KASB_MYCTU
ID KASB_MYCTU Reviewed; 417 AA.
AC P9WQD7; L0TBY1; P63456; Q10525;
DT 16-APR-2014, integrated into UniProtKB/Swiss-Prot.
DT 16-APR-2014, sequence version 1.
DT 03-AUG-2022, entry version 49.
DE RecName: Full=3-oxoacyl-[acyl-carrier-protein] synthase 2;
DE EC=2.3.1.294 {ECO:0000305|PubMed:11600501, ECO:0000305|PubMed:12464486};
DE AltName: Full=Beta-ketoacyl-ACP synthase 2;
DE Short=KAS 2;
DE AltName: Full=Beta-ketoacyl-acyl carrier protein synthase KasB {ECO:0000303|PubMed:11600501};
DE AltName: Full=Meromycolic acid 3-oxoacyl-(acyl carrier protein) synthase II;
GN Name=kasB {ECO:0000303|PubMed:10747933}; OrderedLocusNames=Rv2246;
GN ORFNames=MTCY427.27;
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.
RX PubMed=10747933; DOI=10.1074/jbc.m000569200;
RA Kremer L., Douglas J.D., Baulard A.R., Morehouse C., Guy M.R., Alland D.,
RA Dover L.G., Lakey J.H., Jacobs W.R. Jr., Brennan P.J., Minnikin D.E.,
RA Besra G.S.;
RT "Thiolactomycin and related analogues as novel anti-mycobacterial agents
RT targeting KasA and KasB condensing enzymes in Mycobacterium tuberculosis.";
RL J. Biol. Chem. 275:16857-16864(2000).
RN [3]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND PATHWAY.
RX PubMed=11600501; DOI=10.1074/jbc.m108903200;
RA Schaeffer M.L., Agnihotri G., Volker C., Kallender H., Brennan P.J.,
RA Lonsdale J.T.;
RT "Purification and biochemical characterization of the Mycobacterium
RT tuberculosis beta-ketoacyl-acyl carrier protein synthases KasA and KasB.";
RL J. Biol. Chem. 276:47029-47037(2001).
RN [4]
RP FUNCTION, CATALYTIC ACTIVITY, AND PATHWAY.
RX PubMed=12464486; DOI=10.1054/tube.2002.0333;
RA Slayden R.A., Barry C.E. III;
RT "The role of KasA and KasB in the biosynthesis of meromycolic acids and
RT isoniazid resistance in Mycobacterium tuberculosis.";
RL Tuberculosis 82:149-160(2002).
RN [5]
RP FUNCTION IN VIRULENCE, PATHWAY, DISRUPTION PHENOTYPE, AND IDENTIFICATION AS
RP A DRUG TARGET.
RX PubMed=12950920; DOI=10.1046/j.1365-2958.2003.03667.x;
RA Gao L.Y., Laval F., Lawson E.H., Groger R.K., Woodruff A., Morisaki J.H.,
RA Cox J.S., Daffe M., Brown E.J.;
RT "Requirement for kasB in Mycobacterium mycolic acid biosynthesis, cell wall
RT impermeability and intracellular survival: implications for therapy.";
RL Mol. Microbiol. 49:1547-1563(2003).
RN [6]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND
RP PHOSPHORYLATION.
RX PubMed=16873379; DOI=10.1074/jbc.m601691200;
RA Molle V., Brown A.K., Besra G.S., Cozzone A.J., Kremer L.;
RT "The condensing activities of the Mycobacterium tuberculosis type II fatty
RT acid synthase are differentially regulated by phosphorylation.";
RL J. Biol. Chem. 281:30094-30103(2006).
RN [7]
RP DISRUPTION PHENOTYPE, AND PATHWAY.
RX PubMed=17360388; DOI=10.1073/pnas.0608654104;
RA Bhatt A., Fujiwara N., Bhatt K., Gurcha S.S., Kremer L., Chen B., Chan J.,
RA Porcelli S.A., Kobayashi K., Besra G.S., Jacobs W.R. Jr.;
RT "Deletion of kasB in Mycobacterium tuberculosis causes loss of acid-
RT fastness and subclinical latent tuberculosis in immunocompetent mice.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:5157-5162(2007).
RN [8]
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 [9]
RP DISRUPTION PHENOTYPE, AND PATHWAY.
RX PubMed=22516756; DOI=10.1016/j.tube.2012.02.006;
RA Yamada H., Bhatt A., Danev R., Fujiwara N., Maeda S., Mitarai S.,
RA Chikamatsu K., Aono A., Nitta K., Jacobs W.R. Jr., Nagayama K.;
RT "Non-acid-fastness in Mycobacterium tuberculosis DeltakasB mutant
RT correlates with the cell envelope electron density.";
RL Tuberculosis 92:351-357(2012).
RN [10]
RP PHOSPHORYLATION AT THR-313 AND THR-315, ACTIVITY REGULATION, AND
RP MUTAGENESIS OF THR-313 AND THR-315.
RX PubMed=24809459; DOI=10.1371/journal.ppat.1004115;
RA Vilcheze C., Molle V., Carrere-Kremer S., Leiba J., Mourey L., Shenai S.,
RA Baronian G., Tufariello J., Hartman T., Veyron-Churlet R., Trivelli X.,
RA Tiwari S., Weinrick B., Alland D., Guerardel Y., Jacobs W.R. Jr.,
RA Kremer L.;
RT "Phosphorylation of KasB regulates virulence and acid-fastness in
RT Mycobacterium tuberculosis.";
RL PLoS Pathog. 10:e1004115-e1004115(2014).
RN [11] {ECO:0007744|PDB:2GP6}
RP X-RAY CRYSTALLOGRAPHY (2.40 ANGSTROMS) OF 5-417, AND SUBUNIT.
RX PubMed=17174327; DOI=10.1016/j.jmb.2006.11.006;
RA Sridharan S., Wang L., Brown A.K., Dover L.G., Kremer L., Besra G.S.,
RA Sacchettini J.C.;
RT "X-ray crystal structure of Mycobacterium tuberculosis beta-ketoacyl acyl
RT carrier protein synthase II (mtKasB).";
RL J. Mol. Biol. 366:469-480(2007).
CC -!- FUNCTION: Part of the mycobacterial fatty acid elongation system FAS-
CC II, which is involved in mycolic acid biosynthesis. Catalyzes the
CC elongation of long chain acyl-ACP substrates by the addition of two
CC carbons from malonyl-ACP to an acyl acceptor (PubMed:11600501,
CC PubMed:12464486, PubMed:16873379). Involved in extension of the
CC mycolate chains to full lengths and produces longer chain
CC multiunsaturated hydrocarbons averaging 54 carbons in length
CC (PubMed:12464486). Essential for resistance to macrophage antimicrobial
CC activity (PubMed:12950920). {ECO:0000269|PubMed:11600501,
CC ECO:0000269|PubMed:12464486, ECO:0000269|PubMed:12950920,
CC ECO:0000269|PubMed:16873379}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=an ultra-long-chain di-unsaturated fatty acyl-[ACP] + H(+) +
CC malonyl-[ACP] = a 3-oxo-ultra-long-chain di-unsaturated fatty acyl-
CC [ACP] + CO2 + holo-[ACP]; Xref=Rhea:RHEA:65308, Rhea:RHEA-COMP:9623,
CC Rhea:RHEA-COMP:9685, Rhea:RHEA-COMP:16767, Rhea:RHEA-COMP:16774,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:16526, ChEBI:CHEBI:64479,
CC ChEBI:CHEBI:78449, ChEBI:CHEBI:156401, ChEBI:CHEBI:156402;
CC EC=2.3.1.294; Evidence={ECO:0000305|PubMed:11600501,
CC ECO:0000305|PubMed:12464486};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:65309;
CC Evidence={ECO:0000305|PubMed:11600501, ECO:0000305|PubMed:12464486};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H(+) + hexadecanoyl-[ACP] + malonyl-[ACP] = 3-oxooctadecanoyl-
CC [ACP] + CO2 + holo-[ACP]; Xref=Rhea:RHEA:41916, Rhea:RHEA-COMP:9623,
CC Rhea:RHEA-COMP:9652, Rhea:RHEA-COMP:9653, Rhea:RHEA-COMP:9685,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:16526, ChEBI:CHEBI:64479,
CC ChEBI:CHEBI:78449, ChEBI:CHEBI:78483, ChEBI:CHEBI:78487;
CC Evidence={ECO:0000269|PubMed:11600501, ECO:0000269|PubMed:16873379};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:41917;
CC Evidence={ECO:0000269|PubMed:11600501, ECO:0000269|PubMed:16873379};
CC -!- ACTIVITY REGULATION: Phosphorylation decreases the condensing activity
CC of KasB and leads to the production of shorter mycolic acids, which is
CC associated to dramatic phenotype changes, such as loss of acid-
CC fastness, increase of cell wall permeability, severe attenuation in
CC infected mice and defect in macrophage colonization.
CC {ECO:0000269|PubMed:24809459}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=1.4 uM for hexadecanoyl-[ACP] {ECO:0000269|PubMed:11600501};
CC KM=13.1 uM for hexadecanoyl-[ACP] {ECO:0000269|PubMed:16873379};
CC KM=1.9 uM for eicosanoyl-[ACP] {ECO:0000269|PubMed:11600501};
CC KM=13.5 uM for malonyl-[ACP] {ECO:0000269|PubMed:11600501};
CC KM=35 uM for malonyl-[ACP] {ECO:0000269|PubMed:16873379};
CC Note=kcat is 1.6 min(-1) with hexadecanoyl-[ACP] as substrate. kcat
CC is 0.6 min(-1) with eicosanoyl-[ACP] as substrate. kcat is 1.4 min(-
CC 1) with malonyl-[ACP] as substrate. {ECO:0000269|PubMed:11600501};
CC -!- PATHWAY: Lipid metabolism; mycolic acid biosynthesis.
CC {ECO:0000269|PubMed:12464486, ECO:0000269|PubMed:12950920,
CC ECO:0000269|PubMed:17360388, ECO:0000269|PubMed:22516756,
CC ECO:0000305|PubMed:11600501}.
CC -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:17174327}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000305}.
CC -!- PTM: Phosphorylated on Thr-313 and Thr-315 (PubMed:24809459).
CC Phosphorylated in vitro by several Ser/Thr protein kinases (STPKs)
CC (PubMed:16873379). {ECO:0000269|PubMed:16873379,
CC ECO:0000269|PubMed:24809459}.
CC -!- DISRUPTION PHENOTYPE: Deletion of the gene results in loss of acid-fast
CC staining, which is a simple and rapid diagnostic test for detecting
CC M.tuberculosis (PubMed:17360388, PubMed:22516756). The region between
CC the inner and outer membranes of the mutant, which is composed mainly
CC of cell wall anchored mycolic acids, shows a significant decrease in
CC electron density as compared to the wild type. It suggests that altered
CC mycolic acids patterns in the mutant may have affected the packing of
CC the lipid rich layer of the M.tuberculosis cell envelope, resulting in
CC a reduced electron density of this layer and loss of acid-fastness in
CC light microscopical observation (PubMed:22516756). Mutants synthesize
CC mycolic acids that are 2-6 carbons shorter than wild type and show a
CC significant reduction in the abundance of keto-mycolates
CC (PubMed:12950920, PubMed:17360388). Deletion of the gene affects
CC mycolic acid trans-cyclopropanation, alters the colony morphology and
CC abolishes classic serpentine growth (PubMed:17360388). Mutants exhibit
CC strikingly altered cell wall permeability, leading to a marked increase
CC in susceptibility to lipophilic antibiotics and the host antimicrobial
CC molecules defensin and lysozyme (PubMed:12950920). Deletion mutant can
CC persist in infected immunocompetent mice for up to 600 days without
CC causing disease or mortality (PubMed:17360388).
CC {ECO:0000269|PubMed:12950920, ECO:0000269|PubMed:17360388,
CC ECO:0000269|PubMed:22516756}.
CC -!- MISCELLANEOUS: Identified as a drug target (PubMed:10747933,
CC PubMed:12950920). Inhibited by isoniazid (INH), thiolactomycin (TLM)
CC and related analogs (PubMed:10747933, PubMed:12464486).
CC {ECO:0000269|PubMed:10747933, ECO:0000269|PubMed:12464486,
CC ECO:0000269|PubMed:12950920}.
CC -!- SIMILARITY: Belongs to the thiolase-like superfamily. Beta-ketoacyl-ACP
CC synthases family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=CCP45026.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AL123456; CCP45026.1; ALT_INIT; Genomic_DNA.
DR PIR; B70779; B70779.
DR RefSeq; NP_216762.1; NC_000962.3.
DR RefSeq; WP_003411576.1; NC_018143.2.
DR PDB; 2GP6; X-ray; 2.40 A; A/B=5-417.
DR PDBsum; 2GP6; -.
DR AlphaFoldDB; P9WQD7; -.
DR SMR; P9WQD7; -.
DR STRING; 83332.Rv2246; -.
DR BindingDB; P9WQD7; -.
DR ChEMBL; CHEMBL4543; -.
DR SwissLipids; SLP:000000963; -.
DR PaxDb; P9WQD7; -.
DR DNASU; 887539; -.
DR GeneID; 45426226; -.
DR GeneID; 887539; -.
DR KEGG; mtu:Rv2246; -.
DR PATRIC; fig|83332.12.peg.2504; -.
DR TubercuList; Rv2246; -.
DR eggNOG; COG0304; Bacteria.
DR OMA; QIGHCLG; -.
DR BioCyc; MetaCyc:G185E-6462-MON; -.
DR UniPathway; UPA00915; -.
DR PRO; PR:P9WQD7; -.
DR Proteomes; UP000001584; Chromosome.
DR GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR GO; GO:0009274; C:peptidoglycan-based cell wall; HDA:MTBBASE.
DR GO; GO:0005886; C:plasma membrane; HDA:MTBBASE.
DR GO; GO:0004315; F:3-oxoacyl-[acyl-carrier-protein] synthase activity; IDA:MTBBASE.
DR GO; GO:0006633; P:fatty acid biosynthetic process; IBA:GO_Central.
DR GO; GO:0030497; P:fatty acid elongation; IDA:MTBBASE.
DR GO; GO:0071768; P:mycolic acid biosynthetic process; IMP:MTBBASE.
DR GO; GO:0001666; P:response to hypoxia; IEP:MTBBASE.
DR CDD; cd00834; KAS_I_II; 1.
DR Gene3D; 3.40.47.10; -; 2.
DR InterPro; IPR000794; Beta-ketoacyl_synthase.
DR InterPro; IPR014031; Ketoacyl_synth_C.
DR InterPro; IPR014030; Ketoacyl_synth_N.
DR InterPro; IPR020841; PKS_Beta-ketoAc_synthase_dom.
DR InterPro; IPR016039; Thiolase-like.
DR PANTHER; PTHR11712; PTHR11712; 1.
DR Pfam; PF00109; ketoacyl-synt; 1.
DR Pfam; PF02801; Ketoacyl-synt_C; 1.
DR SMART; SM00825; PKS_KS; 1.
DR SUPFAM; SSF53901; SSF53901; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Acyltransferase; Cytoplasm; Fatty acid biosynthesis;
KW Fatty acid metabolism; Lipid biosynthesis; Lipid metabolism;
KW Phosphoprotein; Reference proteome; Transferase.
FT CHAIN 1..417
FT /note="3-oxoacyl-[acyl-carrier-protein] synthase 2"
FT /id="PRO_0000180334"
FT ACT_SITE 170
FT /evidence="ECO:0000250|UniProtKB:P9WQD9"
FT MOD_RES 313
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:24809459"
FT MOD_RES 315
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:24809459"
FT MUTAGEN 313
FT /note="T->A: Decreases phosphorylation. Lack of
FT phosphorylation; when associated with A-315."
FT /evidence="ECO:0000269|PubMed:24809459"
FT MUTAGEN 313
FT /note="T->D: Phosphomimetic mutant. Loss of acid-fast
FT staining and reduced pathogenicity; when associated with D-
FT 315."
FT /evidence="ECO:0000269|PubMed:24809459"
FT MUTAGEN 315
FT /note="T->A: Decreases phosphorylation. Lack of
FT phosphorylation; when associated with A-313."
FT /evidence="ECO:0000269|PubMed:24809459"
FT MUTAGEN 315
FT /note="T->D: Phosphomimetic mutant. Loss of acid-fast
FT staining and reduced pathogenicity; when associated with D-
FT 313."
FT /evidence="ECO:0000269|PubMed:24809459"
FT TURN 6..9
FT /evidence="ECO:0007829|PDB:2GP6"
FT STRAND 13..21
FT /evidence="ECO:0007829|PDB:2GP6"
FT HELIX 28..36
FT /evidence="ECO:0007829|PDB:2GP6"
FT STRAND 42..44
FT /evidence="ECO:0007829|PDB:2GP6"
FT HELIX 48..53
FT /evidence="ECO:0007829|PDB:2GP6"
FT STRAND 59..61
FT /evidence="ECO:0007829|PDB:2GP6"
FT HELIX 73..77
FT /evidence="ECO:0007829|PDB:2GP6"
FT HELIX 81..96
FT /evidence="ECO:0007829|PDB:2GP6"
FT STRAND 106..112
FT /evidence="ECO:0007829|PDB:2GP6"
FT HELIX 119..128
FT /evidence="ECO:0007829|PDB:2GP6"
FT STRAND 133..136
FT /evidence="ECO:0007829|PDB:2GP6"
FT HELIX 140..144
FT /evidence="ECO:0007829|PDB:2GP6"
FT HELIX 148..156
FT /evidence="ECO:0007829|PDB:2GP6"
FT HELIX 169..171
FT /evidence="ECO:0007829|PDB:2GP6"
FT HELIX 172..185
FT /evidence="ECO:0007829|PDB:2GP6"
FT STRAND 190..197
FT /evidence="ECO:0007829|PDB:2GP6"
FT HELIX 203..210
FT /evidence="ECO:0007829|PDB:2GP6"
FT TURN 211..213
FT /evidence="ECO:0007829|PDB:2GP6"
FT TURN 223..225
FT /evidence="ECO:0007829|PDB:2GP6"
FT STRAND 229..231
FT /evidence="ECO:0007829|PDB:2GP6"
FT STRAND 243..250
FT /evidence="ECO:0007829|PDB:2GP6"
FT HELIX 251..255
FT /evidence="ECO:0007829|PDB:2GP6"
FT TURN 256..258
FT /evidence="ECO:0007829|PDB:2GP6"
FT STRAND 263..272
FT /evidence="ECO:0007829|PDB:2GP6"
FT STRAND 277..279
FT /evidence="ECO:0007829|PDB:2GP6"
FT HELIX 285..297
FT /evidence="ECO:0007829|PDB:2GP6"
FT TURN 302..304
FT /evidence="ECO:0007829|PDB:2GP6"
FT STRAND 305..309
FT /evidence="ECO:0007829|PDB:2GP6"
FT HELIX 316..330
FT /evidence="ECO:0007829|PDB:2GP6"
FT HELIX 341..344
FT /evidence="ECO:0007829|PDB:2GP6"
FT TURN 348..350
FT /evidence="ECO:0007829|PDB:2GP6"
FT HELIX 351..365
FT /evidence="ECO:0007829|PDB:2GP6"
FT STRAND 375..377
FT /evidence="ECO:0007829|PDB:2GP6"
FT STRAND 397..404
FT /evidence="ECO:0007829|PDB:2GP6"
FT TURN 405..407
FT /evidence="ECO:0007829|PDB:2GP6"
FT STRAND 408..415
FT /evidence="ECO:0007829|PDB:2GP6"
SQ SEQUENCE 417 AA; 44277 MW; 239F7D19A6380F66 CRC64;
MTELVTGKAF PYVVVTGIAM TTALATDAET TWKLLLDRQS GIRTLDDPFV EEFDLPVRIG
GHLLEEFDHQ LTRIELRRMG YLQRMSTVLS RRLWENAGSP EVDTNRLMVS IGTGLGSAEE
LVFSYDDMRA RGMKAVSPLT VQKYMPNGAA AAVGLERHAK AGVMTPVSAC ASGAEAIARA
WQQIVLGEAD AAICGGVETR IEAVPIAGFA QMRIVMSTNN DDPAGACRPF DRDRDGFVFG
EGGALLLIET EEHAKARGAN ILARIMGASI TSDGFHMVAP DPNGERAGHA ITRAIQLAGL
APGDIDHVNA HATGTQVGDL AEGRAINNAL GGNRPAVYAP KSALGHSVGA VGAVESILTV
LALRDQVIPP TLNLVNLDPE IDLDVVAGEP RPGNYRYAIN NSFGFGGHNV AIAFGRY
