PaperBLAST

Full List of Papers Linked to VIMSS34268

BKDC_MYCTU / O06159 Dihydrolipoyllysine-residue acyltransferase component of branched-chain alpha-ketoacid dehydrogenase complex; Branched-chain alpha-ketoacid dehydrogenase complex component E2; BCKADH E2; Dihydrolipoyllysine-residue (2-methylpropanoyl)transferase; EC 2.3.1.168 from Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) (see 2 papers)
Rv2495c dihydrolipoamide acetyltransferase from Mycobacterium tuberculosis H37Rv

• function: Component of the branched-chain alpha-ketoacid dehydrogenase (BCKADH) complex, that catalyzes the overall conversion of branched- chain alpha-ketoacids to acyl-CoA and CO(2).
  catalytic activity: N(6)-[(R)-dihydrolipoyl]-L-lysyl-[protein] + 2- methylpropanoyl-CoA = N(6)-[(R)-S(8)-2-methylpropanoyldihydrolipoyl]- L-lysyl-[protein] + CoA (RHEA:18865)
  cofactor: (R)-lipoate (Binds 1 lipoyl cofactor covalently.)
  subunit: Forms a 24-polypeptide structural core with octahedral symmetry (By similarity). Part of the BCKADH complex, consisting of multiple copies of BkdA/BkdB (E1), BkdC (E2) and Lpd (E3).
• Global-scale GWAS associates a subset of SNPs with animal-adapted variants in M. tuberculosis complex
  Brenner, BMC medical genomics 2023
  • “...methyltransferase) Disruption provides growth advantage (DeJesus 2017) Synonymous 2,809,318 0 0.951 4100 2100 161 1 Rv2495c BkdC Probable branched-chain keto acid dehydrogenase E2 component BkdC Arg208Trp 2,812,742 0 0.951 4100 2100 161 1 Rv2498c CitE Probable citrate (pro-3S)-lyase (beta subunit) CitE (citrase) (citratase) (citritase) (citridesmolase) (citrase...”
• Small RNA Mcr11 requires the transcription factor AbmR for stable expression and regulates genes involved in the central metabolism of Mycobacterium tuberculosis
  Girardin, Molecular microbiology 2020
  • “...(Spalding & Prigge, 2010 ; Venugopal et al., 2011 ). BkdC (also called PdhC or Rv2495c) is a component of the branched chain ketoacid dehydrogenase (BCKADH) complex in Mtb that also requires lipoylation for activity. Disruption of components in any of these complexes can cause growth...”
• The unfoldase ClpC1 of Mycobacterium tuberculosis regulates the expression of a distinct subset of proteins having intrinsically disordered termini
  Lunge, The Journal of biological chemistry 2020 (secret)
• Mycobacterium tuberculosis Complex Exhibits Lineage-Specific Variations Affecting Protein Ductility and Epitope Recognition
  Yruela, Genome biology and evolution 2016
  • “...proteins have mutations along their sequences. Among them only four proteins, Rv2215 (DlaT), Rv2358 (SmtB), Rv2495c (BkdC), and Rv3003c (IlvB1) have mutations inside IDRs ( table 1 ). Interestingly, SmtB of M. tuberculosis Beiijing shows five amino acid substitutions in the Phe30Pro37 motif of the N-terminal...”
  • “...265 (G/E) 3141 4891 M. bovis BCG Pasteur (1) 517 (L/V) 117-160 169204 236298 307319 Rv2495c BkdC 7 M. africanum (1) 87116 14 107 (T/A) * 2331 14 Ser55 1 M. canettii (2) 67 (A/V), 107(T/A) * M. bovis (2) 107 (T/A) * , 208 (R/W)...”
• Characterization of the mycobacterial acyl-CoA carboxylase holo complexes reveals their functional expansion into amino acid catabolism
  Ehebauer, PLoS pathogens 2015
  • “....). Interestingly, this pattern of conservation extends into the neighboring pdhABC operon that includes genes Rv2495c to Rv2497c, which encode a lipoamide dehydrogenase-dependent keto acid dehydrogenase complex [ 23 ]. This complex acts upstream in branched amino-acid catabolism and one of its key functions is thought...”
  • “...YCC enzymes. Remarkably, in addition to the conserved operon organization, the expression of most genes (Rv2495c to Rv2501c) of the citE-scoA operon and the pdhABC operon are strongly correlated (for further details see Operon Correlation Browser ( www.broadinstitute.org/annotation/tbdb/operon/ ), suggesting that the effects observed are coupled....”
• bkaR is a TetR-type repressor that controls an operon associated with branched-chain keto-acid metabolism in Mycobacteria
  Balhana, FEMS microbiology letters 2013
  • “...3.3 3.3E-02 bkdB Rv2496c Part of branched-chain keto-acid dehydrogenase complex * MSMEG_4710 1.8 4.9E-01 bkdC Rv2495c Part of branched-chain keto-acid dehydrogenase complex * MSMEG_4005 3.2 2.5E-02 Calcium-binding protein MSMEG_2080 3.1 3.3E-02 fadE23 Rv3140 Putative acyl-CoA dehydrogenase MSMEG_1885 3.3 2.2E-02 Rv3230c Rv3230c Ironsulphur cluster binding domain protein...”
• A multi-level multi-scale approach to study essential genes in Mycobacterium tuberculosis
  Ghosh, BMC systems biology 2013
  • “...to maintain original function. The perturbed path comprise 13 nodes (Rv3441c (mrsA) Rv1151c Rv3667 (acs) Rv2495c (bkdC) Rv2496c (bkdB) Rv1617 (pykA) Rv3457c (rpoA) Rv0707 (rpsC) Rv0703 (rplW) Rv2347c (esxP) Rv2346c (esxO) Rv2498c (citE) Rv1240 (mdh)), including the source and destination. Figure 3 Network topology of protein-protein...”
• Virulence of Mycobacterium tuberculosis depends on lipoamide dehydrogenase, a member of three multienzyme complexes
  Venugopal, Cell host & microbe 2011
  • “...E1 of PDH), pdhB (Rv2496c, annotated as the subunit of E1 of PDH) and pdhC (Rv2495c, annotated as E2 of PDH). In many organisms Lpd is also the E3 of BCKADH, so we hypothesized that the pdhABC operon may encode the E1 and E2 of BCKADH...”
  • “...of metabolites and the activity of lysates. In light of these findings, Rv2497c, Rv2496c and Rv2495c can be re-annotated as bkdA, bkdB and bkdC , respectively. In contrast, WT and Lpd-deficient Mtb grown on a standard rich medium in vitro either did not express a functional...”
• Variation among genome sequences of H37Rv strains of Mycobacterium tuberculosis from multiple laboratories
  Ioerger, Journal of bacteriology 2010
  • “...Rv2048c Rv2101 Rv2205c NC NC Rv2251 NC Rv2450c Rv2495c Rv2614A Rv2627c Rv2680 Rv2695 Rv2896c Rv2932 Rv3011c Rv3144c NC NC Rv3331 NC Rv3479 Rv3655c Rv3704c...”
• Actinobacteria challenge the paradigm: A unique protein architecture for a well-known, central metabolic complex
  Bruch, Proceedings of the National Academy of Sciences of the United States of America 2021 (secret)
• Mycobacterium tuberculosis Complex Exhibits Lineage-Specific Variations Affecting Protein Ductility and Epitope Recognition
  Yruela, Genome biology and evolution 2016
  • “...PyMol 1.4.1 (Schrodinger LLC). Furthermore, Rv2495c, a component of branched-chain alpha-ketoacid dehydrogenase complex (BkdC, UniProt O06159) shows mutations in Tyr103Asp and Thr107Ala in M. tuberculosis Beijing compared with M. tuberculosis H37Rv which increase the flexibility in this region as indicate IUPred/ANCHOR predictions ( supplementary fig. S3...”

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How It Works

PaperBLAST builds a database of protein sequences that are linked to scientific articles. These links come from automated text searches against the articles in EuropePMC and from manually-curated information from GeneRIF, UniProtKB/Swiss-Prot, BRENDA, CAZy (as made available by dbCAN), BioLiP, CharProtDB, MetaCyc, EcoCyc, TCDB, REBASE, the Fitness Browser, and a subset of the European Nucleotide Archive with the /experiment tag. Given this database and a protein sequence query, PaperBLAST uses protein-protein BLAST to find similar sequences with E < 0.001.

To build the database, we query EuropePMC with locus tags, with RefSeq protein identifiers, and with UniProt accessions. We obtain the locus tags from RefSeq or from MicrobesOnline. We use queries of the form "locus_tag AND genus_name" to try to ensure that the paper is actually discussing that gene. Because EuropePMC indexes most recent biomedical papers, even if they are not open access, some of the links may be to papers that you cannot read or that our computers cannot read. We query each of these identifiers that appears in the open access part of EuropePMC, as well as every locus tag that appears in the 500 most-referenced genomes, so that a gene may appear in the PaperBLAST results even though none of the papers that mention it are open access. We also incorporate text-mined links from EuropePMC that link open access articles to UniProt or RefSeq identifiers. (This yields some additional links because EuropePMC uses different heuristics for their text mining than we do.)

For every article that mentions a locus tag, a RefSeq protein identifier, or a UniProt accession, we try to select one or two snippets of text that refer to the protein. If we cannot get access to the full text, we try to select a snippet from the abstract, but unfortunately, unique identifiers such as locus tags are rarely provided in abstracts.

PaperBLAST also incorporates manually-curated protein functions:

• Proteins from NCBI's RefSeq are included if a GeneRIF entry links the gene to an article in PubMed^®. GeneRIF also provides a short summary of the article's claim about the protein, which is shown instead of a snippet.
• Proteins from Swiss-Prot (the curated part of UniProt) are included if the curators identified experimental evidence for the protein's function (evidence code ECO:0000269). For these proteins, the fields of the Swiss-Prot entry that describe the protein's function are shown (with bold headings).
• Proteins from BRENDA, a curated database of enzymes, are included if they are linked to a paper in PubMed and their full sequence is known.
• Every protein from the non-redundant subset of BioLiP, a database of ligand-binding sites and catalytic residues in protein structures, is included. Since BioLiP itself does not include descriptions of the proteins, those are taken from the Protein Data Bank. Descriptions from PDB rely on the original submitter of the structure and cannot be updated by others, so they may be less reliable. (For SitesBLAST and Sites on a Tree, we use a larger subset of BioLiP so that every ligand is represented among a group of structures with similar sequences, but for PaperBLAST, we use the non-redundant set provided by BioLiP.)
• Every protein from EcoCyc, a curated database of the proteins in Escherichia coli K-12, is included, regardless of whether they are characterized or not.
• Proteins from the MetaCyc metabolic pathway database are included if they are linked to a paper in PubMed and their full sequence is known.
• Proteins from the Transport Classification Database (TCDB) are included if they have known substrate(s), have reference(s), and are not described as uncharacterized or putative. (Some of the references are not visible on the PaperBLAST web site.)
• Every protein from CharProtDB, a database of experimentally characterized protein annotations, is included.
• Proteins from the CAZy database of carbohydrate-active enzymes are included if they are associated with an Enzyme Classification number. Even though CAZy does not provide links from individual protein sequences to papers, these should all be experimentally-characterized proteins.
• Proteins from the REBASE database of restriction enzymes are included if they have known specificity.
• Every protein with an evidence-based reannotation (based on mutant phenotypes) in the Fitness Browser is included.
• Sequence-specific transcription factors (including sigma factors and DNA-binding response regulators) with experimentally-determined DNA binding sites from the PRODORIC database of gene regulation in prokaryotes.
• Putative transcription factors from RegPrecise that have manually-curated predictions for their binding sites. These predictions are based on conserved putative regulatory sites across genomes that contain similar transcription factors, so PaperBLAST clusters the TFs at 70% identity and retains just one member of each cluster.
• Coding sequence (CDS) features from the European Nucleotide Archive (ENA) are included if the /experiment tag is set (implying that there is experimental evidence for the annotation), the nucleotide entry links to paper(s) in PubMed, and the nucleotide entry is from the STD data class (implying that these are targeted annotated sequences, not from shotgun sequencing). Also, to filter out genes whose transcription or translation was detected, but whose function was not studied, nucleotide entries or papers with more than 25 such proteins are excluded. Descriptions from ENA rely on the original submitter of the sequence and cannot be updated by others, so they may be less reliable.

Except for GeneRIF and ENA, the curated entries include a short curated description of the protein's function. For entries from BioLiP, the protein's function may not be known beyond binding to the ligand. Many of these entries also link to articles in PubMed.

For more information see the PaperBLAST paper (mSystems 2017) or the code. You can download PaperBLAST's database here.

Changes to PaperBLAST since the paper was written:

• November 2023: incorporated PRODORIC and RegPrecise. Many PRODORIC entries were not linked to a protein sequence (no UniProt identifier), so we added this information.
• February 2023: BioLiP changed their download format. PaperBLAST now includes their non-redundant subset. SitesBLAST and Sites on a Tree use a larger non-redundant subset that ensures that every ligand is represented within each cluster. This should ensure that every binding site is represented.
• June 2022: incorporated some coding sequences from ENA with the /experiment tag.
• March 2022: incorporated BioLiP.
• April 2020: incorporated TCDB.
• April 2019: EuropePMC now returns table entries in their search results. This has expanded PaperBLAST's database, but most of the new entries are of low relevance, and the resulting snippets are often just lists of locus tags with annotations.
• February 2018: the alignment page reports the conservation of the hit's functional sites (if available from from Swiss-Prot or UniProt)
• January 2018: incorporated BRENDA.
• December 2017: incorporated MetaCyc, CharProtDB, CAZy, REBASE, and the reannotations from the Fitness Browser.
• September 2017: EuropePMC no longer returns some table entries in their search results. This has shrunk PaperBLAST's database, but has also reduced the number of low-relevance hits.

Many of these changes are described in Interactive tools for functional annotation of bacterial genomes.

Secrets

PaperBLAST cannot provide snippets for many of the papers that are published in non-open-access journals. This limitation applies even if the paper is marked as "free" on the publisher's web site and is available in PubmedCentral or EuropePMC. If a journal that you publish in is marked as "secret," please consider publishing elsewhere.

Omissions from the PaperBLAST Database

Many important articles are missing from PaperBLAST, either because the article's full text is not in EuropePMC (as for many older articles), or because the paper does not mention a protein identifier such as a locus tag, or because of PaperBLAST's heuristics. If you notice an article that characterizes a protein's function but is missing from PaperBLAST, please notify the curators at UniProt or add an entry to GeneRIF. Entries in either of these databases will eventually be incorporated into PaperBLAST. Note that to add an entry to UniProt, you will need to find the UniProt identifier for the protein. If the protein is not already in UniProt, you can ask them to create an entry. To add an entry to GeneRIF, you will need an NCBI Gene identifier, but unfortunately many prokaryotic proteins in RefSeq do not have corresponding Gene identifers.

References

PaperBLAST: Text-mining papers for information about homologs.
M. N. Price and A. P. Arkin (2017). mSystems, 10.1128/mSystems.00039-17.

Europe PMC in 2017.
M. Levchenko et al (2017). Nucleic Acids Research, 10.1093/nar/gkx1005.

Gene indexing: characterization and analysis of NLM's GeneRIFs.
J. A. Mitchell et al (2003). AMIA Annu Symp Proc 2003:460-464.

UniProt: the universal protein knowledgebase.
The UniProt Consortium (2016). Nucleic Acids Research, 10.1093/nar/gkw1099.

BRENDA in 2017: new perspectives and new tools in BRENDA.
S. Placzek et al (2017). Nucleic Acids Research, 10.1093/nar/gkw952.

The EcoCyc database: reflecting new knowledge about Escherichia coli K-12.
I. M. Keeseler et al (2016). Nucleic Acids Research, 10.1093/nar/gkw1003.

The MetaCyc database of metabolic pathways and enzymes.
R. Caspi et al (2018). Nucleic Acids Research, 10.1093/nar/gkx935.

CharProtDB: a database of experimentally characterized protein annotations.
R. Madupu et al (2012). Nucleic Acids Research, 10.1093/nar/gkr1133.

The carbohydrate-active enzymes database (CAZy) in 2013.
V. Lombard et al (2014). Nucleic Acids Research, 10.1093/nar/gkt1178.

The Transporter Classification Database (TCDB): recent advances
M. H. Saier, Jr. et al (2016). Nucleic Acids Research, 10.1093/nar/gkv1103.

REBASE - a database for DNA restriction and modification: enzymes, genes and genomes.
R. J. Roberts et al (2015). Nucleic Acids Research, 10.1093/nar/gku1046.

Deep annotation of protein function across diverse bacteria from mutant phenotypes.
M. N. Price et al (2016). bioRxiv, 10.1101/072470.