{"gene":"NAA50","run_date":"2026-04-29T11:37:56","timeline":{"discoveries":[{"year":2003,"finding":"Drosophila San (ortholog of NAA50) is required for establishing centromeric sister chromatid cohesion during mitosis; san mutations cause failure of cohesin subunit Scc1 to accumulate at centromeres, activation of the spindle checkpoint, and anaphase segregation errors. San protein is itself acetylated and associates with the Nat1 and Ard1 subunits of the NatA acetyltransferase complex.","method":"Genetic mutant analysis in Drosophila, immunofluorescence, co-immunoprecipitation","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP and clean loss-of-function with defined cellular phenotype, replicated across multiple alleles","pmids":["14653991"],"is_preprint":false},{"year":2009,"finding":"Human NAA50 (hNaa50p) possesses both Nα-terminal acetyltransferase (NAT) and Nε-lysine acetyltransferase (KAT) activities in vitro. Its preferred NAT substrates have N-terminal Met-Leu-X-Pro sequences. hNaa50p autoacetylates lysines 34, 37, and 140 in vitro, and this autoacetylation modulates substrate specificity. Histone H4 was identified as a KAT substrate in vitro.","method":"In vitro acetyltransferase assay with purified recombinant hNaa50p and oligopeptide substrate library; mass spectrometry identification of autoacetylation sites","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with multiple substrates and site identification","pmids":["19744929"],"is_preprint":false},{"year":2011,"finding":"X-ray crystal structure of human Naa50p in ternary complex with a native substrate peptide and CoA revealed that the substrate backbone is anchored via backbone hydrogen bonds, the first methionine is specified through van der Waals contacts creating an α-amino methionine-specific pocket, and conserved histidine and tyrosine residues play catalytic roles. Structure-based mutagenesis confirmed importance of these residues. The GNAT fold differs from lysine acetyltransferases in the substrate-binding groove, explaining NAT vs KAT selectivity.","method":"X-ray crystallography, structure-based mutagenesis, in vitro acetyltransferase assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with mutagenesis validation in single rigorous study","pmids":["21900231"],"is_preprint":false},{"year":2015,"finding":"In vivo N-terminal acetylome profiling in yeast revealed that human NAA50 (hNaa50) primarily Nt-acetylates Met-starting N-termini (iMet-Lys, iMet-Val, iMet-Ala, iMet-Tyr, iMet-Phe, iMet-Leu, iMet-Ser, iMet-Thr), similar to hNaa60/NatF. A kinetic competition between Naa50 and methionine aminopeptidases (MetAPs) was demonstrated: Naa50-mediated Nt-acetylation of iMet followed by a small residue blocks subsequent MetAP cleavage, confirmed by in vitro data.","method":"Quantitative N-terminal acetylome profiling (SILAC-based proteomics) in yeast strains with/without Naa50; in vitro MetAP competition assay","journal":"Proteomics","confidence":"High","confidence_rationale":"Tier 1-2 — quantitative in vivo acetylomics with orthogonal in vitro validation","pmids":["25886145"],"is_preprint":false},{"year":2016,"finding":"Drosophila Naa50/San is required for proper interaction between cohesin subunits Scc1 and Smc3 during tissue proliferation. Biochemical and genetic evidence suggests that Naa50/San co-translationally N-terminally acetylates nascent Scc1, and this modification is required for establishment and/or maintenance of sister chromatid cohesion.","method":"Genetic analysis in Drosophila, co-immunoprecipitation of cohesin subunits, biochemical assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP and genetic approach, single lab, moderate mechanistic follow-up","pmids":["27996020"],"is_preprint":false},{"year":2016,"finding":"Depletion of NAA50 in HeLa cells weakens the interaction between cohesin and its positive regulator sororin, causing cohesion defects in S phase. Co-depletion of NatA rescues the sister-chromatid cohesion defects and mitotic arrest caused by NAA50 depletion, demonstrating antagonistic roles of NatA and NAA50 in cohesion. Purified NatA and NAA50 do not affect each other's NAT activity in vitro, suggesting they act on distinct substrates.","method":"siRNA knockdown in HeLa cells, co-immunoprecipitation, in vitro NAT activity assay with purified proteins, chromosome spread analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — clean KD with defined cellular phenotype, epistasis rescue experiment, and in vitro activity assay","pmids":["27422821"],"is_preprint":false},{"year":2016,"finding":"Crystal structure of human Naa50 with co-purified CoA and acetylated tetrapeptide (AcMMXX) confirmed Met-Met at positions 1-2 as the best substrate. Biochemical studies with a tetrapeptide library showed Naa50 acetylates all MXAA peptides except MPAA.","method":"X-ray crystallography, in vitro acetyltransferase assay with tetrapeptide library, thermal stability assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with systematic substrate biochemistry","pmids":["27484799"],"is_preprint":false},{"year":2019,"finding":"X-ray crystal structure of yeast NatA/Naa50 ternary complex revealed that Naa50 makes evolutionarily conserved contacts to both Naa10 and Naa15 subunits of NatA. These interactions promote catalytic crosstalk within the human complex (but less so in yeast where Naa50 activity is compromised). Yeast Naa50 is catalytically less active than human Naa50 due to structural differences.","method":"X-ray crystallography of yeast NatA/Naa50 complex, in vitro NAT activity assays comparing yeast and human complexes","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional validation across species","pmids":["31155310"],"is_preprint":false},{"year":2020,"finding":"Two novel small-molecule inhibitors of Naa50 were identified and characterized; co-crystal structures with Naa50 revealed their binding modes and mechanism of action. Cellular target engagement experiments confirmed binding selectivity of compound 4a for Naa50 over related enzymes Naa10 and Naa60.","method":"DNA-encoded library screening, X-ray co-crystallography, biochemical inhibition assays, cellular target engagement assay","journal":"ACS medicinal chemistry letters","confidence":"High","confidence_rationale":"Tier 1 — co-crystal structures with biophysical/biochemical validation and cellular confirmation","pmids":["32550998"],"is_preprint":false},{"year":2021,"finding":"High-resolution X-ray crystal structures of Arabidopsis NAA50 (AtNaa50) in complex with AcCoA and a bisubstrate analog defined substrate specificity determinants and functionally important residues. Differences between Arabidopsis and yeast Naa50 were highlighted; yeast Naa50 binds CoA conjugates but is catalytically inactive, whereas AtNaa50 is enzymatically active.","method":"X-ray crystallography, enzymatic kinetics, site-directed mutagenesis","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 — high-resolution crystal structures with mutagenesis and kinetic characterization","pmids":["33400917"],"is_preprint":false}],"current_model":"NAA50 (also called Nat5/San/NatE catalytic subunit) is a ribosome-associated N-terminal acetyltransferase that co-translationally acetylates the α-amino group of Met-starting protein N-termini (preferring Met-Leu-X-Pro and Met-Met sequences) and also autoacetylates internal lysines; it physically associates with the NatA complex (Naa10/Naa15) via conserved contacts to both subunits, promoting catalytic crosstalk; in metazoans it is required for sister-chromatid cohesion by N-terminally acetylating nascent cohesin subunit Scc1 and by supporting the cohesin-sororin interaction, while NatA plays an opposing (antagonistic) role in cohesion; competition between Naa50-mediated Nt-acetylation and methionine aminopeptidases determines whether the initiator methionine is retained on substrates with small penultimate residues."},"narrative":{"teleology":[{"year":2003,"claim":"Establishing that Naa50/San has a cellular function beyond generic acetyltransferase activity, Drosophila genetics revealed it is required for centromeric sister-chromatid cohesion and cohesin subunit Scc1 accumulation, and that it physically associates with the NatA complex.","evidence":"Genetic mutant analysis of san alleles in Drosophila with immunofluorescence and co-immunoprecipitation","pmids":["14653991"],"confidence":"High","gaps":["Whether San/Naa50 acts on cohesion through its acetyltransferase activity or a non-catalytic mechanism was unresolved","Direct substrates relevant to cohesion were not identified","The nature of the NatA–Naa50 association (stoichiometry, structural basis) was unknown"]},{"year":2009,"claim":"Biochemical reconstitution established that human NAA50 possesses dual Nα-terminal and Nε-lysine acetyltransferase activities, defined its preferred NAT substrate motif (Met-Leu-X-Pro), and showed that autoacetylation at specific lysines modulates substrate specificity.","evidence":"In vitro acetyltransferase assays with purified recombinant hNaa50p, oligopeptide substrate library, and mass spectrometry","pmids":["19744929"],"confidence":"High","gaps":["In vivo relevance of KAT activity (e.g., histone H4 acetylation) was not demonstrated","Whether autoacetylation occurs in cells and is physiologically regulatory was untested","Link between enzymatic activity and cohesion phenotype remained indirect"]},{"year":2011,"claim":"The first crystal structure of human Naa50 in a ternary complex with substrate peptide and CoA revealed the molecular basis of α-amino methionine specificity, identified catalytic residues (His and Tyr), and explained structural divergence from lysine acetyltransferases.","evidence":"X-ray crystallography with structure-based mutagenesis and in vitro activity assays","pmids":["21900231"],"confidence":"High","gaps":["How Naa50 engages the ribosome and NatA complex structurally was unknown","Substrate specificity beyond the first residue was incompletely mapped"]},{"year":2015,"claim":"In vivo acetylome profiling revealed the full breadth of Naa50 substrates (various iMet-Xaa N-termini) and demonstrated a kinetic competition with methionine aminopeptidases that determines initiator methionine retention.","evidence":"SILAC-based quantitative N-terminal acetylome profiling in yeast expressing human Naa50; in vitro MetAP competition assay","pmids":["25886145"],"confidence":"High","gaps":["Whether the MetAP–Naa50 competition is regulated in vivo under different conditions was not addressed","Identification of specific endogenous substrates critical for cohesion was still missing"]},{"year":2016,"claim":"Three convergent studies resolved the substrate specificity, cohesion mechanism, and NatA antagonism: crystal structures confirmed Met-Met as an optimal substrate; Drosophila genetics showed Naa50 co-translationally Nt-acetylates Scc1 to promote Scc1–Smc3 interaction; and human cell depletion experiments demonstrated that NAA50 supports the cohesin–sororin interaction and that NatA acts antagonistically to NAA50 in cohesion, with co-depletion rescuing cohesion defects.","evidence":"X-ray crystallography with tetrapeptide library (PMID:27484799); Drosophila genetics and co-IP (PMID:27996020); siRNA knockdown, epistasis rescue, chromosome spreads, and in vitro NAT assays in HeLa cells (PMID:27422821)","pmids":["27484799","27996020","27422821"],"confidence":"High","gaps":["The molecular basis of NatA–NAA50 antagonism (distinct substrate targets) was not fully elucidated","Whether sororin itself is a direct Nt-acetylation substrate of NAA50 was not tested","How cohesion acetylation by NAA50 coordinates with Eco1/ESCO acetyltransferase-mediated cohesion establishment was unclear"]},{"year":2019,"claim":"The crystal structure of the yeast NatA/Naa50 ternary complex defined the conserved binding interface between Naa50 and both NatA subunits and showed that physical association promotes catalytic crosstalk in the human but not yeast enzyme.","evidence":"X-ray crystallography of yeast NatA/Naa50 complex with in vitro NAT activity comparisons across species","pmids":["31155310"],"confidence":"High","gaps":["A structure of the human NatA–Naa50 complex was not yet available","How ribosome association modulates NatE activity and crosstalk was not addressed","Structural basis for species-specific differences in Naa50 catalytic competence was only partially explained"]},{"year":2020,"claim":"Identification and co-crystallization of selective small-molecule Naa50 inhibitors provided chemical tools and confirmed the druggability of the active site.","evidence":"DNA-encoded library screening, co-crystal structures, biochemical inhibition assays, and cellular target engagement","pmids":["32550998"],"confidence":"High","gaps":["Cellular phenotypic consequences of chemical Naa50 inhibition (e.g., cohesion defects) were not reported","In vivo pharmacology and selectivity across the full NAT family were not characterized"]},{"year":2021,"claim":"Structural and kinetic comparison of Arabidopsis Naa50 with yeast Naa50 pinpointed determinants of catalytic competence versus inactivity, clarifying evolutionary variation in NatE function.","evidence":"X-ray crystallography of AtNaa50 with AcCoA and bisubstrate analog; enzymatic kinetics and site-directed mutagenesis","pmids":["33400917"],"confidence":"High","gaps":["Plant-specific substrates and physiological roles of AtNaa50 were not defined","Structural basis for the gain of catalytic activity in metazoan vs. fungal Naa50 remains incompletely resolved"]},{"year":null,"claim":"Key open questions include the structural basis of ribosome-associated NatE complex activity in humans, the identity of NatA substrates that antagonize NAA50-dependent cohesion, and whether NAA50's KAT activity is physiologically relevant.","evidence":"","pmids":[],"confidence":"Low","gaps":["No cryo-EM or crystal structure of ribosome-bound NatE exists","The specific NatA substrate(s) whose Nt-acetylation opposes cohesion have not been identified","In vivo relevance of NAA50 KAT and autoacetylation activities remains untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[1,2,3,6]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,3]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,3,6]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,4,5]}],"complexes":["NatE (Naa50/NatA)"],"partners":["NAA10","NAA15","SCC1","SMC3","CDCA5"],"other_free_text":[]},"mechanistic_narrative":"NAA50 is a ribosome-associated N-terminal acetyltransferase (NatE catalytic subunit) that co-translationally acetylates the α-amino group of initiator methionine-retaining protein N-termini, with preference for Met-Leu, Met-Met, and other Met-Xaa sequences, and competes kinetically with methionine aminopeptidases to determine initiator methionine retention [PMID:25886145, PMID:27484799]. Its GNAT-fold active site contains a methionine-specific pocket anchored by conserved histidine and tyrosine catalytic residues, and it physically associates with both subunits of the NatA complex (Naa10/Naa15) through evolutionarily conserved contacts that promote catalytic crosstalk [PMID:21900231, PMID:31155310]. In addition to possessing Nα-acetyltransferase activity, NAA50 exhibits Nε-lysine acetyltransferase and autoacetylation activities that modulate its substrate specificity in vitro [PMID:19744929]. In metazoans, NAA50 is essential for sister-chromatid cohesion: it N-terminally acetylates the cohesin subunit Scc1, supports the cohesin–sororin interaction, and functions antagonistically to NatA in cohesion regulation [PMID:14653991, PMID:27422821, PMID:27996020]."},"prefetch_data":{"uniprot":{"accession":"Q9GZZ1","full_name":"N-alpha-acetyltransferase 50","aliases":["N-acetyltransferase 13","N-acetyltransferase 5","hNAT5","N-acetyltransferase san homolog","hSAN","N-epsilon-acetyltransferase 50","NatE catalytic subunit"],"length_aa":169,"mass_kda":19.4,"function":"N-alpha-acetyltransferase that acetylates the N-terminus of proteins that retain their initiating methionine (PubMed:19744929, PubMed:21900231, PubMed:22311970, PubMed:27484799). Has a broad substrate specificity: able to acetylate the initiator methionine of most peptides, except for those with a proline in second position (PubMed:27484799). Also displays N-epsilon-acetyltransferase activity by mediating acetylation of the side chain of specific lysines on proteins (PubMed:19744929). Autoacetylates in vivo (PubMed:19744929). The relevance of N-epsilon-acetyltransferase activity is however unclear: able to acetylate H4 in vitro, but this result has not been confirmed in vivo (PubMed:19744929). Component of N-alpha-acetyltransferase complexes containing NAA10 and NAA15, which has N-alpha-acetyltransferase activity (PubMed:16507339, PubMed:27484799, PubMed:29754825, PubMed:32042062). Does not influence the acetyltransferase activity of NAA10 (PubMed:16507339, PubMed:27484799). However, it negatively regulates the N-alpha-acetyltransferase activity of the N-terminal acetyltransferase A complex (also called the NatA complex) (PubMed:32042062). The multiprotein complexes probably constitute the major contributor for N-terminal acetylation at the ribosome exit tunnel, with NAA10 acetylating all amino termini that are devoid of methionine and NAA50 acetylating other peptides (PubMed:16507339, PubMed:27484799). Required for sister chromatid cohesion during mitosis by promoting binding of CDCA5/sororin to cohesin: may act by counteracting the function of NAA10 (PubMed:17502424, PubMed:27422821)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9GZZ1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/NAA50","classification":"Common Essential","n_dependent_lines":1204,"n_total_lines":1208,"dependency_fraction":0.9966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NAA50","total_profiled":1310},"omim":[{"mim_id":"610834","title":"N-ALPHA-ACETYLTRANSFERASE 50, NatE CATALYTIC SUBUNIT; NAA50","url":"https://www.omim.org/entry/610834"},{"mim_id":"300013","title":"N-ALPHA-ACETYLTRANSFERASE 10, NatA CATALYTIC SUBUNIT; NAA10","url":"https://www.omim.org/entry/300013"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoli","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":259.1}],"url":"https://www.proteinatlas.org/search/NAA50"},"hgnc":{"alias_symbol":["FLJ13194","NAT5","San"],"prev_symbol":["MAK3","NAT13"]},"alphafold":{"accession":"Q9GZZ1","domains":[{"cath_id":"3.40.630.30","chopping":"5-152","consensus_level":"medium","plddt":97.6794,"start":5,"end":152}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9GZZ1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9GZZ1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9GZZ1-F1-predicted_aligned_error_v6.png","plddt_mean":92.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NAA50","jax_strain_url":"https://www.jax.org/strain/search?query=NAA50"},"sequence":{"accession":"Q9GZZ1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9GZZ1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9GZZ1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9GZZ1"}},"corpus_meta":[{"pmid":"9203442","id":"PMC_9203442","title":"The homeostasis model in the San Antonio Heart Study.","date":"1997","source":"Diabetes care","url":"https://pubmed.ncbi.nlm.nih.gov/9203442","citation_count":675,"is_preprint":false},{"pmid":"9121505","id":"PMC_9121505","title":"Myoblast implantation in Duchenne muscular dystrophy: the San Francisco study.","date":"1997","source":"Muscle & nerve","url":"https://pubmed.ncbi.nlm.nih.gov/9121505","citation_count":141,"is_preprint":false},{"pmid":"14653991","id":"PMC_14653991","title":"Two putative acetyltransferases, san and deco, are required for establishing sister chromatid cohesion in Drosophila.","date":"2003","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/14653991","citation_count":122,"is_preprint":false},{"pmid":"28242651","id":"PMC_28242651","title":"Metformin Suppresses Systemic Autoimmunity in Roquin Mice through Inhibiting B Cell Differentiation into Plasma Cells via Regulation of AMPK/mTOR/STAT3.","date":"2017","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/28242651","citation_count":112,"is_preprint":false},{"pmid":"19744929","id":"PMC_19744929","title":"Human Naa50p (Nat5/San) displays both protein N alpha- and N epsilon-acetyltransferase activity.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19744929","citation_count":91,"is_preprint":false},{"pmid":"21900231","id":"PMC_21900231","title":"Structure of a ternary Naa50p (NAT5/SAN) N-terminal acetyltransferase complex reveals the molecular basis for substrate-specific acetylation.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21900231","citation_count":84,"is_preprint":false},{"pmid":"10777075","id":"PMC_10777075","title":"Transmission of tuberculosis in San Francisco and its association with immigration and ethnicity.","date":"2000","source":"The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease","url":"https://pubmed.ncbi.nlm.nih.gov/10777075","citation_count":77,"is_preprint":false},{"pmid":"1339437","id":"PMC_1339437","title":"Localized mutagenesis and evidence for post-transcriptional regulation of MAK3. A putative N-acetyltransferase required for double-stranded RNA virus propagation in Saccharomyces cerevisiae.","date":"1992","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/1339437","citation_count":71,"is_preprint":false},{"pmid":"17451673","id":"PMC_17451673","title":"Polychlorinated biphenyls (PCBs) in San Francisco Bay.","date":"2007","source":"Environmental research","url":"https://pubmed.ncbi.nlm.nih.gov/17451673","citation_count":68,"is_preprint":false},{"pmid":"8491733","id":"PMC_8491733","title":"Yeast MAK3 N-acetyltransferase recognizes the N-terminal four amino acids of the major coat protein (gag) of the L-A double-stranded RNA virus.","date":"1993","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/8491733","citation_count":58,"is_preprint":false},{"pmid":"27493835","id":"PMC_27493835","title":"Danggui-Shaoyao-San: New Hope for Alzheimer's Disease.","date":"2015","source":"Aging and disease","url":"https://pubmed.ncbi.nlm.nih.gov/27493835","citation_count":57,"is_preprint":false},{"pmid":"17533844","id":"PMC_17533844","title":"Quantifying PM2.5 source contributions for the San Joaquin Valley with multivariate receptor models.","date":"2007","source":"Environmental science & technology","url":"https://pubmed.ncbi.nlm.nih.gov/17533844","citation_count":56,"is_preprint":false},{"pmid":"25886145","id":"PMC_25886145","title":"N-terminal acetylome analysis reveals the specificity of Naa50 (Nat5) and suggests a kinetic competition between N-terminal acetyltransferases and methionine aminopeptidases.","date":"2015","source":"Proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/25886145","citation_count":53,"is_preprint":false},{"pmid":"32697301","id":"PMC_32697301","title":"Khoe-San Genomes Reveal Unique Variation and Confirm the Deepest Population Divergence in Homo sapiens.","date":"2020","source":"Molecular biology and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/32697301","citation_count":52,"is_preprint":false},{"pmid":"38554577","id":"PMC_38554577","title":"Mechanism of Nicotiflorin in San-Ye-Qing rhizome for anti-inflammatory effect in ulcerative colitis.","date":"2024","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38554577","citation_count":47,"is_preprint":false},{"pmid":"30914691","id":"PMC_30914691","title":"Inhibition of IL-17 ameliorates systemic lupus erythematosus in Roquinsan/san mice through regulating the balance of TFH cells, GC B cells, Treg and Breg.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30914691","citation_count":47,"is_preprint":false},{"pmid":"31155310","id":"PMC_31155310","title":"Structure and Mechanism of Acetylation by the N-Terminal Dual Enzyme NatA/Naa50 Complex.","date":"2019","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/31155310","citation_count":44,"is_preprint":false},{"pmid":"16346539","id":"PMC_16346539","title":"Denitrification in san francisco bay intertidal sediments.","date":"1984","source":"Applied and environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/16346539","citation_count":43,"is_preprint":false},{"pmid":"29217494","id":"PMC_29217494","title":"Regulation of the kynurenine metabolism pathway by Xiaoyao San and the underlying effect in the hippocampus of the depressed rat.","date":"2017","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/29217494","citation_count":40,"is_preprint":false},{"pmid":"29863014","id":"PMC_29863014","title":"Chaihu-Shugan-San exerts an antidepressive effect by downregulating miR-124 and releasing inhibition of the MAPK14 and Gria3 signaling pathways.","date":"2018","source":"Neural regeneration research","url":"https://pubmed.ncbi.nlm.nih.gov/29863014","citation_count":39,"is_preprint":false},{"pmid":"15588656","id":"PMC_15588656","title":"San-Huang-Xie-Xin-Tang reduces lipopolysaccharides-induced hypotension and inflammatory mediators.","date":"2005","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/15588656","citation_count":37,"is_preprint":false},{"pmid":"24015243","id":"PMC_24015243","title":"Chaihu-Shugan-San administration ameliorates perimenopausal anxiety and depression in rats.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24015243","citation_count":36,"is_preprint":false},{"pmid":"16516452","id":"PMC_16516452","title":"Antidepressant-like activity of a Kampo (Japanese herbal) medicine, Koso-san (Xiang-Su-San), and its mode of action via the hypothalamic-pituitary-adrenal axis.","date":"2006","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/16516452","citation_count":36,"is_preprint":false},{"pmid":"30688265","id":"PMC_30688265","title":"Kai Xin San ameliorates scopolamine-induced cognitive dysfunction.","date":"2019","source":"Neural regeneration research","url":"https://pubmed.ncbi.nlm.nih.gov/30688265","citation_count":35,"is_preprint":false},{"pmid":"24486208","id":"PMC_24486208","title":"The effect of Chaihu-Shugan-San and its components on the expression of ERK5 in the hippocampus of depressed rats.","date":"2014","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/24486208","citation_count":35,"is_preprint":false},{"pmid":"32317964","id":"PMC_32317964","title":"Systems Pharmacology Approach to Investigate the Mechanism of Kai-Xin-San in Alzheimer's Disease.","date":"2020","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/32317964","citation_count":34,"is_preprint":false},{"pmid":"37098372","id":"PMC_37098372","title":"Simiao San alleviates hyperuricemia and kidney inflammation by inhibiting NLRP3 inflammasome and JAK2/STAT3 signaling in hyperuricemia mice.","date":"2023","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37098372","citation_count":33,"is_preprint":false},{"pmid":"32754030","id":"PMC_32754030","title":"Antidepressant and Anti-Neuroinflammatory Effects of Bangpungtongsung-San.","date":"2020","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/32754030","citation_count":33,"is_preprint":false},{"pmid":"36460296","id":"PMC_36460296","title":"Sini San ameliorates CCl4-induced liver fibrosis in mice by inhibiting AKT-mediated hepatocyte apoptosis.","date":"2022","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/36460296","citation_count":32,"is_preprint":false},{"pmid":"33611210","id":"PMC_33611210","title":"Si-Ni-San ameliorates chronic colitis by modulating type I interferons-mediated inflammation.","date":"2021","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/33611210","citation_count":32,"is_preprint":false},{"pmid":"22307400","id":"PMC_22307400","title":"The role of Shox2 in SAN development and function.","date":"2012","source":"Pediatric cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/22307400","citation_count":31,"is_preprint":false},{"pmid":"35303280","id":"PMC_35303280","title":"Kai-Xin-San Inhibits Tau Pathology and Neuronal Apoptosis in Aged SAMP8 Mice.","date":"2022","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/35303280","citation_count":30,"is_preprint":false},{"pmid":"32461302","id":"PMC_32461302","title":"NAA50 Is an Enzymatically Active N α-Acetyltransferase That Is Crucial for Development and Regulation of Stress Responses.","date":"2020","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/32461302","citation_count":28,"is_preprint":false},{"pmid":"37237988","id":"PMC_37237988","title":"Pingwei San Ameliorates Spleen Deficiency-Induced Diarrhea through Intestinal Barrier Protection and Gut Microbiota Modulation.","date":"2023","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/37237988","citation_count":27,"is_preprint":false},{"pmid":"32550998","id":"PMC_32550998","title":"Characterization of Specific N-α-Acetyltransferase 50 (Naa50) Inhibitors Identified Using a DNA Encoded Library.","date":"2020","source":"ACS medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/32550998","citation_count":26,"is_preprint":false},{"pmid":"37984123","id":"PMC_37984123","title":"Si-Ni-San inhibits hepatic Fasn expression and lipid accumulation in MAFLD mice through AMPK/p300/SREBP-1c axis.","date":"2023","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37984123","citation_count":25,"is_preprint":false},{"pmid":"29800369","id":"PMC_29800369","title":"Hepatitis D Viremia Among Injection Drug Users in San Francisco.","date":"2018","source":"The Journal of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/29800369","citation_count":25,"is_preprint":false},{"pmid":"36182566","id":"PMC_36182566","title":"The Heart's Pacemaker Mimics Brain Cytoarchitecture and Function: Novel Interstitial Cells Expose Complexity of the SAN.","date":"2022","source":"JACC. Clinical electrophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/36182566","citation_count":25,"is_preprint":false},{"pmid":"23725832","id":"PMC_23725832","title":"Wuling san ameliorates urate under-excretion and renal dysfunction in hyperuricemic mice.","date":"2013","source":"Chinese journal of natural medicines","url":"https://pubmed.ncbi.nlm.nih.gov/23725832","citation_count":23,"is_preprint":false},{"pmid":"27882154","id":"PMC_27882154","title":"Kai-Xin-San, a traditional Chinese medicine formulation, exerts antidepressive and neuroprotective effects by promoting pCREB upstream pathways.","date":"2016","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27882154","citation_count":22,"is_preprint":false},{"pmid":"39047412","id":"PMC_39047412","title":"Efficacy and mechanism of the Ermiao San series of formulas for rheumatoid arthritis based on Chinmedomics strategy.","date":"2024","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39047412","citation_count":21,"is_preprint":false},{"pmid":"16552840","id":"PMC_16552840","title":"Sheng-mai-san reduces adriamycin-induced cardiomyopathy in rats.","date":"2006","source":"The American journal of Chinese medicine","url":"https://pubmed.ncbi.nlm.nih.gov/16552840","citation_count":21,"is_preprint":false},{"pmid":"38723920","id":"PMC_38723920","title":"Danggui-Shaoyao San alleviates cognitive impairment via enhancing HIF-1α/EPO axis in vascular dementia rats.","date":"2024","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38723920","citation_count":20,"is_preprint":false},{"pmid":"36334816","id":"PMC_36334816","title":"Si-Ni-SAN ameliorates obesity through AKT/AMPK/HSL pathway-mediated lipolysis: Network pharmacology and experimental validation.","date":"2022","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/36334816","citation_count":20,"is_preprint":false},{"pmid":"29857298","id":"PMC_29857298","title":"Dangguishaoyao-San attenuates LPS-induced neuroinflammation via the TLRs/NF-κB signaling pathway.","date":"2018","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/29857298","citation_count":20,"is_preprint":false},{"pmid":"16873089","id":"PMC_16873089","title":"Immunomodulatory effects of lingzhi and san-miao-san supplementation on patients with rheumatoid arthritis.","date":"2006","source":"Immunopharmacology and immunotoxicology","url":"https://pubmed.ncbi.nlm.nih.gov/16873089","citation_count":20,"is_preprint":false},{"pmid":"26446078","id":"PMC_26446078","title":"The Chinese medicine Sini-San inhibits HBx-induced migration and invasiveness of human hepatocellular carcinoma cells.","date":"2015","source":"BMC complementary and alternative medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26446078","citation_count":20,"is_preprint":false},{"pmid":"27134645","id":"PMC_27134645","title":"Anti-inflammatory activities of Ganoderma lucidum (Lingzhi) and San-Miao-San supplements in MRL/lpr mice for the treatment of systemic lupus erythematosus.","date":"2016","source":"Chinese medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27134645","citation_count":20,"is_preprint":false},{"pmid":"32457093","id":"PMC_32457093","title":"Loss of the Acetyltransferase NAA50 Induces Endoplasmic Reticulum Stress and Immune Responses and Suppresses Growth.","date":"2020","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/32457093","citation_count":19,"is_preprint":false},{"pmid":"27163672","id":"PMC_27163672","title":"Neuroprotective effects of Danggui-Jakyak-San on rat stroke model through antioxidant/antiapoptotic pathway.","date":"2016","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/27163672","citation_count":19,"is_preprint":false},{"pmid":"36708884","id":"PMC_36708884","title":"Exploring the effect of Er miao San-containing serum on macrophage polarization through miR-33/NLRP3 pathway.","date":"2023","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/36708884","citation_count":19,"is_preprint":false},{"pmid":"36918872","id":"PMC_36918872","title":"Kai-Xin-San protects against mitochondrial dysfunction in Alzheimer's disease through SIRT3/NLRP3 pathway.","date":"2023","source":"Chinese medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36918872","citation_count":19,"is_preprint":false},{"pmid":"24548308","id":"PMC_24548308","title":"Patchwork sequencing of tomato San Marzano and Vesuviano varieties highlights genome-wide variations.","date":"2014","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/24548308","citation_count":19,"is_preprint":false},{"pmid":"32387236","id":"PMC_32387236","title":"Huai hua san alleviates dextran sulphate sodium-induced colitis and modulates colonic microbiota.","date":"2020","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/32387236","citation_count":19,"is_preprint":false},{"pmid":"32544241","id":"PMC_32544241","title":"The N-Terminal Acetyltransferase Naa50 Regulates Arabidopsis Growth and Osmotic Stress Response.","date":"2020","source":"Plant & cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/32544241","citation_count":18,"is_preprint":false},{"pmid":"29808808","id":"PMC_29808808","title":"The regulatory effect of Xiaoyao San on glucocorticoid receptors under the condition of chronic stress.","date":"2018","source":"Cellular and molecular biology (Noisy-le-Grand, France)","url":"https://pubmed.ncbi.nlm.nih.gov/29808808","citation_count":18,"is_preprint":false},{"pmid":"33062007","id":"PMC_33062007","title":"Potential Molecular Mechanisms of Chaihu-Shugan-San in Treatment of Breast Cancer Based on Network Pharmacology.","date":"2020","source":"Evidence-based complementary and alternative medicine : eCAM","url":"https://pubmed.ncbi.nlm.nih.gov/33062007","citation_count":18,"is_preprint":false},{"pmid":"31597939","id":"PMC_31597939","title":"Universal HIV and Birth Cohort HCV Screening in San Diego Emergency Departments.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31597939","citation_count":18,"is_preprint":false},{"pmid":"36586523","id":"PMC_36586523","title":"Si-Ni-San improves experimental colitis by favoring Akkermensia colonization.","date":"2022","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/36586523","citation_count":17,"is_preprint":false},{"pmid":"24444307","id":"PMC_24444307","title":"Soyo-san reduces depressive-like behavior and proinflammatory cytokines in ovariectomized female rats.","date":"2014","source":"BMC complementary and alternative medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24444307","citation_count":17,"is_preprint":false},{"pmid":"36400919","id":"PMC_36400919","title":"Genomic ancestry, diet and microbiomes of Upper Palaeolithic hunter-gatherers from San Teodoro cave.","date":"2022","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/36400919","citation_count":17,"is_preprint":false},{"pmid":"38232540","id":"PMC_38232540","title":"Xie-Bai-San increases NSCLC cells sensitivity to gefitinib by inhibiting Beclin-1 mediated autophagosome formation.","date":"2024","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38232540","citation_count":16,"is_preprint":false},{"pmid":"33400917","id":"PMC_33400917","title":"Structural and functional characterization of the N-terminal acetyltransferase Naa50.","date":"2021","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/33400917","citation_count":15,"is_preprint":false},{"pmid":"37150422","id":"PMC_37150422","title":"Effects of Danggui-Shaoyao-San on central neuroendocrine and pharmacokinetics in female ovariectomized rats.","date":"2023","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37150422","citation_count":15,"is_preprint":false},{"pmid":"36603786","id":"PMC_36603786","title":"The San-Qi-Xue-Shang-Ning formula protects against ulcerative colitis by restoring the homeostasis of gut immunity and microbiota.","date":"2023","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/36603786","citation_count":15,"is_preprint":false},{"pmid":"37073462","id":"PMC_37073462","title":"Kai-Xin-San Improves Cognitive Impairment via Wnt/β-Catenin and IRE1/XBP1s Signalings in APP/PS1 Mice.","date":"2023","source":"Rejuvenation research","url":"https://pubmed.ncbi.nlm.nih.gov/37073462","citation_count":14,"is_preprint":false},{"pmid":"27996020","id":"PMC_27996020","title":"Naa50/San-dependent N-terminal acetylation of Scc1 is potentially important for sister chromatid cohesion.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27996020","citation_count":14,"is_preprint":false},{"pmid":"35076275","id":"PMC_35076275","title":"Genome-Resolved Metagenomic Insights into Massive Seasonal Ammonia-Oxidizing Archaea Blooms in San Francisco Bay.","date":"2022","source":"mSystems","url":"https://pubmed.ncbi.nlm.nih.gov/35076275","citation_count":14,"is_preprint":false},{"pmid":"39179058","id":"PMC_39179058","title":"Si-Ni-San alleviates intestinal and liver damage in ulcerative colitis mice by regulating cholesterol metabolism.","date":"2024","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39179058","citation_count":13,"is_preprint":false},{"pmid":"35926353","id":"PMC_35926353","title":"Shudi Erzi San relieves ovary aging in laying hens.","date":"2022","source":"Poultry science","url":"https://pubmed.ncbi.nlm.nih.gov/35926353","citation_count":13,"is_preprint":false},{"pmid":"27200101","id":"PMC_27200101","title":"Shengmai San Ameliorates Myocardial Dysfunction and Fibrosis in Diabetic db/db Mice.","date":"2016","source":"Evidence-based complementary and alternative medicine : eCAM","url":"https://pubmed.ncbi.nlm.nih.gov/27200101","citation_count":13,"is_preprint":false},{"pmid":"24898679","id":"PMC_24898679","title":"Inflammation and peripheral venous disease. The San Diego Population Study.","date":"2014","source":"Thrombosis and haemostasis","url":"https://pubmed.ncbi.nlm.nih.gov/24898679","citation_count":13,"is_preprint":false},{"pmid":"27484799","id":"PMC_27484799","title":"Human Naa50 Protein Displays Broad Substrate Specificity for Amino-terminal Acetylation: DETAILED STRUCTURAL AND BIOCHEMICAL ANALYSIS USING TETRAPEPTIDE LIBRARY.","date":"2016","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27484799","citation_count":12,"is_preprint":false},{"pmid":"34496266","id":"PMC_34496266","title":"Xiaoyao San attenuates hepatic steatosis through estrogen receptor α pathway in ovariectomized ApoE-/- mice.","date":"2021","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/34496266","citation_count":12,"is_preprint":false},{"pmid":"33437632","id":"PMC_33437632","title":"Lingzhi and San-Miao-San with hyaluronic acid gel mitigate cartilage degeneration in anterior cruciate ligament transection induced osteoarthritis.","date":"2020","source":"Journal of orthopaedic translation","url":"https://pubmed.ncbi.nlm.nih.gov/33437632","citation_count":12,"is_preprint":false},{"pmid":"36687704","id":"PMC_36687704","title":"Mechanisms of the Ping-wei-san plus herbal decoction against Parkinson's disease: Multiomics analyses.","date":"2023","source":"Frontiers in nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/36687704","citation_count":12,"is_preprint":false},{"pmid":"35087596","id":"PMC_35087596","title":"Elucidation of Potential Targets of San-Miao-San in the Treatment of Osteoarthritis Based on Network Pharmacology and Molecular Docking Analysis.","date":"2022","source":"Evidence-based complementary and alternative medicine : eCAM","url":"https://pubmed.ncbi.nlm.nih.gov/35087596","citation_count":12,"is_preprint":false},{"pmid":"38375048","id":"PMC_38375048","title":"Effects of Xiaoyao San on exercise capacity and liver mitochondrial metabolomics in rat depression model.","date":"2023","source":"Chinese herbal medicines","url":"https://pubmed.ncbi.nlm.nih.gov/38375048","citation_count":11,"is_preprint":false},{"pmid":"27422821","id":"PMC_27422821","title":"Opposing Functions of the N-terminal Acetyltransferases Naa50 and NatA in Sister-chromatid Cohesion.","date":"2016","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27422821","citation_count":11,"is_preprint":false},{"pmid":"35182668","id":"PMC_35182668","title":"Effect of Shixiao San on inflammatory factors and pain in rats with endometriosis.","date":"2022","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/35182668","citation_count":11,"is_preprint":false},{"pmid":"32697300","id":"PMC_32697300","title":"Y-Chromosome Variation in Southern African Khoe-San Populations Based on Whole-Genome Sequences.","date":"2020","source":"Genome biology and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/32697300","citation_count":11,"is_preprint":false},{"pmid":"36627003","id":"PMC_36627003","title":"Yupingfeng San exhibits anticancer effect in hepatocellular carcinoma cells via the MAPK pathway revealed by HTS2 technology.","date":"2023","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/36627003","citation_count":11,"is_preprint":false},{"pmid":"12242484","id":"PMC_12242484","title":"Induction of cytokine expression in rat post-ischemic sinoatrial node (SAN).","date":"2002","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/12242484","citation_count":11,"is_preprint":false},{"pmid":"17696247","id":"PMC_17696247","title":"Effect of Qi-protecting powder (Huqi San) on expression of c-jun, c-fos and c-myc in diethylnitrosamine-mediated hepatocarcinogenesis.","date":"2007","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/17696247","citation_count":11,"is_preprint":false},{"pmid":"30151021","id":"PMC_30151021","title":"Modified Si-Ni-San Decoction Ameliorates Central Fatigue by Improving Mitochondrial Biogenesis in the Rat Hippocampus.","date":"2018","source":"Evidence-based complementary and alternative medicine : eCAM","url":"https://pubmed.ncbi.nlm.nih.gov/30151021","citation_count":11,"is_preprint":false},{"pmid":"35161384","id":"PMC_35161384","title":"Identification and Functional Analysis of the CgNAC043 Gene Involved in Lignin Synthesis from Citrusgrandis \"San Hong\".","date":"2022","source":"Plants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/35161384","citation_count":10,"is_preprint":false},{"pmid":"35372072","id":"PMC_35372072","title":"Exploration of the Potential Mechanism of Qi Yin San Liang San Decoction in the Treatment of EGFRI-Related Adverse Skin Reactions Using Network Pharmacology and In Vitro Experiments.","date":"2022","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35372072","citation_count":10,"is_preprint":false},{"pmid":"29253606","id":"PMC_29253606","title":"Effects of Xiao Yao San on interferon-α-induced depression in mice.","date":"2017","source":"Brain research bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/29253606","citation_count":10,"is_preprint":false},{"pmid":"33571617","id":"PMC_33571617","title":"Effects of Shengmai San on key enzymes involved in hepatic and intestinal drug metabolism in rats.","date":"2021","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/33571617","citation_count":10,"is_preprint":false},{"pmid":"40154896","id":"PMC_40154896","title":"Chaihu-Shugan-San alleviates post-stroke depression in mice: Mechanistic insights into exosome-mediated neuroprotection.","date":"2025","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40154896","citation_count":9,"is_preprint":false},{"pmid":"27512390","id":"PMC_27512390","title":"Characterization of Chemosynthetic Microbial Mats Associated with Intertidal Hydrothermal Sulfur Vents in White Point, San Pedro, CA, USA.","date":"2016","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/27512390","citation_count":9,"is_preprint":false},{"pmid":"39571696","id":"PMC_39571696","title":"Shenling Baizhu San alleviates central fatigue through SIRT1-PGC-1α-Mediated mitochondrial biogenesis.","date":"2024","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39571696","citation_count":9,"is_preprint":false},{"pmid":"24688505","id":"PMC_24688505","title":"Presence of enterotoxigenic Staphylococcus aureus in artisan fruit salads in the city of San Luis, Argentina.","date":"2014","source":"Brazilian journal of microbiology : [publication of the Brazilian Society for Microbiology]","url":"https://pubmed.ncbi.nlm.nih.gov/24688505","citation_count":8,"is_preprint":false},{"pmid":"10353166","id":"PMC_10353166","title":"Effect of Choto-san, a kampo medicine, on impairment of passive avoidance performance in mice.","date":"1999","source":"Phytotherapy research : PTR","url":"https://pubmed.ncbi.nlm.nih.gov/10353166","citation_count":8,"is_preprint":false},{"pmid":"29501675","id":"PMC_29501675","title":"Paljung-San, a traditional herbal medicine, attenuates benign prostatic hyperplasia in vitro and in vivo.","date":"2018","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/29501675","citation_count":8,"is_preprint":false},{"pmid":"33381214","id":"PMC_33381214","title":"Antidiarrheal Effect of Sechang-Zhixie-San on Acute Diarrhea Mice and Network Pharmacology Deciphering Its Characteristics and Potential Mechanisms.","date":"2020","source":"Evidence-based complementary and alternative medicine : eCAM","url":"https://pubmed.ncbi.nlm.nih.gov/33381214","citation_count":8,"is_preprint":false},{"pmid":"35764198","id":"PMC_35764198","title":"Exploring therapeutic mechanisms of San-Huang-Tang in nonalcoholic fatty liver disease through network pharmacology and experimental validation.","date":"2022","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/35764198","citation_count":8,"is_preprint":false},{"pmid":"33349071","id":"PMC_33349071","title":"San Huang Decoction Targets Aurora Kinase A to Inhibit Tumor Angiogenesis in Breast Cancer.","date":"2020","source":"Integrative cancer therapies","url":"https://pubmed.ncbi.nlm.nih.gov/33349071","citation_count":7,"is_preprint":false},{"pmid":"40081512","id":"PMC_40081512","title":"Ermiao San attenuating rheumatoid arthritis via PI3K/AKT/mTOR signaling activate HIF-1α induced glycolysis.","date":"2025","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40081512","citation_count":7,"is_preprint":false},{"pmid":"36938448","id":"PMC_36938448","title":"MiR-1281 is involved in depression disorder and the antidepressant effects of Kai-Xin-San by targeting ADCY1 and DVL1.","date":"2023","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/36938448","citation_count":7,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":59763,"output_tokens":2700,"usd":0.109895},"stage2":{"model":"claude-opus-4-6","input_tokens":6020,"output_tokens":2643,"usd":0.144262},"total_usd":0.254157,"stage1_batch_id":"msgbatch_012ZiiCUBfB62NCTQd4Bk1Jo","stage2_batch_id":"msgbatch_01Xuqq9aUHoQouS7UVGZNStZ","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"Drosophila San (ortholog of NAA50) is required for establishing centromeric sister chromatid cohesion during mitosis; san mutations cause failure of cohesin subunit Scc1 to accumulate at centromeres, activation of the spindle checkpoint, and anaphase segregation errors. San protein is itself acetylated and associates with the Nat1 and Ard1 subunits of the NatA acetyltransferase complex.\",\n      \"method\": \"Genetic mutant analysis in Drosophila, immunofluorescence, co-immunoprecipitation\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP and clean loss-of-function with defined cellular phenotype, replicated across multiple alleles\",\n      \"pmids\": [\"14653991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Human NAA50 (hNaa50p) possesses both Nα-terminal acetyltransferase (NAT) and Nε-lysine acetyltransferase (KAT) activities in vitro. Its preferred NAT substrates have N-terminal Met-Leu-X-Pro sequences. hNaa50p autoacetylates lysines 34, 37, and 140 in vitro, and this autoacetylation modulates substrate specificity. Histone H4 was identified as a KAT substrate in vitro.\",\n      \"method\": \"In vitro acetyltransferase assay with purified recombinant hNaa50p and oligopeptide substrate library; mass spectrometry identification of autoacetylation sites\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with multiple substrates and site identification\",\n      \"pmids\": [\"19744929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"X-ray crystal structure of human Naa50p in ternary complex with a native substrate peptide and CoA revealed that the substrate backbone is anchored via backbone hydrogen bonds, the first methionine is specified through van der Waals contacts creating an α-amino methionine-specific pocket, and conserved histidine and tyrosine residues play catalytic roles. Structure-based mutagenesis confirmed importance of these residues. The GNAT fold differs from lysine acetyltransferases in the substrate-binding groove, explaining NAT vs KAT selectivity.\",\n      \"method\": \"X-ray crystallography, structure-based mutagenesis, in vitro acetyltransferase assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with mutagenesis validation in single rigorous study\",\n      \"pmids\": [\"21900231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In vivo N-terminal acetylome profiling in yeast revealed that human NAA50 (hNaa50) primarily Nt-acetylates Met-starting N-termini (iMet-Lys, iMet-Val, iMet-Ala, iMet-Tyr, iMet-Phe, iMet-Leu, iMet-Ser, iMet-Thr), similar to hNaa60/NatF. A kinetic competition between Naa50 and methionine aminopeptidases (MetAPs) was demonstrated: Naa50-mediated Nt-acetylation of iMet followed by a small residue blocks subsequent MetAP cleavage, confirmed by in vitro data.\",\n      \"method\": \"Quantitative N-terminal acetylome profiling (SILAC-based proteomics) in yeast strains with/without Naa50; in vitro MetAP competition assay\",\n      \"journal\": \"Proteomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — quantitative in vivo acetylomics with orthogonal in vitro validation\",\n      \"pmids\": [\"25886145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Drosophila Naa50/San is required for proper interaction between cohesin subunits Scc1 and Smc3 during tissue proliferation. Biochemical and genetic evidence suggests that Naa50/San co-translationally N-terminally acetylates nascent Scc1, and this modification is required for establishment and/or maintenance of sister chromatid cohesion.\",\n      \"method\": \"Genetic analysis in Drosophila, co-immunoprecipitation of cohesin subunits, biochemical assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP and genetic approach, single lab, moderate mechanistic follow-up\",\n      \"pmids\": [\"27996020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Depletion of NAA50 in HeLa cells weakens the interaction between cohesin and its positive regulator sororin, causing cohesion defects in S phase. Co-depletion of NatA rescues the sister-chromatid cohesion defects and mitotic arrest caused by NAA50 depletion, demonstrating antagonistic roles of NatA and NAA50 in cohesion. Purified NatA and NAA50 do not affect each other's NAT activity in vitro, suggesting they act on distinct substrates.\",\n      \"method\": \"siRNA knockdown in HeLa cells, co-immunoprecipitation, in vitro NAT activity assay with purified proteins, chromosome spread analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined cellular phenotype, epistasis rescue experiment, and in vitro activity assay\",\n      \"pmids\": [\"27422821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Crystal structure of human Naa50 with co-purified CoA and acetylated tetrapeptide (AcMMXX) confirmed Met-Met at positions 1-2 as the best substrate. Biochemical studies with a tetrapeptide library showed Naa50 acetylates all MXAA peptides except MPAA.\",\n      \"method\": \"X-ray crystallography, in vitro acetyltransferase assay with tetrapeptide library, thermal stability assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with systematic substrate biochemistry\",\n      \"pmids\": [\"27484799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"X-ray crystal structure of yeast NatA/Naa50 ternary complex revealed that Naa50 makes evolutionarily conserved contacts to both Naa10 and Naa15 subunits of NatA. These interactions promote catalytic crosstalk within the human complex (but less so in yeast where Naa50 activity is compromised). Yeast Naa50 is catalytically less active than human Naa50 due to structural differences.\",\n      \"method\": \"X-ray crystallography of yeast NatA/Naa50 complex, in vitro NAT activity assays comparing yeast and human complexes\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional validation across species\",\n      \"pmids\": [\"31155310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Two novel small-molecule inhibitors of Naa50 were identified and characterized; co-crystal structures with Naa50 revealed their binding modes and mechanism of action. Cellular target engagement experiments confirmed binding selectivity of compound 4a for Naa50 over related enzymes Naa10 and Naa60.\",\n      \"method\": \"DNA-encoded library screening, X-ray co-crystallography, biochemical inhibition assays, cellular target engagement assay\",\n      \"journal\": \"ACS medicinal chemistry letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — co-crystal structures with biophysical/biochemical validation and cellular confirmation\",\n      \"pmids\": [\"32550998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"High-resolution X-ray crystal structures of Arabidopsis NAA50 (AtNaa50) in complex with AcCoA and a bisubstrate analog defined substrate specificity determinants and functionally important residues. Differences between Arabidopsis and yeast Naa50 were highlighted; yeast Naa50 binds CoA conjugates but is catalytically inactive, whereas AtNaa50 is enzymatically active.\",\n      \"method\": \"X-ray crystallography, enzymatic kinetics, site-directed mutagenesis\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution crystal structures with mutagenesis and kinetic characterization\",\n      \"pmids\": [\"33400917\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NAA50 (also called Nat5/San/NatE catalytic subunit) is a ribosome-associated N-terminal acetyltransferase that co-translationally acetylates the α-amino group of Met-starting protein N-termini (preferring Met-Leu-X-Pro and Met-Met sequences) and also autoacetylates internal lysines; it physically associates with the NatA complex (Naa10/Naa15) via conserved contacts to both subunits, promoting catalytic crosstalk; in metazoans it is required for sister-chromatid cohesion by N-terminally acetylating nascent cohesin subunit Scc1 and by supporting the cohesin-sororin interaction, while NatA plays an opposing (antagonistic) role in cohesion; competition between Naa50-mediated Nt-acetylation and methionine aminopeptidases determines whether the initiator methionine is retained on substrates with small penultimate residues.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"NAA50 is a ribosome-associated N-terminal acetyltransferase (NatE catalytic subunit) that co-translationally acetylates the α-amino group of initiator methionine-retaining protein N-termini, with preference for Met-Leu, Met-Met, and other Met-Xaa sequences, and competes kinetically with methionine aminopeptidases to determine initiator methionine retention [PMID:25886145, PMID:27484799]. Its GNAT-fold active site contains a methionine-specific pocket anchored by conserved histidine and tyrosine catalytic residues, and it physically associates with both subunits of the NatA complex (Naa10/Naa15) through evolutionarily conserved contacts that promote catalytic crosstalk [PMID:21900231, PMID:31155310]. In addition to possessing Nα-acetyltransferase activity, NAA50 exhibits Nε-lysine acetyltransferase and autoacetylation activities that modulate its substrate specificity in vitro [PMID:19744929]. In metazoans, NAA50 is essential for sister-chromatid cohesion: it N-terminally acetylates the cohesin subunit Scc1, supports the cohesin–sororin interaction, and functions antagonistically to NatA in cohesion regulation [PMID:14653991, PMID:27422821, PMID:27996020].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing that Naa50/San has a cellular function beyond generic acetyltransferase activity, Drosophila genetics revealed it is required for centromeric sister-chromatid cohesion and cohesin subunit Scc1 accumulation, and that it physically associates with the NatA complex.\",\n      \"evidence\": \"Genetic mutant analysis of san alleles in Drosophila with immunofluorescence and co-immunoprecipitation\",\n      \"pmids\": [\"14653991\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether San/Naa50 acts on cohesion through its acetyltransferase activity or a non-catalytic mechanism was unresolved\",\n        \"Direct substrates relevant to cohesion were not identified\",\n        \"The nature of the NatA–Naa50 association (stoichiometry, structural basis) was unknown\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Biochemical reconstitution established that human NAA50 possesses dual Nα-terminal and Nε-lysine acetyltransferase activities, defined its preferred NAT substrate motif (Met-Leu-X-Pro), and showed that autoacetylation at specific lysines modulates substrate specificity.\",\n      \"evidence\": \"In vitro acetyltransferase assays with purified recombinant hNaa50p, oligopeptide substrate library, and mass spectrometry\",\n      \"pmids\": [\"19744929\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"In vivo relevance of KAT activity (e.g., histone H4 acetylation) was not demonstrated\",\n        \"Whether autoacetylation occurs in cells and is physiologically regulatory was untested\",\n        \"Link between enzymatic activity and cohesion phenotype remained indirect\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"The first crystal structure of human Naa50 in a ternary complex with substrate peptide and CoA revealed the molecular basis of α-amino methionine specificity, identified catalytic residues (His and Tyr), and explained structural divergence from lysine acetyltransferases.\",\n      \"evidence\": \"X-ray crystallography with structure-based mutagenesis and in vitro activity assays\",\n      \"pmids\": [\"21900231\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How Naa50 engages the ribosome and NatA complex structurally was unknown\",\n        \"Substrate specificity beyond the first residue was incompletely mapped\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"In vivo acetylome profiling revealed the full breadth of Naa50 substrates (various iMet-Xaa N-termini) and demonstrated a kinetic competition with methionine aminopeptidases that determines initiator methionine retention.\",\n      \"evidence\": \"SILAC-based quantitative N-terminal acetylome profiling in yeast expressing human Naa50; in vitro MetAP competition assay\",\n      \"pmids\": [\"25886145\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the MetAP–Naa50 competition is regulated in vivo under different conditions was not addressed\",\n        \"Identification of specific endogenous substrates critical for cohesion was still missing\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Three convergent studies resolved the substrate specificity, cohesion mechanism, and NatA antagonism: crystal structures confirmed Met-Met as an optimal substrate; Drosophila genetics showed Naa50 co-translationally Nt-acetylates Scc1 to promote Scc1–Smc3 interaction; and human cell depletion experiments demonstrated that NAA50 supports the cohesin–sororin interaction and that NatA acts antagonistically to NAA50 in cohesion, with co-depletion rescuing cohesion defects.\",\n      \"evidence\": \"X-ray crystallography with tetrapeptide library (PMID:27484799); Drosophila genetics and co-IP (PMID:27996020); siRNA knockdown, epistasis rescue, chromosome spreads, and in vitro NAT assays in HeLa cells (PMID:27422821)\",\n      \"pmids\": [\"27484799\", \"27996020\", \"27422821\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The molecular basis of NatA–NAA50 antagonism (distinct substrate targets) was not fully elucidated\",\n        \"Whether sororin itself is a direct Nt-acetylation substrate of NAA50 was not tested\",\n        \"How cohesion acetylation by NAA50 coordinates with Eco1/ESCO acetyltransferase-mediated cohesion establishment was unclear\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The crystal structure of the yeast NatA/Naa50 ternary complex defined the conserved binding interface between Naa50 and both NatA subunits and showed that physical association promotes catalytic crosstalk in the human but not yeast enzyme.\",\n      \"evidence\": \"X-ray crystallography of yeast NatA/Naa50 complex with in vitro NAT activity comparisons across species\",\n      \"pmids\": [\"31155310\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"A structure of the human NatA–Naa50 complex was not yet available\",\n        \"How ribosome association modulates NatE activity and crosstalk was not addressed\",\n        \"Structural basis for species-specific differences in Naa50 catalytic competence was only partially explained\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification and co-crystallization of selective small-molecule Naa50 inhibitors provided chemical tools and confirmed the druggability of the active site.\",\n      \"evidence\": \"DNA-encoded library screening, co-crystal structures, biochemical inhibition assays, and cellular target engagement\",\n      \"pmids\": [\"32550998\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Cellular phenotypic consequences of chemical Naa50 inhibition (e.g., cohesion defects) were not reported\",\n        \"In vivo pharmacology and selectivity across the full NAT family were not characterized\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Structural and kinetic comparison of Arabidopsis Naa50 with yeast Naa50 pinpointed determinants of catalytic competence versus inactivity, clarifying evolutionary variation in NatE function.\",\n      \"evidence\": \"X-ray crystallography of AtNaa50 with AcCoA and bisubstrate analog; enzymatic kinetics and site-directed mutagenesis\",\n      \"pmids\": [\"33400917\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Plant-specific substrates and physiological roles of AtNaa50 were not defined\",\n        \"Structural basis for the gain of catalytic activity in metazoan vs. fungal Naa50 remains incompletely resolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include the structural basis of ribosome-associated NatE complex activity in humans, the identity of NatA substrates that antagonize NAA50-dependent cohesion, and whether NAA50's KAT activity is physiologically relevant.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No cryo-EM or crystal structure of ribosome-bound NatE exists\",\n        \"The specific NatA substrate(s) whose Nt-acetylation opposes cohesion have not been identified\",\n        \"In vivo relevance of NAA50 KAT and autoacetylation activities remains untested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [1, 2, 3, 6]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 3, 6]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 4, 5]}\n    ],\n    \"complexes\": [\n      \"NatE (Naa50/NatA)\"\n    ],\n    \"partners\": [\n      \"NAA10\",\n      \"NAA15\",\n      \"SCC1\",\n      \"SMC3\",\n      \"CDCA5\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}