@article{MTMT:34075046,
	title = {Structural and Biochemical Investigation of Selected Pathogenic Mutants of the Human Dihydrolipoamide Dehydrogenase},
	url = {https://m2.mtmt.hu/api/publication/34075046},
	author = {Szabó, Eszter and Nemes-Nikodém, Éva and Vass, Krisztina Rubina and Zámbó, Zsófia Melinda and Zrupko, E. and Törőcsik, Beáta and Ozohanics, Olivér and Nagy, Bálint and Ambrus, Attila},
	doi = {10.3390/ijms241310826},
	journal-iso = {INT J MOL SCI},
	journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES},
	volume = {24},
	unique-id = {34075046},
	issn = {1661-6596},
	abstract = {Clinically relevant disease-causing variants of the human dihydrolipoamide dehydrogenase (hLADH, hE3), a common component of the mitochondrial α-keto acid dehydrogenase complexes, were characterized using a multipronged approach to unravel the molecular pathomechanisms that underlie hLADH deficiency. The G101del and M326V substitutions both reduced the protein stability and triggered the disassembly of the functional/obligate hLADH homodimer and significant FAD losses, which altogether eventually manifested in a virtually undetectable catalytic activity in both cases. The I12T-hLADH variant proved also to be quite unstable, but managed to retain the dimeric enzyme form; the LADH activity, both in the forward and reverse catalytic directions and the affinity for the prosthetic group FAD were both significantly compromised. None of the above three variants lent themselves to an in-depth structural analysis via X-ray crystallography due to inherent protein instability. Crystal structures at 2.89 and 2.44 Å resolutions were determined for the I318T- and I358T-hLADH variants, respectively; structure analysis revealed minor conformational perturbations, which correlated well with the residual LADH activities, in both cases. For the dimer interface variants G426E-, I445M-, and R447G-hLADH, enzyme activities and FAD loss were determined and compared against the previously published structural data. © 2023 by the authors.},
	keywords = {Reactive oxygen species; X-RAY CRYSTALLOGRAPHY; Lipoamide Dehydrogenase; disease-causing mutation; alpha-keto acid dehydrogenase complexes},
	year = {2023},
	eissn = {1422-0067},
	orcid-numbers = {Szabó, Eszter/0000-0002-9634-2771; Vass, Krisztina Rubina/0000-0002-1584-7154; Zámbó, Zsófia Melinda/0000-0001-8657-8556; Törőcsik, Beáta/0000-0002-9838-3710; Ozohanics, Olivér/0000-0002-2705-9921; Nagy, Bálint/0000-0003-3669-7041; Ambrus, Attila/0000-0001-6014-3175}
}

@article{MTMT:32804574,
	title = {Tumor Glucose and Fatty Acid Metabolism in the Context of Anthracycline and Taxane-Based (Neo)Adjuvant Chemotherapy in Breast Carcinomas},
	url = {https://m2.mtmt.hu/api/publication/32804574},
	author = {Tőkés, Anna-Mária and Vári-Kakas, S. and Kulka, Janina and Törőcsik, Beáta},
	doi = {10.3389/fonc.2022.850401},
	journal-iso = {FRONT ONCOL},
	journal = {FRONTIERS IN ONCOLOGY},
	volume = {12},
	unique-id = {32804574},
	issn = {2234-943X},
	year = {2022},
	eissn = {2234-943X},
	orcid-numbers = {Tőkés, Anna-Mária/0000-0002-9581-7536; Kulka, Janina/0000-0001-6498-5943; Törőcsik, Beáta/0000-0002-9838-3710}
}

@article{MTMT:31397038,
	title = {Simple binding of protein kinase A, prior to phosphorylation, allows CFTR anion channels to be opened by nucleotides},
	url = {https://m2.mtmt.hu/api/publication/31397038},
	author = {Mihályi, Csaba and Iordanov, Iordan and Törőcsik, Beáta and Csanády, László},
	doi = {10.1073/pnas.2007910117},
	journal-iso = {P NATL ACAD SCI USA},
	journal = {PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA},
	volume = {117},
	unique-id = {31397038},
	issn = {0027-8424},
	year = {2020},
	eissn = {1091-6490},
	pages = {21740-21746},
	orcid-numbers = {Mihályi, Csaba/0000-0001-7536-3066; Iordanov, Iordan/0000-0001-8251-5857; Törőcsik, Beáta/0000-0002-9838-3710; Csanády, László/0000-0002-6547-5889}
}

@article{MTMT:30799456,
	title = {Underlying molecular alterations in human dihydrolipoamide dehydrogenase deficiency revealed by structural analyses of disease-causing enzyme variants},
	url = {https://m2.mtmt.hu/api/publication/30799456},
	author = {Szabó, Eszter and Wilk, Piotr and Nagy, Bálint and Zámbó, Zsófia Melinda and Bui, Dávid and Weichsel, Andrzej and Arjunan, Palaniappa and Törőcsik, Beáta and Hubert, Agnes and Furey, William and Montfort, William R and Jordan, Frank and Weiss, Manfred S and Ádám, Veronika and Ambrus, Attila},
	doi = {10.1093/hmg/ddz177},
	journal-iso = {HUM MOL GENET},
	journal = {HUMAN MOLECULAR GENETICS},
	volume = {28},
	unique-id = {30799456},
	issn = {0964-6906},
	abstract = {Human dihydrolipoamide dehydrogenase (hLADH, hE3) deficiency (OMIM# 246900) is an often prematurely lethal genetic disease usually caused by inactive or partially inactive hE3 variants. Here we report the crystal structure of wild-type hE3 at an unprecedented high resolution of 1.75 Å and the structures of six disease-causing hE3 variants at resolutions ranging from 1.44 to 2.34 Å. P453L proved to be the most deleterious substitution in structure as aberrations extensively compromised the active site. The most prevalent G194C-hE3 variant primarily exhibited structural alterations close to the substitution site, whereas the nearby cofactor-binding residues were left unperturbed. The G426E substitution mainly interfered with the local charge distribution introducing dynamics to the substitution site in the dimer interface; G194C and G426E both led to minor structural changes. The R460G, R447G, and I445M substitutions all perturbed a solvent accessible channel, the so-called H+/H2O channel, leading to the active site. Molecular pathomechanisms of enhanced reactive oxygen species (ROS) generation and impaired binding to multienzyme complexes were also addressed according to the structural data for the relevant mutations. In summary, we present here for the first time a comprehensive study that links three-dimensional structures of disease-causing hE3 variants to residual hLADH activities, altered capacities for ROS generation, compromised affinities for multienzyme complexes, and eventually clinical symptoms. Our results may serve as useful starting points for future therapeutic intervention approaches.},
	year = {2019},
	eissn = {1460-2083},
	pages = {3339-3354},
	orcid-numbers = {Szabó, Eszter/0000-0002-9634-2771; Nagy, Bálint/0000-0003-3669-7041; Zámbó, Zsófia Melinda/0000-0001-8657-8556; Bui, Dávid/0000-0003-3726-2031; Törőcsik, Beáta/0000-0002-9838-3710; Ádám, Veronika/0000-0002-8350-8701; Ambrus, Attila/0000-0001-6014-3175}
}

@article{MTMT:30775333,
	title = {Cystic fibrosis drug ivacaftor stimulates CFTR channels at picomolar concentrations},
	url = {https://m2.mtmt.hu/api/publication/30775333},
	author = {Csanády, László and Törőcsik, Beáta},
	doi = {10.7554/eLife.46450},
	journal-iso = {ELIFE},
	journal = {ELIFE},
	volume = {8},
	unique-id = {30775333},
	issn = {2050-084X},
	abstract = {The devastating inherited disease cystic fibrosis (CF) is caused by mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) anion channel. The recent approval of the CFTR potentiator drug ivacaftor (Vx-770) for the treatment of CF patients has marked the advent of causative CF therapy. Currently, thousands of patients are being treated with the drug, and its molecular mechanism of action is under intensive investigation. Here we determine the solubility profile and true stimulatory potency of Vx-770 towards wild-type (WT) and mutant human CFTR channels in cell-free patches of membrane. We find that its aqueous solubility is ~200 fold lower (~60 nanomolar), whereas the potency of its stimulatory effect is >100 fold higher, than reported, and is unexpectedly fully reversible. Strong, but greatly delayed, channel activation by picomolar Vx-770 identifies multiple sequential slow steps in the activation pathway. These findings provide solid guidelines for the design of in vitro studies using Vx-770. © 2019, Csanády and Töröcsik.},
	keywords = {Xenopus; Solubility; cystic fibrosis; molecular biophysics; Structural biology; F508del; VX-770; G551D; potentiator drug},
	year = {2019},
	eissn = {2050-084X},
	orcid-numbers = {Csanády, László/0000-0002-6547-5889; Törőcsik, Beáta/0000-0002-9838-3710}
}

@article{MTMT:30723780,
	title = {Secretagogin expression in the vertebrate brainstem with focus on the noradrenergic system and implications for Alzheimer's disease},
	url = {https://m2.mtmt.hu/api/publication/30723780},
	author = {Zahola, Péter and Hanics, János and Pintér, Panka and Máté, Zoltán and Gáspárdy, Anna and Hevesi, Zsófia and Echevarria, Diego and Adori, Csaba and Barde, Swapnali and Törőcsik, Beáta and Erdélyi, Ferenc and Szabó, Gábor and Wagner, Ludwig and Kovács, Gábor Géza and Hökfelt, Tomas and Harkany, Tibor and Alpár, Alán},
	doi = {10.1007/s00429-019-01886-w},
	journal-iso = {BRAIN STRUCT FUNC},
	journal = {BRAIN STRUCTURE & FUNCTION},
	volume = {224},
	unique-id = {30723780},
	issn = {1863-2653},
	abstract = {Calcium-binding proteins are widely used to distinguish neuronal subsets in the brain. This study focuses on secretagogin, an EF-hand calcium sensor, to identify distinct neuronal populations in the brainstem of several vertebrate species. By using neural tube whole mounts of mouse embryos, we show that secretagogin is already expressed during the early ontogeny of brainstem noradrenaline cells. In adults, secretagogin-expressing neurons typically populate relay centres of special senses and vegetative regulatory centres of the medulla oblongata, pons and midbrain. Notably, secretagogin expression overlapped with the brainstem column of noradrenergic cell bodies, including the locus coeruleus (A6) and the A1, A5 and A7 fields. Secretagogin expression in avian, mouse, rat and human samples showed quasi-equivalent patterns, suggesting conservation throughout vertebrate phylogeny. We found reduced secretagogin expression in locus coeruleus from subjects with Alzheimer's disease, and this reduction paralleled the loss of tyrosine hydroxylase, the enzyme rate limiting noradrenaline synthesis. Residual secretagogin immunoreactivity was confined to small submembrane domains associated with initial aberrant tau phosphorylation. In conclusion, we provide evidence that secretagogin is a useful marker to distinguish neuronal subsets in the brainstem, conserved throughout several species, and its altered expression may reflect cellular dysfunction of locus coeruleus neurons in Alzheimer's disease.},
	keywords = {NOREPINEPHRINE; Locus coeruleus; CALCIUM-BINDING PROTEINS; Alzheimer's disease; Phylogenetic conservation},
	year = {2019},
	eissn = {1863-2661},
	pages = {2061-2078},
	orcid-numbers = {Zahola, Péter/0000-0002-5057-8252; Hanics, János/0000-0003-3305-2440; Gáspárdy, Anna/0000-0002-9698-5128; Hevesi, Zsófia/0000-0002-9341-9892; Törőcsik, Beáta/0000-0002-9838-3710; Kovács, Gábor Géza/0000-0003-3841-5511; Alpár, Alán/0000-0003-4810-0820}
}

@article{MTMT:3407990,
	title = {Crystal structures of the disease-causing D444V mutant and the relevant wild type human dihydrolipoamide dehydrogenase},
	url = {https://m2.mtmt.hu/api/publication/3407990},
	author = {Szabó, Eszter and Mizsei, Réka and Wilk, P and Zámbó, Zsófia Melinda and Törőcsik, Beáta and Weiss, MS and Ádám, Veronika and Ambrus, Attila},
	doi = {10.1016/j.freeradbiomed.2018.06.008},
	journal-iso = {FREE RADICAL BIO MED},
	journal = {FREE RADICAL BIOLOGY AND MEDICINE},
	volume = {124},
	unique-id = {3407990},
	issn = {0891-5849},
	abstract = {We report the crystal structures of the human (dihydro)lipoamide dehydrogenase (hLADH, hE3) and its disease-causing homodimer interface mutant D444V-hE3 at 2.27 and 1.84 Å resolution, respectively. The wild type structure is a unique uncomplexed, unliganded hE3 structure with the true canonical sequence. Based on the structural information a novel molecular pathomechanism is proposed for the impaired catalytic activity and enhanced capacity for reactive oxygen species generation of the pathogenic mutant. The mechanistic model involves a previously much ignored solvent accessible channel leading to the active site that might be perturbed also by other disease-causing homodimer interface substitutions of this enzyme. © 2018 Elsevier Inc.},
	keywords = {Reactive oxygen species; X-RAY CRYSTALLOGRAPHY; protein structure; Lipoamide Dehydrogenase; Pyruvate Dehydrogenase Complex; Pathogenic mutation; E3 deficiency; Alpha-ketoglutarate dehydrogenase complex; Oxidative stress},
	year = {2018},
	eissn = {1873-4596},
	pages = {214-220},
	orcid-numbers = {Szabó, Eszter/0000-0002-9634-2771; Mizsei, Réka/0000-0003-4519-4307; Zámbó, Zsófia Melinda/0000-0001-8657-8556; Törőcsik, Beáta/0000-0002-9838-3710; Ádám, Veronika/0000-0002-8350-8701; Ambrus, Attila/0000-0001-6014-3175}
}

@article{MTMT:3287727,
	title = {Asymmetry of movements in CFTR's two ATP sites during pore opening serves their distinct functions},
	url = {https://m2.mtmt.hu/api/publication/3287727},
	author = {Sorum, Ben and Törőcsik, Beáta and Csanády, László},
	doi = {10.7554/eLife.29013},
	journal-iso = {ELIFE},
	journal = {ELIFE},
	volume = {6},
	unique-id = {3287727},
	issn = {2050-084X},
	abstract = {CFTR, the chloride channel mutated in cystic fibrosis (CF) patients, is opened by ATP binding to two cytosolic nucleotide binding domains (NBDs), but pore-domain mutations may also impair gating. ATP-bound NBDs dimerize occluding two nucleotides at interfacial binding sites; one site hydrolyzes ATP, the other is inactive. The pore opens upon tightening, and closes upon disengagement, of the catalytic site following ATP hydrolysis. Extent, timing, and role of non-catalytic-site movements are unknown. Here we exploit equilibrium gating of a hydrolysis-deficient mutant and apply Phi value analysis to compare timing of opening-associated movements at multiple locations, from the cytoplasmic ATP sites to the extracellular surface. Marked asynchrony of motion in the two ATP sites reveals their distinct roles in channel gating. The results clarify the molecular mechanisms of functional cross-talk between canonical and degenerate ATP sites in asymmetric ABC proteins, and of the gating defects caused by two common CF mutations.},
	year = {2017},
	eissn = {2050-084X},
	orcid-numbers = {Sorum, Ben/0000-0001-6742-1094; Törőcsik, Beáta/0000-0002-9838-3710; Csanády, László/0000-0002-6547-5889}
}

@article{MTMT:3262509,
	title = {Crystal structure of the D444V disease-causing mutant of human dihydrolipoamide dehydrogenase},
	url = {https://m2.mtmt.hu/api/publication/3262509},
	author = {Szabó, Eszter and Mizsei, Réka and Zámbó, Zsófia Melinda and Törőcsik, Beáta and Weiss, Manfred S and Ádám, Veronika and Ambrus, Attila},
	doi = {10.1016/j.bbabio.2016.04.337},
	journal-iso = {BBA-BIOENERGETICS},
	journal = {BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS},
	volume = {1857},
	unique-id = {3262509},
	issn = {0005-2728},
	year = {2016},
	eissn = {1879-2650},
	pages = {e100},
	orcid-numbers = {Szabó, Eszter/0000-0002-9634-2771; Mizsei, Réka/0000-0003-4519-4307; Zámbó, Zsófia Melinda/0000-0001-8657-8556; Törőcsik, Beáta/0000-0002-9838-3710; Ádám, Veronika/0000-0002-8350-8701; Ambrus, Attila/0000-0001-6014-3175}
}

@article{MTMT:3114546,
	title = {Structural alterations induced by ten disease-causing mutations of human dihydrolipoamide dehydrogenase analyzed by hydrogen/deuterium-exchange mass spectrometry: Implications for the structural basis of E3 deficiency},
	url = {https://m2.mtmt.hu/api/publication/3114546},
	author = {Ambrus, Attila and Wang, J and Mizsei, Réka and Zámbó, Zsófia Melinda and Törőcsik, Beáta and Jordan, F and Ádám, Veronika},
	doi = {10.1016/j.bbadis.2016.08.013},
	journal-iso = {BBA-MOL BASIS DIS},
	journal = {BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE},
	volume = {1862},
	unique-id = {3114546},
	issn = {0925-4439},
	abstract = {Pathogenic amino acid substitutions of the common E3 component (hE3) of the human alpha-ketoglutarate dehydrogenase and the pyruvate dehydrogenase complexes lead to severe metabolic diseases (E3 deficiency), which usually manifest themselves in cardiological and/or neurological symptoms and often cause premature death. To date, 14 disease-causing amino acid substitutions of the hE3 component have been reported in the clinical literature. None of the pathogenic protein variants has lent itself to high-resolution structure elucidation by X-ray or NMR. Hence, the structural alterations of the hE3 protein caused by the disease-causing mutations and leading to dysfunction, including the enhanced generation of reactive oxygen species by selected disease-causing variants, could only be speculated. Here we report results of an examination of the effects on the protein structure of ten pathogenic mutations of hE3 using hydrogen/deuterium-exchange mass spectrometry (HDX-MS), a new and state-of-the-art approach of solution structure elucidation. On the basis of the results, putative structural and mechanistic conclusions were drawn regarding the molecular pathogenesis of each disease-causing hE3 mutation addressed in this study. © 2016 Elsevier B.V.},
	keywords = {Mass spectrometry; Dihydrolipoamide dehydrogenase; Hydrogen/deuterium exchange; Pathogenic mutation; E3 deficiency},
	year = {2016},
	eissn = {1879-260X},
	pages = {2098-2109},
	orcid-numbers = {Ambrus, Attila/0000-0001-6014-3175; Mizsei, Réka/0000-0003-4519-4307; Zámbó, Zsófia Melinda/0000-0001-8657-8556; Törőcsik, Beáta/0000-0002-9838-3710; Ádám, Veronika/0000-0002-8350-8701}
}