FABG4_MYCTU
ID FABG4_MYCTU Reviewed; 454 AA.
AC I6Y778;
DT 10-FEB-2021, integrated into UniProtKB/Swiss-Prot.
DT 03-OCT-2012, sequence version 1.
DT 03-AUG-2022, entry version 61.
DE RecName: Full=3-oxoacyl-[acyl-carrier-protein] reductase [NADH] {ECO:0000305};
DE EC=1.1.1.212 {ECO:0000305|PubMed:23163771};
DE AltName: Full=Beta-ketoacyl CoA reductase {ECO:0000303|PubMed:21081168};
DE AltName: Full=FASII-like 3-oxoacyl-thioester reductase {ECO:0000303|PubMed:19685079};
DE AltName: Full=HMwFabG {ECO:0000303|PubMed:21081168};
GN Name=fabG4 {ECO:0000303|PubMed:19685079};
GN OrderedLocusNames=Rv0242c {ECO:0000312|EMBL:CCP42971.1};
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 FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=19685079; DOI=10.1007/s00438-009-0474-2;
RA Gurvitz A.;
RT "The essential mycobacterial genes, fabG1 and fabG4, encode 3-oxoacyl-
RT thioester reductases that are functional in yeast mitochondrial fatty acid
RT synthase type 2.";
RL Mol. Genet. Genomics 282:407-416(2009).
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 SUBUNIT, AND CRYSTALLIZATION.
RC STRAIN=H37Rv;
RX PubMed=22750865; DOI=10.1107/s1744309112020301;
RA Dutta D., Bhattacharyya S., Das A.K.;
RT "Crystallization and preliminary X-ray diffraction analysis of the high
RT molecular weight ketoacyl reductase FabG4 complexed with NADH.";
RL Acta Crystallogr. F 68:786-789(2012).
RN [5]
RP IDENTIFICATION AS A DRUG TARGET.
RX PubMed=24129589; DOI=10.1039/c3ob41676c;
RA Banerjee D.R., Dutta D., Saha B., Bhattacharyya S., Senapati K., Das A.K.,
RA Basak A.;
RT "Design, synthesis and characterization of novel inhibitors against
RT mycobacterial beta-ketoacyl CoA reductase FabG4.";
RL Org. Biomol. Chem. 12:73-85(2014).
RN [6]
RP IDENTIFICATION AS A DRUG TARGET.
RX PubMed=25666821; DOI=10.1016/j.bmcl.2015.01.014;
RA Banerjee D.R., Senapati K., Biswas R., Das A.K., Basak A.;
RT "Inhibition of M. tuberculosis beta-ketoacyl CoA reductase FabG4 (Rv0242c)
RT by triazole linked polyphenol-aminobenzene hybrids: comparison with the
RT corresponding gallate counterparts.";
RL Bioorg. Med. Chem. Lett. 25:1343-1347(2015).
RN [7]
RP REVIEW.
RX PubMed=29946302; DOI=10.3389/fmicb.2018.01184;
RA Dutta D.;
RT "Advance in research on Mycobacterium tuberculosis FabG4 and its
RT inhibitor.";
RL Front. Microbiol. 9:1184-1184(2018).
RN [8] {ECO:0007744|PDB:3M1L}
RP X-RAY CRYSTALLOGRAPHY (2.52 ANGSTROMS) OF 17-448, FUNCTION, CATALYTIC
RP ACTIVITY, SUBUNIT, DOMAIN, AND MUTAGENESIS OF 449-GLN--ALA-454.
RX PubMed=21081168; DOI=10.1016/j.jsb.2010.11.012;
RA Dutta D., Bhattacharyya S., Mukherjee S., Saha B., Das A.K.;
RT "Crystal structure of FabG4 from Mycobacterium tuberculosis reveals the
RT importance of C-terminal residues in ketoreductase activity.";
RL J. Struct. Biol. 174:147-155(2011).
RN [9] {ECO:0007744|PDB:3Q6I}
RP X-RAY CRYSTALLOGRAPHY (2.59 ANGSTROMS) OF 17-454 IN COMPLEX WITH NAD.
RA Dutta D., Bhattacharyya S., Das A.K.;
RT "Crystal structure of holoFabG4.";
RL Submitted (JAN-2011) to the PDB data bank.
RN [10] {ECO:0007744|PDB:3V1T}
RP X-RAY CRYSTALLOGRAPHY (1.88 ANGSTROMS).
RA Dutta D., Bhattacharyya S., Das A.K.;
RT "Crystal structure of a putative ketoacyl reductase (FabG4) from
RT Mycobacterium tuberculosis H37Rv at 1.9 Angstrom resolution.";
RL Submitted (DEC-2011) to the PDB data bank.
RN [11] {ECO:0007744|PDB:3V1U, ECO:0007744|PDB:4FW8}
RP X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) IN COMPLEXES WITH NAD; NADH AND
RP HEXANOYL-COA, FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES,
RP PATHWAY, SUBUNIT, DOMAIN, AND MUTAGENESIS OF ARG-146 AND ARG-445.
RX PubMed=23163771; DOI=10.1042/bj20121107;
RA Dutta D., Bhattacharyya S., Roychowdhury A., Biswas R., Das A.K.;
RT "Crystal structure of hexanoyl-CoA bound to beta-ketoacyl reductase FabG4
RT of Mycobacterium tuberculosis.";
RL Biochem. J. 450:127-139(2013).
CC -!- FUNCTION: Catalyzes the NADH-dependent reduction of beta-ketoacyl
CC derivatives (PubMed:19685079, PubMed:21081168, PubMed:23163771). Can
CC accept the beta-oxo fatty acyl group covalently linked with CoA or ACP
CC for catalysis (PubMed:23163771). Highly specific for NADH
CC (PubMed:19685079, PubMed:21081168). Could be involved in fatty acid
CC biosynthesis (Probable). {ECO:0000269|PubMed:19685079,
CC ECO:0000269|PubMed:21081168, ECO:0000269|PubMed:23163771,
CC ECO:0000305|PubMed:19685079, ECO:0000305|PubMed:23163771}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a (3R)-hydroxyacyl-[ACP] + NAD(+) = a 3-oxoacyl-[ACP] + H(+) +
CC NADH; Xref=Rhea:RHEA:19913, Rhea:RHEA-COMP:9916, Rhea:RHEA-COMP:9945,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945,
CC ChEBI:CHEBI:78776, ChEBI:CHEBI:78827; EC=1.1.1.212;
CC Evidence={ECO:0000305|PubMed:23163771};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:19915;
CC Evidence={ECO:0000305|PubMed:23163771};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=3-hydroxybutanoyl-CoA + NAD(+) = acetoacetyl-CoA + H(+) +
CC NADH; Xref=Rhea:RHEA:42048, ChEBI:CHEBI:15378, ChEBI:CHEBI:57286,
CC ChEBI:CHEBI:57540, ChEBI:CHEBI:57945, ChEBI:CHEBI:78611;
CC Evidence={ECO:0000269|PubMed:21081168, ECO:0000269|PubMed:23163771};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:42050;
CC Evidence={ECO:0000269|PubMed:21081168, ECO:0000269|PubMed:23163771};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(3R)-hydroxyhexanoyl-CoA + NAD(+) = 3-oxohexanoyl-CoA + H(+) +
CC NADH; Xref=Rhea:RHEA:45828, ChEBI:CHEBI:15378, ChEBI:CHEBI:57540,
CC ChEBI:CHEBI:57945, ChEBI:CHEBI:62418, ChEBI:CHEBI:74280;
CC Evidence={ECO:0000269|PubMed:19685079};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(3R)-3-hydroxydecanoyl-CoA + NAD(+) = 3-oxodecanoyl-CoA + H(+)
CC + NADH; Xref=Rhea:RHEA:45832, ChEBI:CHEBI:15378, ChEBI:CHEBI:57540,
CC ChEBI:CHEBI:57945, ChEBI:CHEBI:62548, ChEBI:CHEBI:74272;
CC Evidence={ECO:0000269|PubMed:19685079};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=141.9 uM for acetoacetyl-CoA {ECO:0000269|PubMed:23163771};
CC KM=252 uM for 3-hydroxybutanoyl-CoA {ECO:0000269|PubMed:23163771};
CC KM=24.2 uM for NADH {ECO:0000269|PubMed:23163771};
CC KM=228.3 uM for NAD(+) {ECO:0000269|PubMed:23163771};
CC Note=kcat is 454 sec(-1) with acetoacetyl-CoA as substrate. kcat is
CC 169 sec(-1) with 3-hydroxybutanoyl-CoA as substrate. kcat is 319
CC sec(-1) with NADH as substrate. kcat is 83 sec(-1) with NAD(+) as
CC substrate. {ECO:0000269|PubMed:23163771};
CC -!- PATHWAY: Lipid metabolism; fatty acid metabolism.
CC {ECO:0000305|PubMed:23163771}.
CC -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:21081168,
CC ECO:0000269|PubMed:22750865, ECO:0000269|PubMed:23163771}.
CC -!- DOMAIN: Contains an N-terminal flavodoxin-type domain and a C-terminal
CC ketoreductase domain (PubMed:21081168). The C-terminal residues
CC participate in intercatalytic domain interaction and play a pivotal
CC role in stabilization of loop I, which is responsible for interaction
CC with phosphopentethine moiety-linked fatty acyl substrates of CoA or
CC ACP (PubMed:23163771). {ECO:0000269|PubMed:21081168,
CC ECO:0000269|PubMed:23163771}.
CC -!- MISCELLANEOUS: Restores respiratory growth of S.cerevisiae oar1
CC deletion mutant. {ECO:0000269|PubMed:19685079}.
CC -!- MISCELLANEOUS: Was identified as a putative drug target. Inhibited by
CC triazole linked polyphenol-gallol hybrids and triazole linked
CC polyphenol-aminobenzene hybrids. These compounds may be possible
CC candidates for alternate anti-tubercular drugs.
CC {ECO:0000269|PubMed:24129589, ECO:0000269|PubMed:25666821}.
CC -!- SIMILARITY: Belongs to the short-chain dehydrogenases/reductases (SDR)
CC family. {ECO:0000305}.
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DR EMBL; AL123456; CCP42971.1; -; Genomic_DNA.
DR RefSeq; NP_214756.1; NC_000962.3.
DR RefSeq; WP_003899869.1; NZ_NVQJ01000001.1.
DR PDB; 3M1L; X-ray; 2.52 A; A/B=17-448.
DR PDB; 3Q6I; X-ray; 2.59 A; A/B/C/D=17-454.
DR PDB; 3V1T; X-ray; 1.88 A; C/D=1-454.
DR PDB; 3V1U; X-ray; 2.50 A; A=1-454.
DR PDB; 4FW8; X-ray; 2.79 A; A/B/C/D=1-454.
DR PDBsum; 3M1L; -.
DR PDBsum; 3Q6I; -.
DR PDBsum; 3V1T; -.
DR PDBsum; 3V1U; -.
DR PDBsum; 4FW8; -.
DR AlphaFoldDB; I6Y778; -.
DR SMR; I6Y778; -.
DR STRING; 83332.Rv0242c; -.
DR SwissLipids; SLP:000001158; -.
DR PaxDb; I6Y778; -.
DR PRIDE; I6Y778; -.
DR DNASU; 886697; -.
DR GeneID; 886697; -.
DR KEGG; mtu:Rv0242c; -.
DR PATRIC; fig|83332.111.peg.275; -.
DR TubercuList; Rv0242c; -.
DR eggNOG; COG1028; Bacteria.
DR OMA; LYEFFTP; -.
DR PhylomeDB; I6Y778; -.
DR UniPathway; UPA00199; -.
DR Proteomes; UP000001584; Chromosome.
DR GO; GO:0047025; F:3-oxoacyl-[acyl-carrier-protein] reductase (NADH) activity; IEA:UniProtKB-EC.
DR GO; GO:0016616; F:oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor; IBA:GO_Central.
DR GO; GO:0030497; P:fatty acid elongation; IBA:GO_Central.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR InterPro; IPR020904; Sc_DH/Rdtase_CS.
DR InterPro; IPR002347; SDR_fam.
DR PRINTS; PR00081; GDHRDH.
DR PRINTS; PR00080; SDRFAMILY.
DR SUPFAM; SSF51735; SSF51735; 1.
DR PROSITE; PS00061; ADH_SHORT; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Fatty acid metabolism; Lipid metabolism; NAD; Oxidoreductase;
KW Reference proteome.
FT CHAIN 1..454
FT /note="3-oxoacyl-[acyl-carrier-protein] reductase [NADH]"
FT /id="PRO_0000451898"
FT ACT_SITE 360
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10001"
FT BINDING 223..225
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:23163771,
FT ECO:0007744|PDB:3V1U, ECO:0007744|PDB:4FW8"
FT BINDING 244
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:23163771, ECO:0000269|Ref.9,
FT ECO:0007744|PDB:3Q6I, ECO:0007744|PDB:3V1U,
FT ECO:0007744|PDB:4FW8"
FT BINDING 267..268
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:23163771, ECO:0000269|Ref.9,
FT ECO:0007744|PDB:3Q6I, ECO:0007744|PDB:3V1U,
FT ECO:0007744|PDB:4FW8"
FT BINDING 295..297
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:23163771, ECO:0000269|Ref.9,
FT ECO:0007744|PDB:3Q6I, ECO:0007744|PDB:3V1U,
FT ECO:0007744|PDB:4FW8"
FT BINDING 302..306
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:23163771"
FT BINDING 354
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:23163771"
FT BINDING 360
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:23163771, ECO:0000269|Ref.9,
FT ECO:0007744|PDB:3Q6I, ECO:0007744|PDB:3V1U,
FT ECO:0007744|PDB:4FW8"
FT BINDING 364
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:23163771, ECO:0000269|Ref.9,
FT ECO:0007744|PDB:3Q6I, ECO:0007744|PDB:3V1U,
FT ECO:0007744|PDB:4FW8"
FT BINDING 395
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:23163771, ECO:0000269|Ref.9,
FT ECO:0007744|PDB:3Q6I, ECO:0007744|PDB:4FW8"
FT MUTAGEN 146
FT /note="R->A: 2.2-fold decrease in catalytic efficiency with
FT NADH as substrate. 26-fold decrease in catalytic
FT efficiency; when associated with A-445."
FT /evidence="ECO:0000269|PubMed:23163771"
FT MUTAGEN 445
FT /note="R->A: 12-fold decrease in catalytic efficiency with
FT NADH as substrate. 26-fold decrease in catalytic
FT efficiency; when associated with A-146."
FT /evidence="ECO:0000269|PubMed:23163771"
FT MUTAGEN 449..454
FT /note="Missing: Drastic reduction of ketoreductase
FT activity."
FT /evidence="ECO:0000269|PubMed:21081168"
SQ SEQUENCE 454 AA; 46830 MW; C5B89B6FEA38BD91 CRC64;
MAPKRSSDLF SQVVNSGPGS FLARQLGVPQ PETLRRYRAG EPPLTGSLLI GGAGRVVEPL
RAALEKDYDL VGNNLGGRWA DSFGGLVFDA TGITEPAGLK GLHEFFTPVL RNLGRCGRVV
VVGGTPEAAA STNERIAQRA LEGFTRSLGK ELRRGATTAL VYLSPDAKPA ATGLESTMRF
LLSAKSAYVD GQVFSVGADD STPPADWEKP LDGKVAIVTG AARGIGATIA EVFARDGAHV
VAIDVESAAE NLAETASKVG GTALWLDVTA DDAVDKISEH LRDHHGGKAD ILVNNAGITR
DKLLANMDDA RWDAVLAVNL LAPLRLTEGL VGNGSIGEGG RVIGLSSIAG IAGNRGQTNY
ATTKAGMIGI TQALAPGLAA KGITINAVAP GFIETQMTAA IPLATREVGR RLNSLLQGGQ
PVDVAEAIAY FASPASNAVT GNVIRVCGQA MIGA
