Rv2497c (bkdA)

Current annotations:
- TBCAP: (community-based annotations - see table at bottom of page)
- TBDB: pyruvate dehydrogenase (acetyl-transferring) E1 component alpha subunit
- REFSEQ: pyruvate dehydrogenase E1 component alpha subunit PdhA
- PATRIC: Branched-chain alpha-keto acid dehydrogenase E1 component alpha subunit (EC 1.2.4.4)
- TUBERCULIST: Probable branched-chain keto acid dehydrogenase E1 component alpha subunit BkdA
- NCBI: Probable branched-chain keto acid dehydrogenase E1 component, alpha subunit BkdA
- updated information (H37Rv4):
  - gene name: bkdA
  - function:
  - reference:
Type: Not Target
Start: 2810993
End: 2812096
Operon:

Trans-membrane region:
Role: I.B.2 - Pyruvate dehydrogenase
GO terms:
- GO:0055114 - oxidation-reduction process (Uniprot)
- GO:0046872 - metal ion binding (Uniprot)
- GO:0016624 - oxidoreductase activity, acting on the aldehyde or oxo group of donors, disulfide as acceptor (Uniprot)
- GO:0016491 - oxidoreductase activity (Uniprot)
- GO:0008152 - metabolic process (Uniprot)
- GO:0005515 - protein binding (Uniprot)
- GO:0003863 - 3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring) activity (Uniprot)
Reaction(s) (based on iSM810 metabolic model):
Gene Expression Profile (Transcriptional Responses to Drugs; Boshoff et al, 2004)
Gene Modules extracted from cluster analysis of 249 transcriptomic datasets using ICA
Orthologs among selected mycobacteria
Protein structure:
Search for Homologs in PDB

Top 10 Homologs in PDB (as of Nov 2020):

PDB	aa ident	species	PDB title
1UMD	40%	Thermus thermophilus	branched-chain 2-oxo acid dehydrogenase (E1) from Thermus thermophilus HB8 with 4-methyl-2-oxopentanoate as an intermediate
1UMC	40%	Thermus thermophilus	branched-chain 2-oxo acid dehydrogenase (E1) from Thermus thermophilus HB8 with 4-methylpentanoate
1UMB	40%	Thermus thermophilus	branched-chain 2-oxo acid dehydrogenase (E1) from Thermus thermophilus HB8 in holo-form
1UM9	40%	Thermus thermophilus	branched-chain 2-oxo acid dehydrogenase (E1) from Thermus thermophilus HB8 in apo-form
3DV0	39%	Bacillus stearothermophilus	Snapshots of catalysis in the E1 subunit of the pyruvate dehydrogenase multi-enzyme complex
3DUF	39%	Bacillus stearothermophilus	Snapshots of catalysis in the E1 subunit of the pyruvate dehydrogenase multi-enzyme complex
1W85	39%	GEOBACILLUS STEAROTHERMOPHILUS	The crystal structure of pyruvate dehydrogenase E1 bound to the peripheral subunit binding domain of E2
2BFF	38%	HOMO SAPIENS	Reactivity modulation of human branched-chain alpha-ketoacid dehydrogenase by an internal molecular switch
2BEW	38%	HOMO SAPIENS	Reactivity modulation of human branched-chain alpha-ketoacid dehydrogenase by an internal molecular switch
2BEV	38%	HOMO SAPIENS	Reactivity modulation of human branched-chain alpha-ketoacid dehydrogenase by an internal molecular switch

Links to additional information on bkdA:
- TBDB (updated)
- Phyre2 structure prediction, model: final.casp.pdb (from Mao et al, 2013)
- UniProt
- AlphaFold model
- Vulnerability = 0.956 (from Jeremy Rock's lab)
- KEGG - nucleotide and amino acid sequences of gene
- Mycobrowser
- PATRIC
- BioCyc
- Systems Biology

Amino Acid Sequence

MGEGSRRPSGMLMSVDLEPVQLVGPDGTPTAERRYHRDLPEETLRWLYEMMVVTRELDTEFVNLQRQGELALYTPCRGQEAAQVGAAACLRKTDWLFPQY
RELGVYLVRGIPPGHVGVAWRGTWHGGLQFTTKCCAPMSVPIGTQTLHAVGAAMAAQRLDEDSVTVAFLGDGATSEGDVHEALNFAAVFTTPCVFYVQNN
QWAISMPVSRQTAAPSIAHKAIGYGMPGIRVDGNDVLACYAVMAEAAARARAGDGPTLIEAVTYRLGPHTTADDPTRYRSQEEVDRWATLDPIPRYRTYL
QDQGLWSQRLEEQVTARAKHVRSELRDAVFDAPDFDVDEVFTTVYAEITPGLQAQREQLRAELARTD

(Nucleotide sequence available on KEGG)

Additional Information

ESSENTIALITY

MtbTnDB - interactive tool for exploring a database of published TnSeq datasets for Mtb

TnSeqCorr - genes with correlated TnSeq profiles across >100 conditions *new*

Classification	Condition	Strain	Method	Reference	Notes
Non-Essential	Sodium Oleate	H37RvMA	Gumbel	Subhalaxmi Nambi	Probability of Essentiality: 0.000100; 5 non-insertions in a row out of 22 sites
Non-Essential	Lignoceric Acid	H37RvMA	Gumbel	Subhalaxmi Nambi	Probability of Essentiality: 0.000000; 2 non-insertions in a row out of 22 sites
Non-Essential	Phosphatidylcholine	H37RvMA	Gumbel	Subhalaxmi Nambi	Probability of Essentiality: 0.000000; 3 non-insertions in a row out of 22 sites
Non-Essential	minimal media + 0.1% glycerol	H37RvMA	Gumbel	Griffin et al. (2011)	Probability of Essentiality: 0.000000; 4 non-insertions in a row out of 22 sites
Non-Essential	minimal media + 0.01% cholesterol	H37RvMA	Gumbel	Griffin et al. (2011)	Probability of Essentiality: 0.000000; 4 non-insertions in a row out of 22 sites
Non-Essential	7H10-glycerol	H37RvMA	TraSH	Sassetti et al. (2003a)
Non-Essential	C57BL/6J mice (8 weeks)	H37RvMA	TraSH	Sassetti et al. (2003b)	Hybridization Ratio: 1.3
Non-Essential	7H09/7H10 + rich media	H37RvMA	MotifHMM	DeJesus et al. (2017)	Fully saturated (14 reps).

TnSeq Data No data currently available.

No TnSeq data currently available for this Target.

RNASeq Data No data currently available.

No RNA-Seq data currently available for this Target.

Metabolomic Profiles No data currently available.

No Metabolomic data currently available for this Target.

Proteomic Data No data currently available.

No Proteomic data currently available for this Target.

Regulatory Relationships from Systems Biology

BioCyc

Gene interactions based on ChIPSeq and Transcription Factor Over-Expression (TFOE) (Systems Biology)

NOTE: Green edges represent the connected genes being classified as differentially essential as a result of the middle gene being knocked out. These interactions are inferred based on RNASeq.

Interactions based on ChIPSeq data

RNA processing and modification

Energy production and conversion

Chromatin structure and dynamics

Amino acid transport and metabolism

Cell cycle control, cell division, chromosome partitioning

Carbohydrate transport and metabolism

Nucleotide transport and metabolism

Lipid transport and metabolism

Coenzyme transport and metabolism

Transcription

Translation, ribosomal structure and biogenesis

Cell wall/membrane/envelope biogenesis

Replication, recombination and repair

Posttranslational modification, protein turnover, chaperones

Cell motility

Secondary metabolites biosynthesis, transport and catabolism

Inorganic ion transport and metabolism

Function unknown

General function prediction only

Intracellular trafficking, secretion, and vesicular transport

Signal transduction mechanisms

Extracellular structures

Defense mechanisms

Nuclear structure

Cytoskeleton

BioCyc Co-regulated genes based on gene expression profiling (Systems Biology, Inferelator Network)

Differentially expressed as result of RNASeq in glycerol environment (Only top 20 genes shown sorted by log fold change with p_adj 0.05).

Conditionally essential as result of TNSeq (Only top 20 genes shown sorted by log fold change with p_adj 0.05).

BioCyc Transcription factor binding based on ChIP-Seq (Systems Biology)

Binds To:
- No bindings to other targets were found.
Bound By:
- No bindings from other targets were found.

Interactions based on ChIPSeq data (Minch et al. 2014)

Binds To:
- No bindings to other targets were found.
Bound By:
- Rv1816 (-) (Direct binding)

Interactions based on TFOE data (Rustad et al. 2014)

Upregulates:
- Does not upregulate other genes.
Upregulated by:
- Not upregulated by other genes.
Downregulates:
- Does not downregulate other genes.
Downregulated by:
- Not downregulated by other genes.

Property	Value	Creator	Evidence	PMID	Comment
Citation	Mycobacterium tuberculosis appears to lack alpha-ketoglutarate dehydrogenase and encodes pyruvate dehydrogenase in widely separated genes. J. Tian, R. Bryk et al. Mol. Microbiol. 2005	akankshajain.21	IEP	16045627	Coexpression
Interaction	Operon Rv2495c	akankshajain.21	IEP		Coexpression J. Tian, R. Bryk et al. Mycobacterium tuberculosis appears to lack alpha-ketoglutarate dehydrogenase and encodes pyruvate dehydrogenase in widely separated genes. Mol. Microbiol. 2005
Interaction	Operon Rv2496c	akankshajain.21	IEP		Coexpression J. Tian, R. Bryk et al. Mycobacterium tuberculosis appears to lack alpha-ketoglutarate dehydrogenase and encodes pyruvate dehydrogenase in widely separated genes. Mol. Microbiol. 2005
Interaction	Operon Rv2495c	akankshajain.21	IEP		Coexpression J. Tian, R. Bryk et al. Mycobacterium tuberculosis appears to lack alpha-ketoglutarate dehydrogenase and encodes pyruvate dehydrogenase in widely separated genes. Mol. Microbiol. 2005
Interaction	Operon Rv2496c	akankshajain.21	IEP		Coexpression J. Tian, R. Bryk et al. Mycobacterium tuberculosis appears to lack alpha-ketoglutarate dehydrogenase and encodes pyruvate dehydrogenase in widely separated genes. Mol. Microbiol. 2005
Interaction	RegulatedBy Rv0348	yamir.moreno	IEP		Microarrays. mRNA levels of regulated element measured and compared between wild-type and trans-element mutation (knockout, over expression etc.) performed by using microarray (or macroarray) experiments.. B. Abomoelak, EA. Hoye et al. mosR, a novel transcriptional regulator of hypoxia and virulence in Mycobacterium tuberculosis. J. Bacteriol. 2009
Interaction	RegulatedBy Rv0182c	yamir.moreno	IEP		Microarrays. mRNA levels of regulated element measured and compared between wild-type and trans-element mutation (knockout, over expression etc.) performed by using microarray (or macroarray) experiments.. JH. Lee, DE. Geiman et al. Role of stress response sigma factor SigG in Mycobacterium tuberculosis. J. Bacteriol. 2008
Citation	Central carbon metabolism in Mycobacterium tuberculosis: an unexpected frontier. authors,KY. Rhee,LP. de Carvalho,R. Bryk,S. Ehrt,J. Marrero,SW. Park,D. Schnappinger,A. Venugopal,C. Nathan Trends Microbiol. 2011	extern:JZUCKER		21561773	Traceable author statement to experimental support
Term	EC:1.2.4.1 Pyruvate dehydrogenase (acetyl-transferring). - NR	extern:JZUCKER	NR		Traceable author statement to experimental support authors,KY. Rhee,LP. de Carvalho,R. Bryk,S. Ehrt,J. Marrero,SW. Park,D. Schnappinger,A. Venugopal,C. Nathan Central carbon metabolism in Mycobacterium tuberculosis: an unexpected frontier. Trends Microbiol. 2011
Term	EC:1.2.4.4 3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring). - NR	extern:JZUCKER	NR		Traceable author statement to experimental support authors,KY. Rhee,LP. de Carvalho,R. Bryk,S. Ehrt,J. Marrero,SW. Park,D. Schnappinger,A. Venugopal,C. Nathan Central carbon metabolism in Mycobacterium tuberculosis: an unexpected frontier. Trends Microbiol. 2011
Citation	Virulence of Mycobacterium tuberculosis depends on lipoamide dehydrogenase, a member of three multienzyme complexes. authors,A. Venugopal,R. Bryk,S. Shi,K. Rhee,P. Rath,D. Schnappinger,S. Ehrt,C. Nathan Cell Host Microbe 2011	extern:JZUCKER		21238944	Inferred from mutant phenotype
Term	EC:1.2.4.1 Pyruvate dehydrogenase (acetyl-transferring). - NR	extern:JZUCKER	NR		Inferred from mutant phenotype authors,A. Venugopal,R. Bryk,S. Shi,K. Rhee,P. Rath,D. Schnappinger,S. Ehrt,C. Nathan Virulence of Mycobacterium tuberculosis depends on lipoamide dehydrogenase, a member of three multienzyme complexes. Cell Host Microbe 2011
Term	EC:1.2.4.4 3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring). - NR	extern:JZUCKER	NR		Inferred from mutant phenotype authors,A. Venugopal,R. Bryk,S. Shi,K. Rhee,P. Rath,D. Schnappinger,S. Ehrt,C. Nathan Virulence of Mycobacterium tuberculosis depends on lipoamide dehydrogenase, a member of three multienzyme complexes. Cell Host Microbe 2011

TB Genome Annotation Portal