Rv3285 (accA3)

Current annotations:
- TBCAP: (community-based annotations - see table at bottom of page)
- TBDB: acetyl-/propionyl-coenzyme A carboxylase alpha chain
- REFSEQ: bifunctional acetyl-/propionyl-coenzyme A carboxylase subunit alpha
- PATRIC: Biotin carboxylase of acetyl-CoA carboxylase (EC 6.3.4.14) / Biotin carboxyl carrier protein of acetyl-CoA carboxylase
- TUBERCULIST: Probable bifunctional protein acetyl-/propionyl-coenzyme A carboxylase (alpha chain) AccA3: biotin carboxylase + biotin carboxyl carrier protein (BCCP)
- NCBI: Probable bifunctional protein acetyl-/propionyl-coenzyme A carboxylase (alpha chain) AccA3: biotin carboxylase + biotin carboxyl carrier protein (BCCP)
- updated information (H37Rv4):
  - gene name: accA3
  - function:
  - reference:
Type: Essential
Start: 3666357
End: 3668159
Operon:

Trans-membrane region:
Role: I.H.1 - Synthesis of fatty and mycolic acids
GO terms:
- GO:0046872 - metal ion binding (Uniprot)
- GO:0040007 - growth (Uniprot)
- GO:0015977 - carbon fixation (Uniprot)
- GO:0009317 - acetyl-CoA carboxylase complex (Uniprot)
- GO:0005886 - plasma membrane (Uniprot)
- GO:0005618 - cell wall (Uniprot)
- GO:0005524 - ATP binding (Uniprot)
- GO:0005515 - protein binding (Uniprot)
- GO:0004658 - propionyl-CoA carboxylase activity (Uniprot)
- GO:0003989 - acetyl-CoA carboxylase activity (Uniprot)
- GO:0000166 - nucleotide binding (Uniprot)
Reaction(s) (based on iSM810 metabolic model):
- BIOTIN_CO2[c] + HEXACOSANOYL_COA[c] -> BIOTIN[c] + HEXACOSANOYL_COA_CO2[c]
- ATP[c] + HCO3[c] + BIOTIN_BCCP[c] -> ADP[c] + PI[c] + BIOTIN_CO2[c]
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
5MLK	99%	Mycobacterium tuberculosis H37Rv	Biotin dependent carboxylase AccA3 dimer from Mycobacterium tuberculosis (Rv3285)
2VQD	47%	PSEUDOMONAS AERUGINOSA	Crystal Structure of Biotin Carboxylase from Pseudomonas aeruginosa complexed with AMPCP
2C00	47%	PSEUDOMONAS AERUGINOSA	Crystal Structure of Biotin Carboxylase from Pseudomonas aeruginosa in apo form
6OJH	47%	Haemophilus influenzae (strain ATCC 51907 / DSM 11121 / KW20 / Rd)	Crystal Structure of Haemophilus Influenzae Biotin Carboxylase Complexed with (R)-7-(3-aminopyrrolidin-1-yl)-6-(naphthalen-1-yl)pyrido[2,3-d]pyrimidin-2-amine
6OI8	47%	Haemophilus influenzae (strain ATCC 51907 / DSM 11121 / KW20 / Rd)	Crystal Structure of Haemophilus Influenzae Biotin Carboxylase Complexed with 7-((1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-6-(2-chloro-6-(pyridin-3-yl)phenyl)pyrido[2,3-d]pyrimidin-2-amine
4RZQ	47%	Haemophilus influenzae Rd KW20	Structural Analysis of Substrate, Reaction Intermediate and Product Binding in Haemophilus influenzae Biotin Carboxylase
4MV9	47%	Haemophilus influenzae	Crystal Structure of Biotin Carboxylase from Haemophilus influenzae in Complex with Bicarbonate
4MV8	47%	Haemophilus influenzae	Crystal Structure of Biotin Carboxylase from Haemophilus influenzae in Complex with AMPPCP and Phosphate
4MV7	47%	Haemophilus influenzae	Crystal Structure of Biotin Carboxylase form Haemophilus influenzae in Complex with Phosphonoformate
4MV6	47%	Haemophilus influenzae	Crystal Structure of Biotin Carboxylase from Haemophilus influenzae in Complex with Phosphonoacetamide

Links to additional information on accA3:
- TBDB (updated)
- Phyre2 structure prediction, model: final.casp.pdb (from Mao et al, 2013)
- UniProt
- AlphaFold model
- Vulnerability = -13.378 (from Jeremy Rock's lab)
- KEGG - nucleotide and amino acid sequences of gene
- Mycobrowser
- PATRIC
- BioCyc
- Systems Biology

Amino Acid Sequence

VASHAGSRIARISKVLVANRGEIAVRVIRAARDAGLPSVAVYAEPDAESPHVRLADEAFALGGQTSAESYLDFAKILDAAAKSGANAIHPGYGFLAENAD
FAQAVIDAGLIWIGPSPQSIRDLGDKVTARHIAARAQAPLVPGTPDPVKGADEVVAFAEEYGLPIAIKAAHGGGGKGMKVARTIDEIPELYESAVREATA
AFGRGECYVERYLDKPRHVEAQVIADQHGNVVVAGTRDCSLQRRYQKLVEEAPAPFLTDFQRKEIHDSAKRICKEAHYHGAGTVEYLVGQDGLISFLEVN
TRLQVEHPVTEETAGIDLVLQQFRIANGEKLDITEDPTPRGHAIEFRINGEDAGRNFLPAPGPVTKFHPPSGPGVRVDSGVETGSVIGGQFDSMLAKLIV
HGADRAEALARARRALNEFGVEGLATVIPFHRAVVSDPAFIGDANGFSVHTRWIETEWNNTIEPFTDGEPLDEDARPRQKVVVEIDGRRVEVSLPADLAL
SNGGGCDPVGVIRRKPKPRKRGAHTGAAASGDAVTAPMQGTVVKFAVEEGQEVVAGDLVVVLEAMKMENPVTAHKDGTITGLAVEAGAAITQGTVLAEIK

(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
Essential	Sodium Oleate	H37RvMA	Gumbel	Subhalaxmi Nambi	Probability of Essentiality: 1.000000; 26 non-insertions in a row out of 26 sites
Essential	Lignoceric Acid	H37RvMA	Gumbel	Subhalaxmi Nambi	Probability of Essentiality: 1.000000; 26 non-insertions in a row out of 26 sites
Essential	Phosphatidylcholine	H37RvMA	Gumbel	Subhalaxmi Nambi	Probability of Essentiality: 1.000000; 26 non-insertions in a row out of 26 sites
Essential	minimal media + 0.1% glycerol	H37RvMA	Gumbel	Griffin et al. (2011)	Probability of Essentiality: 1.000000; 26 non-insertions in a row out of 27 sites
Essential	minimal media + 0.01% cholesterol	H37RvMA	Gumbel	Griffin et al. (2011)	Probability of Essentiality: 1.000000; 26 non-insertions in a row out of 27 sites
Essential	7H10-glycerol	H37RvMA	TraSH	Sassetti et al. (2003a)
Essential	C57BL/6J mice (8 weeks)	H37RvMA	TraSH	Sassetti et al. (2003b)	Hybridization Ratio: 0.08
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

Rv3285.tar.gz
peak counts: Rv3208_pos.txt, Rv3208_neg.txt
peaks showing trend: Rv3285Info_1.txt

accA3 KO Metabolomic Profile

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:
- Rv0678 (-) (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
Interaction	PhysicalInteraction Rv3801c	sourish10	TAS		Affinity purification (Physical interaction) SK. Parker, RM. Barkley et al. Mycobacterium tuberculosis Rv3802c encodes a phospholipase/thioesterase and is inhibited by the antimycobacterial agent tetrahydrolipstatin. PLoS ONE 2009
Name	Biotin-dependent propionyl-CoA carboxylase alpha-3 subunit involved in the synthesis of methyl-malonyl-CoA required for the biosynthesis of multiple methyl-branched fatty acids; the enzyme complex made of AccA3-AccD5-AccE5 shows a clear substrate preference for propionyl-CoA compared with acetyl-CoA (used in the generation of malonyl-CoA)	mjackson	IDA		Claisen-type condensation
Citation	Identification and characterization of Rv3281 as a novel subunit of a biotin-dependent acyl-CoA Carboxylase in Mycobacterium tuberculosis H37Rv. TJ. Oh, J. Daniel et al. J. Biol. Chem. 2006	mjackson		16354663	Biotin-dependent propionyl-CoA carboxylase alpha-3 subunit involved in the synthesis of methyl-malonyl-CoA required for the biosynthesis of multiple methyl-branched fatty acids (enzymatic); the enzyme complex made of AccA3-AccD5-AccE5 shows a clear substrate preference for propionyl-CoA compared with acetyl-CoA (used in the generation of malonyl-CoA)
Other	TBPWY:Methyl-malonyl-CoA synthesis	mjackson			Biotin-dependent propionyl-CoA carboxylase alpha-3 subunit involved in the synthesis of methyl-malonyl-CoA required for the biosynthesis of multiple methyl-branched fatty acids (enzymatic); the enzyme complex made of AccA3-AccD5-AccE5 shows a clear substrate preference for propionyl-CoA compared with acetyl-CoA (used in the generation of malonyl-CoA) TJ. Oh, J. Daniel et al. Identification and characterization of Rv3281 as a novel subunit of a biotin-dependent acyl-CoA Carboxylase in Mycobacterium tuberculosis H37Rv. J. Biol. Chem. 2006
Citation	Biochemical and structural characterization of an essential acyl coenzyme A carboxylase from Mycobacterium tuberculosis. G. Gago, D. Kurth et al. J. Bacteriol. 2006	mjackson		16385038	Biotin-dependent propionyl-CoA carboxylase alpha-3 subunit involved in the synthesis of methyl-malonyl-CoA required for the biosynthesis of multiple methyl-branched fatty acids (enzymatic); the enzyme complex made of AccA3-AccD5-AccE5 shows a clear substrate preference for propionyl-CoA compared with acetyl-CoA (used in the generation of malonyl-CoA)
Other	TBPWY:Methyl-malonyl-CoA synthesis	mjackson			Biotin-dependent propionyl-CoA carboxylase alpha-3 subunit involved in the synthesis of methyl-malonyl-CoA required for the biosynthesis of multiple methyl-branched fatty acids (enzymatic); the enzyme complex made of AccA3-AccD5-AccE5 shows a clear substrate preference for propionyl-CoA compared with acetyl-CoA (used in the generation of malonyl-CoA) G. Gago, D. Kurth et al. Biochemical and structural characterization of an essential acyl coenzyme A carboxylase from Mycobacterium tuberculosis. J. Bacteriol. 2006
Citation	The acyl-AMP ligase FadD32 and AccD4-containing acyl-CoA carboxylase are required for the synthesis of mycolic acids and essential for mycobacterial growth: identification of the carboxylation product and determination of the acyl-CoA carboxylase components. D. Portevin, C. de Sousa-D'Auria et al. J. Biol. Chem. 2005	jjmcfadden		15632194	Inferred from direct assay
Term	EC:6.4.1.2 Acetyl-CoA carboxylase. - NR	jjmcfadden	NR		Inferred from direct assay D. Portevin, C. de Sousa-D'Auria et al. The acyl-AMP ligase FadD32 and AccD4-containing acyl-CoA carboxylase are required for the synthesis of mycolic acids and essential for mycobacterial growth: identification of the carboxylation product and determination of the acyl-CoA carboxylase components. J. Biol. Chem. 2005
Term	EC:6.3.4.14 Biotin carboxylase. - NR	jjmcfadden	NR		Inferred from direct assay D. Portevin, C. de Sousa-D'Auria et al. The acyl-AMP ligase FadD32 and AccD4-containing acyl-CoA carboxylase are required for the synthesis of mycolic acids and essential for mycobacterial growth: identification of the carboxylation product and determination of the acyl-CoA carboxylase components. J. Biol. Chem. 2005
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:6.3.4.14 Biotin carboxylase. - 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:6.4.1.2 Acetyl-CoA carboxylase. - 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:6.4.1.3 Propionyl-CoA carboxylase. - 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	Biochemical and structural characterization of an essential acyl coenzyme A carboxylase from Mycobacterium tuberculosis. G. Gago, D. Kurth et al. J. Bacteriol. 2006	extern:JZUCKER		16385038	Inferred from mutant phenotype
Term	EC:6.3.4.14 Biotin carboxylase. - NR	extern:JZUCKER	NR		Inferred from mutant phenotype G. Gago, D. Kurth et al. Biochemical and structural characterization of an essential acyl coenzyme A carboxylase from Mycobacterium tuberculosis. J. Bacteriol. 2006
Term	EC:6.4.1.2 Acetyl-CoA carboxylase. - NR	extern:JZUCKER	NR		Inferred from mutant phenotype G. Gago, D. Kurth et al. Biochemical and structural characterization of an essential acyl coenzyme A carboxylase from Mycobacterium tuberculosis. J. Bacteriol. 2006
Term	EC:6.4.1.3 Propionyl-CoA carboxylase. - NR	extern:JZUCKER	NR		Inferred from mutant phenotype G. Gago, D. Kurth et al. Biochemical and structural characterization of an essential acyl coenzyme A carboxylase from Mycobacterium tuberculosis. J. Bacteriol. 2006

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