Rv3602c (panC)

Current annotations:
- TBCAP: (community-based annotations - see table at bottom of page)
- TBDB: pantothenate synthetase
- REFSEQ: pantoate--beta-alanine ligase
- PATRIC: Pantoate--beta-alanine ligase (EC 6.3.2.1)
- TUBERCULIST: Pantoate--beta-alanine ligase PanC (pantothenate synthetase) (pantoate activating enzyme)
- NCBI: Pantoate--beta-alanine ligase PanC (pantothenate synthetase) (pantoate activating enzyme)
- updated information (H37Rv4):
  - gene name: panC
  - function:
  - reference:
Type: Not Target
Start: 4044281
End: 4045210
Operon:

Trans-membrane region:
Role: I.G.5 - Pantothenate
GO terms:
- GO:0046872 - metal ion binding (Uniprot)
- GO:0040007 - growth (Uniprot)
- GO:0033317 - pantothenate biosynthetic process from valine (Uniprot)
- GO:0030145 - manganese ion binding (Uniprot)
- GO:0019482 - beta-alanine metabolic process (Uniprot)
- GO:0016874 - ligase activity (Uniprot)
- GO:0015940 - pantothenate biosynthetic process (Uniprot)
- GO:0009405 - pathogenesis (Uniprot)
- GO:0005829 - cytosol (Uniprot)
- GO:0005737 - cytoplasm (Uniprot)
- GO:0005524 - ATP binding (Uniprot)
- GO:0005515 - protein binding (Uniprot)
- GO:0004592 - pantoate-beta-alanine ligase activity (Uniprot)
- GO:0000287 - magnesium ion binding (Uniprot)
- GO:0000166 - nucleotide binding (Uniprot)
Reaction(s) (based on iSM810 metabolic model):
- ATP[c] + bALA[c] + PANT[c] -> PPI[c] + AMP[c] + PNTO[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: 3coy, 3coz, 3cov, 3cow, 1n2e, 1n2g, 1n2b, 1n2o, 1n2h, 1n2i, 1n2j, 3iod, 3ioe, 3iob, 3ioc, 3ime, 3ivc, 3img, 4fzj, 3ivg, 3imc, 3ivx, 4ddm, 1mop, 2a7x, 4ddh, 4ddk, 4efk, 2a88, 2a84, 2a86, 4ef6, 3le8, 3iue, 3iub, 3isj, 4de5, 3ime, 3iue, 3ioe, 3ioc, 3iub
Search for Homologs in PDB

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

PDB	aa ident	species	PDB title
4MUN	99%	Mycobacterium tuberculosis	Crystal structure of pantothenate synthetase in complex with 2-(5-methoxy-2-(2-nitro-4-(trifluoromethyl)phenylsulfonylcarbamoyl)-1H-indol-1-yl)acetic acid
4MUL	99%	Mycobacterium tuberculosis	Crystal structure of pantothenate synthetase in complex with 2-(5-methoxy-2-(naphthalen-2-ylsulfonylcarbamoyl)-1H-indol-1-yl)acetic acid
4MUK	99%	Mycobacterium tuberculosis	Crystal structure of pantothenate synthetase in complex with 2-(5-methoxy-2-(4-(trifluoromethyl)benzylsulfonylcarbamoyl)-1H-indol-1-yl)acetic acid
4MUJ	99%	Mycobacterium tuberculosis	Crystal structure of pantothenate synthetase in complex with 2-(2-(benzylsulfonylcarbamoyl)-5-methoxy-1H-indol-1-yl)acetic acid
4MUI	99%	Mycobacterium tuberculosis	Crystal structure of pantothenate synthetase in complex with 2-(5-methoxy-2-(4-methoxyphenylsulfonylcarbamoyl)-1H-indol-1-yl)acetic acid
4MUH	99%	Mycobacterium tuberculosis	Crystal structure of pantothenate synthetase in complex with 2-(2-(5-acetamido-1,3,4-thiadiazol-2-ylsulfonylcarbamoyl)-5-methoxy-1H-indol-1-yl)acetic acid
4MUG	99%	Mycobacterium tuberculosis	Crystal structure of pantothenate synthetase in complex with 2-(5-methoxy-2-(morpholinosulfonylcarbamoyl)-1H-indol-1-yl)acetic acid
4MUF	99%	Mycobacterium tuberculosis	Crystal structure of pantothenate synthetase in complex with 2-(2-(4-tert-butylphenylsulfonylcarbamoyl)-5-methoxy-1H-indol-1-yl)acetic acid
4MUE	99%	Mycobacterium tuberculosis	Crystal strcture of pantothenate synthetase in complex with 2-(5-methoxy-2-(4-(trifluoromethyl)phenylsulfonylcarbamoyl)-1H-indol-1-yl)acetic acid
4MQ6	99%	Mycobacterium tuberculosis	Pantothenate synthase in complex with 2-(5-methoxy-2-(tosylcarbamoyl)-1H-indol-1-yl)acetic acid

Links to additional information on panC:
- KEGG - nucleotide and amino acid sequences of gene
- Mycobrowser
- PATRIC
- BioCyc
- Systems Biology
- TBDB (updated)
- Phyre2 structure prediction, model: final.casp.pdb (from Mao et al, 2013)
- UniProt
- AlphaFold model
- Vulnerability = -3.926 (from Jeremy Rock's lab)

Amino Acid Sequence

MTIPAFHPGELNVYSAPGDVADVSRALRLTGRRVMLVPTMGALHEGHLALVRAAKRVPGSVVVVSIFVNPMQFGAGEDLDAYPRTPDDDLAQLRAEGVEI
AFTPTTAAMYPDGLRTTVQPGPLAAELEGGPRPTHFAGVLTVVLKLLQIVRPDRVFFGEKDYQQLVLIRQLVADFNLDVAVVGVPTVREADGLAMSSRNR
YLDPAQRAAAVALSAALTAAAHAATAGAQAALDAARAVLDAAPGVAVDYLELRDIGLGPMPLNGSGRLLVAARLGTTRLLDNIAIEIGTFAGTDRPDGYR
AILESHWRN

(Nucleotide sequence available on KEGG)

Additional Information

Analysis of Positive Selection in Clinical Isolates new

Analysis of dN/dS (omega) in two collections of Mtb clinical isolates using GenomegaMap (Window model) (see description of methods)
- Moldova: 2,057 clinical isolates
- global set: 5,195 clinical isolates from 15 other countries
In the omega plots, the black line shows the mean estimate of omega (dN/dS) at each codon, and the blue lines are the bounds for the 95% credible interval (95%CI, from MCMC sampling).
A gene is under significant positive selection if the lower-bound of the 95%CI of omega (lower blue line) exceeds 1.0 at any codon.

	Moldova (2,057)	global set (5,195)
under significant positive selection?	NO	NO
omega peak height (95%CI lower bound)	1.42 (0.21)	1.27 (0.58)
codons under selection
omega plots
genetic variants*	link	link
statistics at each codon	link	link

* example format for variants: "D27 (GAC): D27H (CAC,11)" means "Asp27 (native codon GAC) mutated to His (codon CAC) in 11 isolates"

ESSENTIALITY

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

TnSeqCorr - genes with correlated TnSeq profiles across ~100 conditions

Rv3602c/panC, gene len: 929 bp, num TA sites: 13

condition	dataset	call	medium	method	notes
in-vitro	DeJesus 2017 mBio	essential	7H9	HMM	fully saturated, 14 TnSeq libraries combined
in-vitro	Sassetti 2003 Mol Micro	essential	7H9	TRASH	essential if hybridization ratio<0.2
in-vivo (mice)	Sassetti 2003 PNAS	no data	BL6 mice	TRASH	essential if hybridization ratio<0.4, min over 4 timepoints (1-8 weeks)
in-vitro (glycerol)	Griffin 2011 PPath	essential	M9 minimal+glycerol	Gumbel	2 replicates; Padj<0.05
in-vitro (cholesterol)	Griffin 2011 PPath	essential	M9 minimal+cholesterol	Gumbel	3 replicates; Padj<0.05
differentially essential in cholesterol	Griffin 2011 PPath	NO (LFC=0.0)	cholesterol vs glycerol	resampling-SR	YES if Padj<0.05, else not significant; LFC<0 means less insertions/more essential in cholesterol
in-vitro	Smith 2022 eLife	essential	7H9	HMM	6 replicates (raw data in Subramaniam 2017, PMID 31752678)
in-vivo (mice)	Smith 2022 eLife	essential	BL6 mice	HMM	6 replicates (raw data in Subramaniam 2017, PMID 31752678)
differentially essential in mice	Smith 2022 eLife	NO (LFC=0.0)	in-vivo vs in-vitro	ZINB	YES if Padj<0.05, else not significant; LFC<0 means less insertions/more essential in mice
in-vitro (minimal)	Minato 2019 mSys	essential	minimal medium	HMM
in-vitro (YM rich medium)	Minato 2019 mSys	non-essential	YM rich medium	HMM	7H9 supplemented with ~20 metabolites (amino acids, cofactors)
differentially essential in YM rich medium	Minato 2019 mSys	YES (LFC=6.93)	YM rich vs minimal medium	resampling

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

Binds To:
- No bindings to other targets were found.
Bound By:
- Rv3058c (-)

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

Binds To:
- No bindings to other targets were found.
Bound By:
- Rv3736 (-) (Direct binding)
- Rv0135c (-) (Upstream of operon)
- Rv1353c (-) (Upstream of operon)

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:
- Rv3058c (-)

Property	Value	Creator	Evidence	PMID	Comment
Interaction	RegulatedBy Rv0981	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.. H. He, R. Hovey et al. MprAB is a stress-responsive two-component system that directly regulates expression of sigma factors SigB and SigE in Mycobacterium tuberculosis. J. Bacteriol. 2006
Citation	Active site residues in Mycobacterium tuberculosis pantothenate synthetase required in the formation and stabilization of the adenylate intermediate. authors,R. Zheng,TK. Dam,CF. Brewer,JS. Blanchard Biochemistry 2004	jevans		15170354	Highly conserved residues His44, His47, Asn69, Gln72 and Lys160 are essential for formationof the pantoyl-adenylate intermediate
Citation	The design and synthesis of inhibitors of pantothenate synthetase. authors,KL. Tuck,SA. Saldanha,LM. Birch,AG. Smith,C. Abell Org. Biomol. Chem. 2006	jevans		16990935	Analogues of the pantoyl-adenylate intermediate in which the phosphodiester is replaced by a sulfamoyl group are potent inhibitors.
Citation	A novel inhibitor of Mycobacterium tuberculosis pantothenate synthetase. EL. White, K. Southworth et al. Journal of biomolecular screening : the official journal of the Society for Biomolecular Screening 2007	jevans		17175524	Inhibited by the vasodilator, nafronyl oxalate, but no whole cell activity in vitro.
Citation	5-tert-butyl-N-pyrazol-4-yl-4,5,6,7-tetrahydrobenzo[d]isoxazole-3-carboxamide derivatives as novel potent inhibitors of Mycobacterium tuberculosis pantothenate synthetase: initiating a quest for new antitubercular drugs. authors,S. Velaparthi,M. Brunsteiner,R. Uddin,B. Wan,SG. Franzblau,PA. Petukhov J. Med. Chem. 2008	jevans		18335974	The tert-butyl and pyrazole portions of 5-tert-Butyl-N-pyrazol-4-yl-4,5,6,7-tetrahydrobenzo[d]isoxazole-3-carboxamide derivatives are crucial for pantothenate synthetase inhibition.
Citation	Application of fragment growing and fragment linking to the discovery of inhibitors of Mycobacterium tuberculosis pantothenate synthetase. authors,AW. Hung,HL. Silvestre,S. Wen,A. Ciulli,TL. Blundell,C. Abell Angew. Chem. Int. Ed. Engl. 2009	jevans		19780086	5-methoxyindole competitively inhibits ATP binding.
Citation	A comparison of the dynamics of pantothenate synthetase from M. tuberculosis and E. coli: computational studies. authors,YS. Tan,G. Fuentes,C. Verma Proteins 2011	jevans		21425349	N-terminal domain gate loop motions dominate in Mtb pantothenate synthetase, as opposed to C-terminal domain motions that dominate in E. coli PS
Citation	A discovery of novel Mycobacterium tuberculosis pantothenate synthetase inhibitors based on the molecular mechanism of actinomycin D inhibition. authors,Y. Yang,P. Gao,Y. Liu,X. Ji,M. Gan,Y. Guan,X. Hao,Z. Li,C. Xiao Bioorg. Med. Chem. Lett. 2011	jevans		21641210	Weakly inhibited by actinomycin D
Citation	Positional isotope exchange analysis of the pantothenate synthetase reaction. authors,L. Williams,R. Zheng,JS. Blanchard,FM. Raushel Biochemistry 2003	jevans		12718554	Catalyses the formation of a pantoyl-adenylate intermediate upon the ordered addition of ATP and pantoate.

TB Genome Annotation Portal