COABC_MYCTU
ID COABC_MYCTU Reviewed; 418 AA.
AC P9WNZ1; L0T847; P67733; P71661;
DT 16-APR-2014, integrated into UniProtKB/Swiss-Prot.
DT 16-APR-2014, sequence version 1.
DT 03-AUG-2022, entry version 46.
DE RecName: Full=Coenzyme A biosynthesis bifunctional protein CoaBC {ECO:0000255|HAMAP-Rule:MF_02225};
DE AltName: Full=DNA/pantothenate metabolism flavoprotein {ECO:0000255|HAMAP-Rule:MF_02225};
DE AltName: Full=Phosphopantothenoylcysteine synthetase/decarboxylase {ECO:0000255|HAMAP-Rule:MF_02225};
DE Short=PPCS-PPCDC {ECO:0000255|HAMAP-Rule:MF_02225};
DE Includes:
DE RecName: Full=Phosphopantothenoylcysteine decarboxylase {ECO:0000255|HAMAP-Rule:MF_02225};
DE Short=PPC decarboxylase {ECO:0000255|HAMAP-Rule:MF_02225};
DE Short=PPC-DC {ECO:0000255|HAMAP-Rule:MF_02225};
DE EC=4.1.1.36 {ECO:0000255|HAMAP-Rule:MF_02225};
DE AltName: Full=CoaC {ECO:0000255|HAMAP-Rule:MF_02225};
DE Includes:
DE RecName: Full=Phosphopantothenate--cysteine ligase {ECO:0000255|HAMAP-Rule:MF_02225};
DE EC=6.3.2.5 {ECO:0000255|HAMAP-Rule:MF_02225};
DE AltName: Full=CoaB {ECO:0000255|HAMAP-Rule:MF_02225};
DE AltName: Full=Phosphopantothenoylcysteine synthetase {ECO:0000255|HAMAP-Rule:MF_02225};
DE Short=PPC synthetase {ECO:0000255|HAMAP-Rule:MF_02225};
DE Short=PPC-S {ECO:0000255|HAMAP-Rule:MF_02225};
GN Name=coaBC {ECO:0000255|HAMAP-Rule:MF_02225, ECO:0000303|PubMed:27676316};
GN Synonyms=dfp; OrderedLocusNames=Rv1391; ORFNames=MTCY21B4.08;
OS Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv).
OC Bacteria; Actinobacteria; Corynebacteriales; Mycobacteriaceae;
OC Mycobacterium; Mycobacterium tuberculosis complex.
OX NCBI_TaxID=83332;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=9634230; DOI=10.1038/31159;
RA Cole S.T., Brosch R., Parkhill J., Garnier T., Churcher C.M., Harris D.E.,
RA Gordon S.V., Eiglmeier K., Gas S., Barry C.E. III, Tekaia F., Badcock K.,
RA Basham D., Brown D., Chillingworth T., Connor R., Davies R.M., Devlin K.,
RA Feltwell T., Gentles S., Hamlin N., Holroyd S., Hornsby T., Jagels K.,
RA Krogh A., McLean J., Moule S., Murphy L.D., Oliver S., Osborne J.,
RA Quail M.A., Rajandream M.A., Rogers J., Rutter S., Seeger K., Skelton S.,
RA Squares S., Squares R., Sulston J.E., Taylor K., Whitehead S.,
RA Barrell B.G.;
RT "Deciphering the biology of Mycobacterium tuberculosis from the complete
RT genome sequence.";
RL Nature 393:537-544(1998).
RN [2]
RP IDENTIFICATION AS A DRUG TARGET [LARGE SCALE ANALYSIS].
RX PubMed=19099550; DOI=10.1186/1752-0509-2-109;
RA Raman K., Yeturu K., Chandra N.;
RT "targetTB: a target identification pipeline for Mycobacterium tuberculosis
RT through an interactome, reactome and genome-scale structural analysis.";
RL BMC Syst. Biol. 2:109-109(2008).
RN [3]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=21969609; DOI=10.1074/mcp.m111.011627;
RA Kelkar D.S., Kumar D., Kumar P., Balakrishnan L., Muthusamy B., Yadav A.K.,
RA Shrivastava P., Marimuthu A., Anand S., Sundaram H., Kingsbury R.,
RA Harsha H.C., Nair B., Prasad T.S., Chauhan D.S., Katoch K., Katoch V.M.,
RA Kumar P., Chaerkady R., Ramachandran S., Dash D., Pandey A.;
RT "Proteogenomic analysis of Mycobacterium tuberculosis by high resolution
RT mass spectrometry.";
RL Mol. Cell. Proteomics 10:M111.011627-M111.011627(2011).
RN [4]
RP FUNCTION, DISRUPTION PHENOTYPE, AND IDENTIFICATION AS A DRUG TARGET.
RX PubMed=27676316; DOI=10.1021/acsinfecdis.6b00150;
RA Evans J.C., Trujillo C., Wang Z., Eoh H., Ehrt S., Schnappinger D.,
RA Boshoff H.I., Rhee K.Y., Barry C.E. III, Mizrahi V.;
RT "Validation of CoaBC as a bactericidal target in the coenzyme A pathway of
RT Mycobacterium tuberculosis.";
RL ACS Infect. Dis. 2:958-968(2016).
RN [5]
RP ACTIVITY REGULATION, SUBUNIT, AND IDENTIFICATION AS A DRUG TARGET.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=33420031; DOI=10.1038/s41467-020-20224-x;
RA Mendes V., Green S.R., Evans J.C., Hess J., Blaszczyk M., Spry C.,
RA Bryant O., Cory-Wright J., Chan D.S., Torres P.H.M., Wang Z., Nahiyaan N.,
RA O'Neill S., Damerow S., Post J., Bayliss T., Lynch S.L., Coyne A.G.,
RA Ray P.C., Abell C., Rhee K.Y., Boshoff H.I.M., Barry C.E. III, Mizrahi V.,
RA Wyatt P.G., Blundell T.L.;
RT "Inhibiting Mycobacterium tuberculosis CoaBC by targeting an allosteric
RT site.";
RL Nat. Commun. 12:143-143(2021).
CC -!- FUNCTION: Catalyzes two sequential steps in the biosynthesis of
CC coenzyme A. In the first step cysteine is conjugated to 4'-
CC phosphopantothenate to form 4-phosphopantothenoylcysteine. In the
CC second step the latter compound is decarboxylated to form 4'-
CC phosphopantotheine (By similarity). Required for growth and persistence
CC in mice (PubMed:27676316). {ECO:0000255|HAMAP-Rule:MF_02225,
CC ECO:0000269|PubMed:27676316}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H(+) + N-[(R)-4-phosphopantothenoyl]-L-cysteine = (R)-4'-
CC phosphopantetheine + CO2; Xref=Rhea:RHEA:16793, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:16526, ChEBI:CHEBI:59458, ChEBI:CHEBI:61723; EC=4.1.1.36;
CC Evidence={ECO:0000255|HAMAP-Rule:MF_02225};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(R)-4'-phosphopantothenate + CTP + L-cysteine = CMP +
CC diphosphate + H(+) + N-[(R)-4-phosphopantothenoyl]-L-cysteine;
CC Xref=Rhea:RHEA:19397, ChEBI:CHEBI:10986, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:33019, ChEBI:CHEBI:35235, ChEBI:CHEBI:37563,
CC ChEBI:CHEBI:59458, ChEBI:CHEBI:60377; EC=6.3.2.5;
CC Evidence={ECO:0000255|HAMAP-Rule:MF_02225};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000255|HAMAP-Rule:MF_02225};
CC -!- COFACTOR:
CC Name=FMN; Xref=ChEBI:CHEBI:58210;
CC Evidence={ECO:0000255|HAMAP-Rule:MF_02225};
CC Note=Binds 1 FMN per subunit. {ECO:0000255|HAMAP-Rule:MF_02225};
CC -!- ACTIVITY REGULATION: Inhibited by coenzyme A (CoA) and CoA thioesthers
CC (PubMed:33420031). Two related chemical scaffolds that potently inhibit
CC the activity of the CoaB moiety of CoaBC through a cryptic allosteric
CC site that sits in the dimer interface region of the CoaB enzyme were
CC identified (PubMed:33420031). {ECO:0000269|PubMed:33420031}.
CC -!- PATHWAY: Cofactor biosynthesis; coenzyme A biosynthesis; CoA from (R)-
CC pantothenate: step 2/5. {ECO:0000255|HAMAP-Rule:MF_02225}.
CC -!- PATHWAY: Cofactor biosynthesis; coenzyme A biosynthesis; CoA from (R)-
CC pantothenate: step 3/5. {ECO:0000255|HAMAP-Rule:MF_02225}.
CC -!- SUBUNIT: Homododecamer. {ECO:0000269|PubMed:33420031}.
CC -!- DISRUPTION PHENOTYPE: Transcriptional silencing of this gene leads to
CC growth attenuation and results in a bactericidal phenotype in vitro and
CC in vivo, whether initiated at infection or during either the acute or
CC chronic stages of infection. {ECO:0000269|PubMed:27676316}.
CC -!- MISCELLANEOUS: Was identified as a high-confidence drug target.
CC {ECO:0000269|PubMed:19099550, ECO:0000269|PubMed:27676316,
CC ECO:0000269|PubMed:33420031}.
CC -!- SIMILARITY: In the N-terminal section; belongs to the HFCD (homo-
CC oligomeric flavin containing Cys decarboxylase) superfamily.
CC {ECO:0000255|HAMAP-Rule:MF_02225}.
CC -!- SIMILARITY: In the C-terminal section; belongs to the PPC synthetase
CC family. {ECO:0000255|HAMAP-Rule:MF_02225}.
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DR EMBL; AL123456; CCP44150.1; -; Genomic_DNA.
DR PIR; E70899; E70899.
DR RefSeq; NP_215907.1; NC_000962.3.
DR RefSeq; WP_003898859.1; NZ_NVQJ01000050.1.
DR AlphaFoldDB; P9WNZ1; -.
DR SMR; P9WNZ1; -.
DR STRING; 83332.Rv1391; -.
DR ChEMBL; CHEMBL4662928; -.
DR PaxDb; P9WNZ1; -.
DR DNASU; 886749; -.
DR GeneID; 886749; -.
DR KEGG; mtu:Rv1391; -.
DR PATRIC; fig|83332.111.peg.1550; -.
DR TubercuList; Rv1391; -.
DR eggNOG; COG0452; Bacteria.
DR OMA; LDMIVAN; -.
DR PhylomeDB; P9WNZ1; -.
DR UniPathway; UPA00241; UER00353.
DR UniPathway; UPA00241; UER00354.
DR Proteomes; UP000001584; Chromosome.
DR GO; GO:0071513; C:phosphopantothenoylcysteine decarboxylase complex; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; HDA:MTBBASE.
DR GO; GO:0010181; F:FMN binding; IBA:GO_Central.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0004632; F:phosphopantothenate--cysteine ligase activity; IEA:UniProtKB-UniRule.
DR GO; GO:0004633; F:phosphopantothenoylcysteine decarboxylase activity; IDA:MTBBASE.
DR GO; GO:0015937; P:coenzyme A biosynthetic process; IDA:MTBBASE.
DR GO; GO:0015941; P:pantothenate catabolic process; IEA:InterPro.
DR Gene3D; 3.40.50.10300; -; 1.
DR Gene3D; 3.40.50.1950; -; 1.
DR HAMAP; MF_02225; CoaBC; 1.
DR InterPro; IPR035929; CoaB-like_sf.
DR InterPro; IPR005252; CoaBC.
DR InterPro; IPR007085; DNA/pantothenate-metab_flavo_C.
DR InterPro; IPR036551; Flavin_trans-like.
DR InterPro; IPR003382; Flavoprotein.
DR Pfam; PF04127; DFP; 1.
DR Pfam; PF02441; Flavoprotein; 1.
DR SUPFAM; SSF102645; SSF102645; 1.
DR SUPFAM; SSF52507; SSF52507; 1.
DR TIGRFAMs; TIGR00521; coaBC_dfp; 1.
PE 1: Evidence at protein level;
KW Decarboxylase; Flavoprotein; FMN; Ligase; Lyase; Magnesium; Metal-binding;
KW Multifunctional enzyme; Reference proteome.
FT CHAIN 1..418
FT /note="Coenzyme A biosynthesis bifunctional protein CoaBC"
FT /id="PRO_0000232694"
FT REGION 1..195
FT /note="Phosphopantothenoylcysteine decarboxylase"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_02225"
FT REGION 196..418
FT /note="Phosphopantothenate--cysteine ligase"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_02225"
FT BINDING 285
FT /ligand="CTP"
FT /ligand_id="ChEBI:CHEBI:37563"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_02225"
FT BINDING 295
FT /ligand="CTP"
FT /ligand_id="ChEBI:CHEBI:37563"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_02225"
FT BINDING 336
FT /ligand="CTP"
FT /ligand_id="ChEBI:CHEBI:37563"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_02225"
FT BINDING 354
FT /ligand="CTP"
FT /ligand_id="ChEBI:CHEBI:37563"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_02225"
FT BINDING 358
FT /ligand="CTP"
FT /ligand_id="ChEBI:CHEBI:37563"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_02225"
SQ SEQUENCE 418 AA; 43577 MW; 48BD95E536595506 CRC64;
MVDHKRIPKQ VIVGVSGGIA AYKACTVVRQ LTEASHRVRV IPTESALRFV GAATFEALSG
EPVCTDVFAD VPAVPHVHLG QQADLVVVAP ATADLLARAA AGRADDLLTA TLLTARCPVL
FAPAMHTEMW LHPATVDNVA TLRRRGAVVL EPATGRLTGA DSGAGRLPEA EEITTLAQLL
LERHDALPYD LAGRKLLVTA GGTREPIDPV RFIGNRSSGK QGYAVARVAA QRGADVTLIA
GHTAGLVDPA GVEVVHVSSA QQLADAVSKH APTADVLVMA AAVADFRPAQ VATAKIKKGV
EGPPTIELLR NDDVLAGVVR ARAHGQLPNM RAIVGFAAET GDANGDVLFH ARAKLRRKGC
DLLVVNAVGE GRAFEVDSND GWLLASDGTE SALQHGSKTL MASRIVDAIV TFLAGCSS
