF-ATPase inhibitory domain, but lack the antiparallel α-helical coiled-coil structure compared with mammalian IF1s. Read More

Eur J Med Chem 2020 Dec 3;207:112779. Epub 2020 Sep 3.

Department of Chemistry and Biochemistry, 305 McCourtney Hall, University of Notre Dame, IN, 46545, United States. Electronic address:

FF ATP synthase is responsible for the production of >95% of all ATP synthesis within the cell. Dysregulation of its expression, activity or localization is linked to various human diseases including cancer, diabetes, and Alzheimer's and Parkinson's disease. In addition, ATP synthase is a novel and viable drug target for the development of antimicrobials as evidenced by bedaquiline, which was approved in 2012 for the treatment of tuberculosis. Read More

Nat Struct Mol Biol 2020 11 14;27(11):1077-1085. Epub 2020 Sep 14.

Institute of Science and Technology Austria, Klosterneuburg, Austria.

The majority of adenosine triphosphate (ATP) powering cellular processes in eukaryotes is produced by the mitochondrial F1Fo ATP synthase. Here, we present the atomic models of the membrane Fo domain and the entire mammalian (ovine) F1Fo, determined by cryo-electron microscopy. Subunits in the membrane domain are arranged in the 'proton translocation cluster' attached to the c-ring and a more distant 'hook apparatus' holding subunit e. Read More

EMBO J 2020 07 22;39(14):e104105. Epub 2020 Jun 22.

Department of NanoBiophotonics, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.

Mitochondrial function is critically dependent on the folding of the mitochondrial inner membrane into cristae; indeed, numerous human diseases are associated with aberrant crista morphologies. With the MICOS complex, OPA1 and the F F -ATP synthase, key players of cristae biogenesis have been identified, yet their interplay is poorly understood. Harnessing super-resolution light and 3D electron microscopy, we dissect the roles of these proteins in the formation of cristae in human mitochondria. Read More

Biochem Pharmacol 2020 07 25;177:113995. Epub 2020 Apr 25.

Yale University School of Medicine, Department of Internal Medicine, 333 Cedar St., New Haven, CT 06510, United States; TheraStat LLC, 44 Kings Grant Rd., Weston, MA 02493, United States.

Few discoveries have influenced drug discovery programs more than the finding that mitochondrial membranes undergo swings in permeability in response to cellular perturbations. The conductor of these permeability changes is the aptly named mitochondrial permeability transition pore which, although not yet precisely defined, is comprised of several integral proteins that differentially act to regulate the flux of ions, proteins and metabolic byproducts during the course of cellular physiological functions but also pathophysiological insults. Pursuit of the pore's exact identity remains a topic of keen interest, but decades of research have unearthed provocative functions for the integral proteins leading to their evaluation to develop novel therapeutics for a wide range of clinical indications. Read More

J Biol Chem 2020 05 9;295(21):7235-7248. Epub 2020 Apr 9.

Center for Molecular Parasitology, Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19129. Electronic address:

The mitochondrion of malaria parasites contains several clinically validated drug targets. Within spp., the causative agents of malaria, the mitochondrial DNA (mtDNA) is only 6 kb long, being the smallest mitochondrial genome among all eukaryotes. Read More

Cardiovasc Res 2021 Jan;117(1):212-223

Cardiovascular Branch, NHLBI, National Institutes of Health, Bethesda, MD, USA.

Aims: Cyclophilin-D is a well-known regulator of the mitochondrial permeability transition pore (PTP), the main effector of cardiac ischaemia/reperfusion injury. However, the binding of CypD to the PTP is poorly understood. Cysteine 202 (C202) of CypD is highly conserved among species and can undergo redox-sensitive post-translational modifications. Read More

Protein J 2020 04;39(2):152-159

Department of Biology and Center for Computational and Integrative Biology, Rutgers The State University of New Jersey, Camden, NJ, 08102, USA.

The segmented annelid worm, Mesenchytraeus solifugus, is a permanent resident of temperate, maritime glaciers in the Pacific northwestern region of North America, displaying atypically high intracellular ATP levels which have been linked to its unusual ability to thrive in hydrated glacier ice. We have shown previously that ice worms contain a highly basic, carboxy terminal extension on their ATP6 regulatory subunit, likely acquired by horizontal gene transfer from a microbial dietary source. Here we examine the full complement of FF ATP synthase structural subunits with attention to non-conservative, ice worm-specific structural modifications. Read More

Comput Biol Chem 2020 Apr 13;85:107204. Epub 2020 Jan 13.

Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa. Electronic address:

Bedaquiline (BDQ) has demonstrated formidable bactericidal activity towards Mycobacterium tuberculosis (Mtb) in the treatment of multi-drug resistant (MDR) and extensively drug resistant (XDR) tuberculosis (TB). BDQ elicits its therapeutic function by halting the ionic shuttle of Mtb via mycobacterial FF ATP-synthase blockade. However, triple mutations (L59 V, E61D and I66 M) at the ligand-binding cavity characterize emerging BDQ-resistant strains thereby restraining the potentials embedded in this anti-microbial compound, particularly in MDR/XDR-TB therapy. Read More

Proc Natl Acad Sci U S A 2020 02 21;117(5):2412-2421. Epub 2020 Jan 21.

Center for Biomembrane Research, Department of Biochemistry and Biophysics, Stockholm University, SE-106 91 Stockholm, Sweden;

Mitochondria have a characteristic ultrastructure with invaginations of the inner membrane called cristae that contain the protein complexes of the oxidative phosphorylation system. How this particular morphology of the respiratory membrane impacts energy conversion is currently unknown. One proposed role of cristae formation is to facilitate the establishment of local proton gradients to fuel ATP synthesis. Read More

Fish Shellfish Immunol 2020 Mar 13;98:245-254. Epub 2020 Jan 13.

Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Qingdao, Shandong, 266237, China. Electronic address:

ATPase Inhibitory Factor 1 (IF1) is a mitochondrial protein that functions as a physiological inhibitor of FF-ATP synthase. In the present study, a mitochondrial ATPase inhibitor factor 1 (MjATPIF1) was identified from kuruma shrimp (Marsupenaeus japonicus), which was demonstrated to participate in the viral immune reaction of white spot syndrome virus (WSSV). MjATPIF1 contained a mitochondrial ATPase inhibitor (IATP) domain, and was widely distributed in hemocytes, heart, hepatopancreas, gills, stomach, and intestine of shrimp. Read More

Front Microbiol 2019 6;10:2831. Epub 2019 Dec 6.

Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, South Korea.

Upon intracellular cues, bacterial mRNA leaders often form secondary structures that determine expression of a downstream protein-coding region(s), thereby providing bacteria with a mechanism to control the amounts of necessary proteins in the right locales. Here we describe a polycistronic mRNA leader that secures bacterial growth by preventing dysregulated expression of the protein-coding regions. In , the mRNA encodes the virulence protein MgtC and the Mg transporter MgtB. Read More

SLAS Discov 2019 10 2;24(9):893-903. Epub 2019 Jul 2.

Department of Veterinary Medical Sciences, University of Bologna, Ozzano Emilia, Bologna, Italy.

Recently, the FF-ATP synthase, due to its dual role of life enzyme as main adenosine triphosphate (ATP) maker and of death enzyme, as ATP dissipator and putative structural component of the mitochondrial permeability transition pore (mPTP), which triggers cell death, has been increasingly considered as a drug target. Accordingly, the enzyme offers new strategies to counteract the increased antibiotic resistance. The challenge is to find or synthesize compounds able to discriminate between prokaryotic and mitochondrial FF-ATP synthase, exploiting subtle structural differences to kill pathogens without affecting the host. Read More

J Struct Biol 2019 08 24;207(2):199-208. Epub 2019 May 24.

Nanyang Technological University, School of Biological Sciences, 60 Nanyang Drive, Singapore 637551, Singapore; Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), #07-01 Matrix, 30 Biopolis Street, Singapore 138671, Singapore. Electronic address:

In contrast to other prokaryotes, the Mycobacterial FF ATP synthase (α:β:γ:δ:ε:a:b:b':c) is essential for growth. The mycobacterial enzyme is also unique as a result of its 111 amino acids extended δ subunit, whose gene is fused to the peripheral stalk subunit b. Recently, the crystallographic structures of the mycobacterial α:β:γ:ε-domain and c subunit ring were resolved. Read More

J Cell Biochem 2019 09 24;120(9):16108-16119. Epub 2019 May 24.

Molecular Bio-computation and Drug Design Laboratory, Discipline of Pharmaceutical Chemistry, University of KwaZulu-Natal, Westville Campus, Durban, South Africa.

Therapeutic targeting of the adenosine triphosphate (ATP) machinery of Mycobacterium tuberculosis (Mtb) has recently presented a potent and alternative measure to halt the pathogenesis of tuberculosis. This has been potentiated by the development of bedaquiline (BDQ), a novel small molecule inhibitor that selectively inhibits mycobacterial F F -ATP synthase by targeting its rotor c-ring, resulting in the disruption of ATP synthesis and consequential cell death. Although the structural resolution of the mycobacterial C ring in co`mplex with BDQ provided the first-hand detail of BDQ interaction at the c-ring region of the ATP synthase, there still remains a need to obtain essential and dynamic insights into the mechanistic activity of this drug molecule towards crucial survival machinery of Mtb. Read More

Elife 2019 03 26;8. Epub 2019 Mar 26.

Molecular, Structural and Computational Biology Division, The Victor Chang Cardiac Research Institute, Darlinghurst, Australia.

ATP synthase produces the majority of cellular energy in most cells. We have previously reported cryo-EM maps of autoinhibited ATP synthase imaged without addition of nucleotide (Sobti et al. 2016), indicating that the subunit ε engages the α, β and γ subunits to lock the enzyme and prevent functional rotation. Read More

Biomol Concepts 2019 Mar 7;10(1):1-10. Epub 2019 Mar 7.

Department of Biotechnology, Kathmandu University Dhulikhel, Nepal India.

Oxidative phosphorylation is carried out by five complexes, which are the sites for electron transport and ATP synthesis. Among those, Complex V (also known as the F1F0 ATP Synthase or ATPase) is responsible for the generation of ATP through phosphorylation of ADP by using electrochemical energy generated by proton gradient across the inner membrane of mitochondria. A multi subunit structure that works like a pump functions along the proton gradient across the membranes which not only results in ATP synthesis and breakdown, but also facilitates electron transport. Read More

Sci Rep 2019 02 28;9(1):3070. Epub 2019 Feb 28.

Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, 3012, Bern, Switzerland.

Synthesis of ATP by the FF ATP synthase in mitochondria and most bacteria is energized by the proton motive force (pmf) established and maintained by respiratory chain enzymes. Conversely, in the presence of ATP and in the absence of a pmf, the enzyme works as an ATP-driven proton pump. Here, we investigate how high concentrations of ATP affect the enzymatic activity of the FF ATP synthase under high pmf conditions, which is the typical situation in mitochondria or growing bacteria. Read More

Amino Acids 2019 Apr 23;51(4):579-587. Epub 2019 Feb 23.

Department of Veterinary Medical Sciences, University of Bologna, Via Tolara di Sopra 50, 40064, Ozzano Emilia, BO, Italy.

The eukaryotic FF-ATP synthase/hydrolase activity is coupled to H translocation through the inner mitochondrial membrane. According to a recent model, two asymmetric H half-channels in the a subunit translate a transmembrane vertical H flux into the rotor rotation required for ATP synthesis/hydrolysis. Along the H pathway, conserved aminoacid residues, mainly glutamate, address H both in the downhill and uphill transmembrane movements to synthesize or hydrolyze ATP, respectively. Read More

J Med Chem 2019 03 1;62(5):2305-2332. Epub 2019 Mar 1.

Department of Medicinal Chemistry , University of Minnesota , Minneapolis , Minnesota 55455 , United States.

Optochin, a cinchona alkaloid derivative discovered over 100 years ago, possesses highly selective antibacterial activity toward Streptococcus pneumoniae. Pneumococcal disease remains the leading source of bacterial pneumonia and meningitis worldwide. The structure-activity relationships of optochin were examined through modification to both the quinoline and quinuclidine subunits, which led to the identification of analogue 48 with substantially improved activity. Read More

FASEB J 2019 03 19;33(3):4327-4340. Epub 2018 Dec 19.

Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan Town, Taiwan, Republic of China.

Knockdown of the suppression of tumorigenicity 14-encoding type II transmembrane serine protease matriptase (MTP) in neural stem/progenitor (NS/P) cells impairs cell mobility, response to chemo-attractants, and neurovascular niche interaction. In the present study, we showed by Western blot that a portion of MTP can be detected in the mitochondrial fraction of mouse NS/P cells by immunostaining that it is co-stained with the mitochondrial dye MitoTracker (Thermo Fisher Scientific, Waltham, MA, USA) inside the cells. Co-immunoprecipitation showed that MTP is bound to the β subunit of mitochondrial FF-ATP synthase complex (ATP-β). Read More

J Biol Chem 2019 02 7;294(6):1936-1943. Epub 2018 Dec 7.

From the School of Biological Sciences, Nanyang Technological University, Singapore 637551,

Energy metabolism has recently gained interest as a target space for antibiotic drug development in mycobacteria. Of particular importance is bedaquiline (Sirturo), which kills mycobacteria by inhibiting the FF ATP synthase. Other components of the electron transport chain such as the NADH dehydrogenases (NDH-2 and NdhA) and the terminal respiratory oxidase : are also susceptible to chemical inhibition. Read More

Science 2018 11;362(6416):829-834

Physical and Theoretical Chemistry Laboratory, University of Oxford, South Parks Road, Oxford OX1 3QZ, UK.

Membrane proteins reside in lipid bilayers and are typically extracted from this environment for study, which often compromises their integrity. In this work, we ejected intact assemblies from membranes, without chemical disruption, and used mass spectrometry to define their composition. From outer membranes, we identified a chaperone-porin association and lipid interactions in the β-barrel assembly machinery. Read More

J Struct Biol 2018 12 17;204(3):420-434. Epub 2018 Oct 17.

Nanyang Technological University, School of Biological Sciences, 60 Nanyang Drive, Singapore 637551, Republic of Singapore. Electronic address:

The Mycobacterium tuberculosis (Mtb) FF-ATP synthase (α:β:γ:δ:ε:a:b:b':c) is an essential enzyme that supplies energy for both the aerobic growing and the hypoxic dormant stage of the mycobacterial life cycle. Employing the heterologous F-ATP synthase model system α:β:γ we showed previously, that transfer of the C-terminal domain (CTD) of Mtb subunit α (Mtα) to a standard F-ATP synthase α subunit suppresses ATPase activity. Here we determined the 3D reconstruction from electron micrographs of the α:β:γ complex reconstituted with the Mtb subunit ε (Mtε), which has been shown to crosstalk with the CTD of Mtα. Read More

Neurobiol Dis 2019 01 26;121:138-147. Epub 2018 Sep 26.

Department of Biological Sciences, The University of Texas at Dallas, United States. Electronic address:

Mitochondrial dysfunction is pivotal in inducing synaptic injury and neuronal stress in Alzheimer's disease (AD). Mitochondrial F1Fo ATP synthase deregulation is a hallmark mitochondrial defect leading to oxidative phosphorylation (OXPHOS) failure in this neurological disorder. Oligomycin sensitivity conferring protein (OSCP) is a crucial F1Fo ATP synthase subunit. Read More