{"gene":"LIAS","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2023,"finding":"FDX1 (ferredoxin 1) directly binds to LIAS (lipoyl synthase) and promotes LIAS's functional binding to the lipoyl carrier protein GCSH, thereby regulating cellular protein lipoylation; this regulation is not indirect through Fe-S cluster biosynthesis.","method":"Co-immunoprecipitation, metabolite profiling, transcriptional profiling, loss-of-function studies","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding demonstrated, replicated across peer-reviewed and preprint versions, multiple orthogonal methods (Co-IP, metabolite profiling, transcriptional profiling), direct functional consequence established","pmids":["37453661","36778498"],"is_preprint":false},{"year":2021,"finding":"Human LIAS contains two [4Fe-4S] clusters (a reducing cluster and an auxiliary cluster); [2Fe-2S]-cluster-bound ISCU and ISCA2 are capable of reconstituting human LIAS enabling complete product turnover; EPR studies indicate the auxiliary [4Fe-4S] cluster is added before the reducing cluster during reconstitution.","method":"In vitro reconstitution, LC-MS activity assay, EPR spectroscopy, mutagenesis of cluster-binding sites","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with LC-MS assay, EPR with mutagenesis in a single rigorous study; single lab but multiple orthogonal methods","pmids":["33562493"],"is_preprint":false},{"year":2013,"finding":"Loss-of-function mutations in LIAS cause deficient lipoylation of mitochondrial proteins, reduced pyruvate dehydrogenase activity, and variant nonketotic hyperglycinemia; transfection with wild-type LIAS corrects the biochemical deficiency, establishing LIAS as required for mitochondrial protein lipoylation in human cells.","method":"Patient mutation identification, biochemical assays of mitochondrial protein lipoylation and enzyme activity, complementation by transfection of native LIAS","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function with defined biochemical phenotype, complementation rescue, replicated across multiple patients in multiple labs","pmids":["24334290"],"is_preprint":false},{"year":2023,"finding":"PCSK9 directly interacts with LIAS as shown by protein docking and co-immunoprecipitation; this interaction promotes cardiomyocyte cuproptosis in myocardial ischemia-reperfusion injury, and blocking PCSK9 with evolocumab inhibits this interaction and reduces cuproptosis.","method":"Co-immunoprecipitation, protein docking, in vivo mouse I/R model with echocardiography and histopathology","journal":"Basic research in cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and docking for binding, in vivo phenotypic rescue; single lab, limited mechanistic dissection of the PCSK9-LIAS interaction","pmids":["39930254"],"is_preprint":false},{"year":2025,"finding":"Iron overload during ischemia-reperfusion causes Fe(II) accumulation that downregulates [4Fe-4S] cluster assembly proteins, leading to [4Fe-4S] cluster loss from LIAS, impaired protein lipoylation, and cuproptosis in renal tubular cells; overexpression of [4Fe-4S] cluster assembly machinery or iron chelation rescues LIAS function.","method":"Loss-of-function/overexpression in cell and mouse models, biochemical assays of Fe-S cluster integrity, lipoylation assays, cuproptosis markers","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — defined mechanistic pathway with rescue experiments; single lab, no direct structural or in vitro reconstitution of cluster loss","pmids":["40753758"],"is_preprint":false},{"year":2021,"finding":"Overexpression of Lias in mice (LiasHigh/High) increases endogenous antioxidant capacity, reduces oxidative stress, improves liver mitochondrial function, and attenuates NAFLD/NASH in a leptin-deficient obesity model, establishing that LIAS activity protects mitochondrial function in vivo.","method":"Transgenic mouse model (Lias overexpression crossed to Leprdb/db), histopathology, mitochondrial function assays, oxidative stress markers","journal":"The Journal of endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gain-of-function with multiple biological readouts; single lab","pmids":["33263565"],"is_preprint":false},{"year":2023,"finding":"Novel compound heterozygous LIAS variants (p.Leu93Ter and p.Asp181Val) cause loss of LIAS function; the p.Asp181Val missense variant was validated by functional complementation in Saccharomyces cerevisiae lip5Δ (LIAS ortholog knockout), where expression of p.Asp181Val failed to rescue oxidative growth, similar to known pathogenic variants.","method":"Yeast complementation assay (lip5Δ), exome sequencing, functional growth assay","journal":"Molecular genetics and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — yeast complementation establishes loss of function for specific residue; single lab, single method","pmids":["36680912"],"is_preprint":false}],"current_model":"LIAS (lipoyl synthase) is a radical SAM enzyme containing two [4Fe-4S] clusters (auxiliary and reducing) that catalyzes the final step of lipoic acid biosynthesis; in human cells, it requires direct binding by the electron donor FDX1 to promote its interaction with the lipoyl carrier protein GCSH, and its [4Fe-4S] clusters are donated by ISCA2 and ISCU; loss of LIAS function causes deficient lipoylation of key mitochondrial enzymes (including components of the pyruvate dehydrogenase and glycine cleavage complexes), resulting in impaired TCA cycle function, mitochondrial dysfunction, and diseases including variant nonketotic hyperglycinemia."},"narrative":{"mechanistic_narrative":"LIAS is a mitochondrial radical SAM enzyme that catalyzes the final step of lipoic acid biosynthesis and is required for lipoylation of key mitochondrial enzymes, with loss of function causing deficient protein lipoylation, reduced pyruvate dehydrogenase activity, and variant nonketotic hyperglycinemia rescuable by wild-type LIAS [PMID:24334290]. The human enzyme harbors two [4Fe-4S] clusters — a reducing cluster and an auxiliary cluster — whose assembly can be reconstituted in vitro by [2Fe-2S]-bound ISCU and ISCA2, with the auxiliary cluster added before the reducing cluster [PMID:33562493]. Beyond carrying its cofactors, LIAS function is gated by direct binding of ferredoxin FDX1, which promotes LIAS's productive engagement of the lipoyl carrier protein GCSH to drive cellular protein lipoylation independently of Fe-S cluster biosynthesis [PMID:37453661, PMID:36778498]. The integrity of its [4Fe-4S] clusters renders LIAS sensitive to iron overload, which strips the clusters, impairs lipoylation, and triggers cuproptosis [PMID:40753758], and LIAS activity protects mitochondrial function and antioxidant capacity in vivo [PMID:33263565].","teleology":[{"year":2013,"claim":"Establishing whether LIAS is genuinely required for human mitochondrial protein lipoylation, this work linked loss-of-function mutations to a defined biochemical and clinical phenotype with rescue.","evidence":"Patient mutation identification, lipoylation and enzyme activity assays, complementation by transfection of native LIAS","pmids":["24334290"],"confidence":"High","gaps":["Did not resolve the enzymatic mechanism or cofactor requirements","Spectrum of affected lipoylated enzymes only partially defined"]},{"year":2021,"claim":"To define the catalytic machinery, this work showed human LIAS uses two distinct [4Fe-4S] clusters and identified the Fe-S donors and assembly order needed for activity.","evidence":"In vitro reconstitution, LC-MS activity assay, EPR spectroscopy, and cluster-site mutagenesis","pmids":["33562493"],"confidence":"High","gaps":["No high-resolution structure of holo-LIAS","In vivo relevance of the reconstitution order not tested"]},{"year":2021,"claim":"Addressing whether LIAS activity is protective at the organismal level, gain-of-function in mice showed enhanced antioxidant capacity and improved mitochondrial function in metabolic disease.","evidence":"Transgenic Lias-overexpression mice crossed to Leprdb/db, histopathology, mitochondrial and oxidative stress assays","pmids":["33263565"],"confidence":"Medium","gaps":["Single lab","Mechanism connecting lipoylation to antioxidant capacity not dissected"]},{"year":2023,"claim":"To explain how lipoylation is controlled beyond cofactor supply, this work showed FDX1 directly binds LIAS and promotes its functional engagement of GCSH, a regulatory role separable from Fe-S biosynthesis.","evidence":"Co-immunoprecipitation, metabolite and transcriptional profiling, loss-of-function studies","pmids":["37453661","36778498"],"confidence":"High","gaps":["Structural basis of the FDX1-LIAS interface unresolved","Stoichiometry and electron-transfer kinetics not quantified"]},{"year":2023,"claim":"Extending LIAS into disease signaling, this work reported a direct PCSK9-LIAS interaction driving cardiomyocyte cuproptosis in ischemia-reperfusion injury.","evidence":"Co-immunoprecipitation, protein docking, in vivo mouse I/R model with echocardiography and histopathology","pmids":["39930254"],"confidence":"Medium","gaps":["Single Co-IP and docking without reciprocal structural validation","Mechanistic basis of how the interaction promotes cuproptosis not dissected"]},{"year":2023,"claim":"To validate pathogenicity of specific human variants, yeast complementation confirmed that a missense LIAS variant abolishes function.","evidence":"Yeast lip5Δ complementation growth assay and exome sequencing","pmids":["36680912"],"confidence":"Medium","gaps":["Single method, single ortholog system","Residue-level mechanism of dysfunction not defined"]},{"year":2025,"claim":"Connecting iron homeostasis to LIAS activity, this work showed iron overload strips LIAS [4Fe-4S] clusters to impair lipoylation and induce cuproptosis, reversible by restoring assembly machinery or chelating iron.","evidence":"Loss/gain-of-function in cell and mouse I/R models, Fe-S integrity, lipoylation, and cuproptosis assays","pmids":["40753758"],"confidence":"Medium","gaps":["No direct in vitro reconstitution of cluster loss","Single lab, no structural confirmation"]},{"year":null,"claim":"How FDX1-LIAS-GCSH assembly, cofactor delivery, and iron-sensitive cluster loss are integrated structurally and kinetically remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No high-resolution structure of the LIAS-FDX1-GCSH assembly","Quantitative coupling between cluster integrity and lipoylation output not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[1,2]},{"term_id":"GO:0140097","term_label":"catalytic activity, acting on DNA","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[2,5]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2,1]}],"complexes":[],"partners":["FDX1","GCSH","ISCU","ISCA2","PCSK9"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O43766","full_name":"Lipoyl synthase, mitochondrial","aliases":["Lipoate synthase","LS","Lip-syn","Lipoic acid synthase"],"length_aa":372,"mass_kda":41.9,"function":"Catalyzes the radical-mediated insertion of two sulfur atoms into the C-6 and C-8 positions of the octanoyl moiety bound to the lipoyl domains of lipoate-dependent enzymes, thereby converting the octanoylated domains into lipoylated derivatives","subcellular_location":"Mitochondrion","url":"https://www.uniprot.org/uniprotkb/O43766/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LIAS","classification":"Not Classified","n_dependent_lines":444,"n_total_lines":1208,"dependency_fraction":0.3675496688741722},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LIAS","total_profiled":1310},"omim":[{"mim_id":"616859","title":"SPASTICITY, CHILDHOOD-ONSET, WITH HYPERGLYCINEMIA; SPAHGC","url":"https://www.omim.org/entry/616859"},{"mim_id":"616370","title":"MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 4; MMDS4","url":"https://www.omim.org/entry/616370"},{"mim_id":"615330","title":"MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 3; MMDS3","url":"https://www.omim.org/entry/615330"},{"mim_id":"615317","title":"IRON-SULFUR CLUSTER ASSEMBLY 2; ISCA2","url":"https://www.omim.org/entry/615317"},{"mim_id":"615316","title":"IRON-SULFUR CLUSTER ASSEMBLY FACTOR IBA57; IBA57","url":"https://www.omim.org/entry/615316"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Mitochondria","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LIAS"},"hgnc":{"alias_symbol":["LAS"],"prev_symbol":[]},"alphafold":{"accession":"O43766","domains":[{"cath_id":"3.20.20.70","chopping":"89-372","consensus_level":"medium","plddt":90.0638,"start":89,"end":372}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O43766","model_url":"https://alphafold.ebi.ac.uk/files/AF-O43766-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O43766-F1-predicted_aligned_error_v6.png","plddt_mean":81.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LIAS","jax_strain_url":"https://www.jax.org/strain/search?query=LIAS"},"sequence":{"accession":"O43766","fasta_url":"https://rest.uniprot.org/uniprotkb/O43766.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O43766/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O43766"}},"corpus_meta":[{"pmid":"9294432","id":"PMC_9294432","title":"Roles of Pseudomonas aeruginosa las and rhl quorum-sensing systems in control of elastase and rhamnolipid biosynthesis genes.","date":"1997","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/9294432","citation_count":772,"is_preprint":false},{"pmid":"9150205","id":"PMC_9150205","title":"Regulation of las and rhl quorum sensing in Pseudomonas aeruginosa.","date":"1997","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/9150205","citation_count":663,"is_preprint":false},{"pmid":"17449617","id":"PMC_17449617","title":"Environmental regulation of Pseudomonas aeruginosa PAO1 Las and Rhl quorum-sensing systems.","date":"2007","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/17449617","citation_count":187,"is_preprint":false},{"pmid":"24334290","id":"PMC_24334290","title":"Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5.","date":"2013","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/24334290","citation_count":170,"is_preprint":false},{"pmid":"21368905","id":"PMC_21368905","title":"Cooperation and cheating in Pseudomonas aeruginosa: the roles of the las, rhl and pqs quorum-sensing systems.","date":"2011","source":"The ISME journal","url":"https://pubmed.ncbi.nlm.nih.gov/21368905","citation_count":169,"is_preprint":false},{"pmid":"37453661","id":"PMC_37453661","title":"FDX1 regulates cellular protein lipoylation through direct binding to LIAS.","date":"2023","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37453661","citation_count":163,"is_preprint":false},{"pmid":"10049396","id":"PMC_10049396","title":"Roles of Pseudomonas aeruginosa las and rhl quorum-sensing systems in control of twitching motility.","date":"1999","source":"Journal of 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letters","url":"https://pubmed.ncbi.nlm.nih.gov/12076794","citation_count":75,"is_preprint":false},{"pmid":"3007320","id":"PMC_3007320","title":"Immunohistochemical demonstration of p24 HTLV III major core protein in different cell types within lymph nodes from patients with lymphadenopathy syndrome (LAS).","date":"1986","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/3007320","citation_count":62,"is_preprint":false},{"pmid":"19517106","id":"PMC_19517106","title":"The neuroendocrine hormone norepinephrine increases Pseudomonas aeruginosa PA14 virulence through the las quorum-sensing pathway.","date":"2009","source":"Applied microbiology and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/19517106","citation_count":62,"is_preprint":false},{"pmid":"3924442","id":"PMC_3924442","title":"Paraproteinemia in patients with acquired immunodeficiency syndrome (AIDS) or lymphadenopathy syndrome (LAS).","date":"1985","source":"Clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/3924442","citation_count":61,"is_preprint":false},{"pmid":"3436097","id":"PMC_3436097","title":"Evidence for activation of complement in patients with AIDS related complex (ARC) and/or lymphoadenopathy syndrome (LAS).","date":"1987","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/3436097","citation_count":59,"is_preprint":false},{"pmid":"16497345","id":"PMC_16497345","title":"Diterpene resin acid biosynthesis in loblolly pine (Pinus taeda): functional characterization of abietadiene/levopimaradiene synthase (PtTPS-LAS) cDNA and subcellular targeting of PtTPS-LAS and abietadienol/abietadienal oxidase (PtAO, CYP720B1).","date":"2006","source":"Phytochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16497345","citation_count":56,"is_preprint":false},{"pmid":"11112115","id":"PMC_11112115","title":"Community-acquired bacterial pneumonia in human immunodeficiency virus-infected patients: validation of severity criteria. The Grupo Andaluz para el Estudio de las Enfermedades Infecciosas.","date":"2000","source":"American journal of respiratory and critical care medicine","url":"https://pubmed.ncbi.nlm.nih.gov/11112115","citation_count":52,"is_preprint":false},{"pmid":"22327581","id":"PMC_22327581","title":"Assessing the contributions of the LiaS histidine kinase to the innate resistance of Listeria monocytogenes to nisin, cephalosporins, and disinfectants.","date":"2012","source":"Applied and environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/22327581","citation_count":50,"is_preprint":false},{"pmid":"9493328","id":"PMC_9493328","title":"Terrestrial risk assessment for linear alkyl benzene sulfonate (LAS) in sludge-amended soils.","date":"1998","source":"Chemosphere","url":"https://pubmed.ncbi.nlm.nih.gov/9493328","citation_count":50,"is_preprint":false},{"pmid":"2992856","id":"PMC_2992856","title":"Cellular targets of antilymphocyte antibodies in AIDS and LAS.","date":"1985","source":"Clinical immunology and immunopathology","url":"https://pubmed.ncbi.nlm.nih.gov/2992856","citation_count":47,"is_preprint":false},{"pmid":"19383702","id":"PMC_19383702","title":"Pseudomonas aeruginosa Las quorum sensing autoinducer suppresses growth and biofilm production in Legionella species.","date":"2009","source":"Microbiology (Reading, England)","url":"https://pubmed.ncbi.nlm.nih.gov/19383702","citation_count":46,"is_preprint":false},{"pmid":"20121087","id":"PMC_20121087","title":"Anaerobic degradation pathway of linear Alkylbenzene sulfonates (LAS) in sulfate-reducing marine sediments.","date":"2010","source":"Environmental science & technology","url":"https://pubmed.ncbi.nlm.nih.gov/20121087","citation_count":46,"is_preprint":false},{"pmid":"18560152","id":"PMC_18560152","title":"Structural analysis of the L-alanoyl-D-glutamate endopeptidase domain of Listeria bacteriophage endolysin Ply500 reveals a new member of the LAS peptidase family.","date":"2008","source":"Acta crystallographica. Section D, Biological crystallography","url":"https://pubmed.ncbi.nlm.nih.gov/18560152","citation_count":44,"is_preprint":false},{"pmid":"3202117","id":"PMC_3202117","title":"Expression of HIV in lymph node cells of LAS patients. Immunohistology, in situ hybridization, and identification of target cells.","date":"1988","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/3202117","citation_count":41,"is_preprint":false},{"pmid":"2863990","id":"PMC_2863990","title":"Arbovirus investigations in Argentina, 1977-1980. III. Identification and characterization of viruses isolated, including new subtypes of western and Venezuelan equine encephalitis viruses and four new bunyaviruses (Las Maloyas, Resistencia, Barranqueras, and Antequera).","date":"1985","source":"The American journal of tropical medicine and hygiene","url":"https://pubmed.ncbi.nlm.nih.gov/2863990","citation_count":41,"is_preprint":false},{"pmid":"30371625","id":"PMC_30371625","title":"The Las Vegas mass shooting: An analysis of blood component administration and blood bank donations.","date":"2019","source":"The journal of trauma and acute care surgery","url":"https://pubmed.ncbi.nlm.nih.gov/30371625","citation_count":38,"is_preprint":false},{"pmid":"15292190","id":"PMC_15292190","title":"Peptidoglycan amidase MepA is a LAS metallopeptidase.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15292190","citation_count":35,"is_preprint":false},{"pmid":"36758698","id":"PMC_36758698","title":"Identification and genome sequencing of an influenza H3N2 variant in wastewater from elementary schools during a surge of influenza A cases in Las Vegas, Nevada.","date":"2023","source":"The Science of the total environment","url":"https://pubmed.ncbi.nlm.nih.gov/36758698","citation_count":34,"is_preprint":false},{"pmid":"11751385","id":"PMC_11751385","title":"LAS, a novel selective estrogen receptor modulator with chemopreventive and therapeutic activity in the N-nitroso-N-methylurea-induced rat mammary tumor model.","date":"2001","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/11751385","citation_count":33,"is_preprint":false},{"pmid":"18458070","id":"PMC_18458070","title":"LiaS regulates virulence factor expression in Streptococcus mutans.","date":"2008","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/18458070","citation_count":31,"is_preprint":false},{"pmid":"20189800","id":"PMC_20189800","title":"Anaerobic degradation of linear alkylbenzene sulfonate (LAS) in fluidized bed reactor by microbial consortia in different support materials.","date":"2010","source":"Bioresource technology","url":"https://pubmed.ncbi.nlm.nih.gov/20189800","citation_count":31,"is_preprint":false},{"pmid":"31533077","id":"PMC_31533077","title":"Musa acuminata and its bioactive metabolite 5-Hydroxymethylfurfural mitigates quorum sensing (las and rhl) mediated biofilm and virulence production of nosocomial pathogen Pseudomonas aeruginosa in vitro.","date":"2019","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/31533077","citation_count":30,"is_preprint":false},{"pmid":"15853813","id":"PMC_15853813","title":"Control analysis as a tool to understand the formation of the las operon in Lactococcus lactis.","date":"2005","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/15853813","citation_count":30,"is_preprint":false},{"pmid":"17030516","id":"PMC_17030516","title":"Expression of the las and rhl quorum-sensing systems in clinical isolates of Pseudomonas aeruginosa does not correlate with efflux pump expression or antimicrobial resistance.","date":"2006","source":"The Journal of antimicrobial chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/17030516","citation_count":29,"is_preprint":false},{"pmid":"28400017","id":"PMC_28400017","title":"Screening of the two-component-system histidine kinases of Listeria monocytogenes EGD-e. LiaS is needed for growth under heat, acid, alkali, osmotic, ethanol and oxidative stresses.","date":"2017","source":"Food microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/28400017","citation_count":27,"is_preprint":false},{"pmid":"3913634","id":"PMC_3913634","title":"Systemic lymphadenopathy (LAS) in intravenous drug abusers. Histology, immunohistochemistry and electron microscopy: pathogenic correlations.","date":"1985","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/3913634","citation_count":27,"is_preprint":false},{"pmid":"16878078","id":"PMC_16878078","title":"Effect of low-density lipoprotein apheresis on patients with peripheral arterial disease. Peripheral Arterial Disease LDL Apheresis Multicenter Study (P-LAS).","date":"2006","source":"International angiology : a journal of the International Union of Angiology","url":"https://pubmed.ncbi.nlm.nih.gov/16878078","citation_count":27,"is_preprint":false},{"pmid":"21415115","id":"PMC_21415115","title":"Function of the bacteriophytochrome BphP in the RpoS/Las quorum-sensing network of Pseudomonas aeruginosa.","date":"2011","source":"Microbiology (Reading, England)","url":"https://pubmed.ncbi.nlm.nih.gov/21415115","citation_count":26,"is_preprint":false},{"pmid":"29120612","id":"PMC_29120612","title":"Cell-Free and In Vivo Characterization of Lux, Las, and Rpa Quorum Activation Systems in E. coli.","date":"2017","source":"ACS synthetic biology","url":"https://pubmed.ncbi.nlm.nih.gov/29120612","citation_count":25,"is_preprint":false},{"pmid":"18331743","id":"PMC_18331743","title":"Effect of linear alkylbenzene sulfonate (LAS) and atrazine on marine microalgae.","date":"2008","source":"Marine pollution bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/18331743","citation_count":25,"is_preprint":false},{"pmid":"1974628","id":"PMC_1974628","title":"A multicenter clinical trial of oral ribavirin in HIV-infected patients with lymphadenopathy. 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standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2023,\n      \"finding\": \"FDX1 (ferredoxin 1) directly binds to LIAS (lipoyl synthase) and promotes LIAS's functional binding to the lipoyl carrier protein GCSH, thereby regulating cellular protein lipoylation; this regulation is not indirect through Fe-S cluster biosynthesis.\",\n      \"method\": \"Co-immunoprecipitation, metabolite profiling, transcriptional profiling, loss-of-function studies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding demonstrated, replicated across peer-reviewed and preprint versions, multiple orthogonal methods (Co-IP, metabolite profiling, transcriptional profiling), direct functional consequence established\",\n      \"pmids\": [\"37453661\", \"36778498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Human LIAS contains two [4Fe-4S] clusters (a reducing cluster and an auxiliary cluster); [2Fe-2S]-cluster-bound ISCU and ISCA2 are capable of reconstituting human LIAS enabling complete product turnover; EPR studies indicate the auxiliary [4Fe-4S] cluster is added before the reducing cluster during reconstitution.\",\n      \"method\": \"In vitro reconstitution, LC-MS activity assay, EPR spectroscopy, mutagenesis of cluster-binding sites\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with LC-MS assay, EPR with mutagenesis in a single rigorous study; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"33562493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Loss-of-function mutations in LIAS cause deficient lipoylation of mitochondrial proteins, reduced pyruvate dehydrogenase activity, and variant nonketotic hyperglycinemia; transfection with wild-type LIAS corrects the biochemical deficiency, establishing LIAS as required for mitochondrial protein lipoylation in human cells.\",\n      \"method\": \"Patient mutation identification, biochemical assays of mitochondrial protein lipoylation and enzyme activity, complementation by transfection of native LIAS\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function with defined biochemical phenotype, complementation rescue, replicated across multiple patients in multiple labs\",\n      \"pmids\": [\"24334290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PCSK9 directly interacts with LIAS as shown by protein docking and co-immunoprecipitation; this interaction promotes cardiomyocyte cuproptosis in myocardial ischemia-reperfusion injury, and blocking PCSK9 with evolocumab inhibits this interaction and reduces cuproptosis.\",\n      \"method\": \"Co-immunoprecipitation, protein docking, in vivo mouse I/R model with echocardiography and histopathology\",\n      \"journal\": \"Basic research in cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and docking for binding, in vivo phenotypic rescue; single lab, limited mechanistic dissection of the PCSK9-LIAS interaction\",\n      \"pmids\": [\"39930254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Iron overload during ischemia-reperfusion causes Fe(II) accumulation that downregulates [4Fe-4S] cluster assembly proteins, leading to [4Fe-4S] cluster loss from LIAS, impaired protein lipoylation, and cuproptosis in renal tubular cells; overexpression of [4Fe-4S] cluster assembly machinery or iron chelation rescues LIAS function.\",\n      \"method\": \"Loss-of-function/overexpression in cell and mouse models, biochemical assays of Fe-S cluster integrity, lipoylation assays, cuproptosis markers\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — defined mechanistic pathway with rescue experiments; single lab, no direct structural or in vitro reconstitution of cluster loss\",\n      \"pmids\": [\"40753758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Overexpression of Lias in mice (LiasHigh/High) increases endogenous antioxidant capacity, reduces oxidative stress, improves liver mitochondrial function, and attenuates NAFLD/NASH in a leptin-deficient obesity model, establishing that LIAS activity protects mitochondrial function in vivo.\",\n      \"method\": \"Transgenic mouse model (Lias overexpression crossed to Leprdb/db), histopathology, mitochondrial function assays, oxidative stress markers\",\n      \"journal\": \"The Journal of endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gain-of-function with multiple biological readouts; single lab\",\n      \"pmids\": [\"33263565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Novel compound heterozygous LIAS variants (p.Leu93Ter and p.Asp181Val) cause loss of LIAS function; the p.Asp181Val missense variant was validated by functional complementation in Saccharomyces cerevisiae lip5Δ (LIAS ortholog knockout), where expression of p.Asp181Val failed to rescue oxidative growth, similar to known pathogenic variants.\",\n      \"method\": \"Yeast complementation assay (lip5Δ), exome sequencing, functional growth assay\",\n      \"journal\": \"Molecular genetics and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — yeast complementation establishes loss of function for specific residue; single lab, single method\",\n      \"pmids\": [\"36680912\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LIAS (lipoyl synthase) is a radical SAM enzyme containing two [4Fe-4S] clusters (auxiliary and reducing) that catalyzes the final step of lipoic acid biosynthesis; in human cells, it requires direct binding by the electron donor FDX1 to promote its interaction with the lipoyl carrier protein GCSH, and its [4Fe-4S] clusters are donated by ISCA2 and ISCU; loss of LIAS function causes deficient lipoylation of key mitochondrial enzymes (including components of the pyruvate dehydrogenase and glycine cleavage complexes), resulting in impaired TCA cycle function, mitochondrial dysfunction, and diseases including variant nonketotic hyperglycinemia.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LIAS is a mitochondrial radical SAM enzyme that catalyzes the final step of lipoic acid biosynthesis and is required for lipoylation of key mitochondrial enzymes, with loss of function causing deficient protein lipoylation, reduced pyruvate dehydrogenase activity, and variant nonketotic hyperglycinemia rescuable by wild-type LIAS [#2]. The human enzyme harbors two [4Fe-4S] clusters — a reducing cluster and an auxiliary cluster — whose assembly can be reconstituted in vitro by [2Fe-2S]-bound ISCU and ISCA2, with the auxiliary cluster added before the reducing cluster [#1]. Beyond carrying its cofactors, LIAS function is gated by direct binding of ferredoxin FDX1, which promotes LIAS's productive engagement of the lipoyl carrier protein GCSH to drive cellular protein lipoylation independently of Fe-S cluster biosynthesis [#0]. The integrity of its [4Fe-4S] clusters renders LIAS sensitive to iron overload, which strips the clusters, impairs lipoylation, and triggers cuproptosis [#4], and LIAS activity protects mitochondrial function and antioxidant capacity in vivo [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Establishing whether LIAS is genuinely required for human mitochondrial protein lipoylation, this work linked loss-of-function mutations to a defined biochemical and clinical phenotype with rescue.\",\n      \"evidence\": \"Patient mutation identification, lipoylation and enzyme activity assays, complementation by transfection of native LIAS\",\n      \"pmids\": [\"24334290\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the enzymatic mechanism or cofactor requirements\", \"Spectrum of affected lipoylated enzymes only partially defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"To define the catalytic machinery, this work showed human LIAS uses two distinct [4Fe-4S] clusters and identified the Fe-S donors and assembly order needed for activity.\",\n      \"evidence\": \"In vitro reconstitution, LC-MS activity assay, EPR spectroscopy, and cluster-site mutagenesis\",\n      \"pmids\": [\"33562493\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of holo-LIAS\", \"In vivo relevance of the reconstitution order not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Addressing whether LIAS activity is protective at the organismal level, gain-of-function in mice showed enhanced antioxidant capacity and improved mitochondrial function in metabolic disease.\",\n      \"evidence\": \"Transgenic Lias-overexpression mice crossed to Leprdb/db, histopathology, mitochondrial and oxidative stress assays\",\n      \"pmids\": [\"33263565\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanism connecting lipoylation to antioxidant capacity not dissected\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"To explain how lipoylation is controlled beyond cofactor supply, this work showed FDX1 directly binds LIAS and promotes its functional engagement of GCSH, a regulatory role separable from Fe-S biosynthesis.\",\n      \"evidence\": \"Co-immunoprecipitation, metabolite and transcriptional profiling, loss-of-function studies\",\n      \"pmids\": [\"37453661\", \"36778498\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the FDX1-LIAS interface unresolved\", \"Stoichiometry and electron-transfer kinetics not quantified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extending LIAS into disease signaling, this work reported a direct PCSK9-LIAS interaction driving cardiomyocyte cuproptosis in ischemia-reperfusion injury.\",\n      \"evidence\": \"Co-immunoprecipitation, protein docking, in vivo mouse I/R model with echocardiography and histopathology\",\n      \"pmids\": [\"39930254\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP and docking without reciprocal structural validation\", \"Mechanistic basis of how the interaction promotes cuproptosis not dissected\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"To validate pathogenicity of specific human variants, yeast complementation confirmed that a missense LIAS variant abolishes function.\",\n      \"evidence\": \"Yeast lip5Δ complementation growth assay and exome sequencing\",\n      \"pmids\": [\"36680912\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single method, single ortholog system\", \"Residue-level mechanism of dysfunction not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connecting iron homeostasis to LIAS activity, this work showed iron overload strips LIAS [4Fe-4S] clusters to impair lipoylation and induce cuproptosis, reversible by restoring assembly machinery or chelating iron.\",\n      \"evidence\": \"Loss/gain-of-function in cell and mouse I/R models, Fe-S integrity, lipoylation, and cuproptosis assays\",\n      \"pmids\": [\"40753758\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct in vitro reconstitution of cluster loss\", \"Single lab, no structural confirmation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How FDX1-LIAS-GCSH assembly, cofactor delivery, and iron-sensitive cluster loss are integrated structurally and kinetically remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structure of the LIAS-FDX1-GCSH assembly\", \"Quantitative coupling between cluster integrity and lipoylation output not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [2, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"FDX1\", \"GCSH\", \"ISCU\", \"ISCA2\", \"PCSK9\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":4,"faith_total":4,"faith_pct":100.0}}