TUBAT_MYCTU
ID TUBAT_MYCTU Reviewed; 296 AA.
AC P9WJ61; F2GEC4; L0TCL2; O50407; Q7D5L5;
DT 16-APR-2014, integrated into UniProtKB/Swiss-Prot.
DT 16-APR-2014, sequence version 1.
DT 03-AUG-2022, entry version 42.
DE RecName: Full=Tuberculosinyl adenosine transferase {ECO:0000303|PubMed:24516143};
DE EC=2.5.1.153 {ECO:0000269|PubMed:24516143};
DE AltName: Full=Diterpene synthase {ECO:0000303|PubMed:21228491};
DE AltName: Full=Isotuberculosinol synthase;
DE AltName: Full=Nosyberkol synthase;
DE AltName: Full=Tuberculosinol synthase;
GN OrderedLocusNames=Rv3378c;
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 AS A DITERPENE SYNTHASE AND IN TUBERCULOSINOL BIOSYNTHESIS,
RP MUTAGENESIS OF ASP-81; ASP-82 AND ASP-85, CATALYTIC ACTIVITY, REACTION
RP MECHANISM, BIOPHYSICOCHEMICAL PROPERTIES, COFACTOR, AND SUBUNIT.
RX PubMed=21228491; DOI=10.1271/bbb.100570;
RA Nakano C., Ootsuka T., Takayama K., Mitsui T., Sato T., Hoshino T.;
RT "Characterization of the Rv3378c gene product, a new diterpene synthase for
RT producing tuberculosinol and (13R, S)-isotuberculosinol (nosyberkol), from
RT the Mycobacterium tuberculosis H37Rv genome.";
RL Biosci. Biotechnol. Biochem. 75:75-81(2011).
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, CATALYTIC ACTIVITY, AND SUBSTRATE SPECIFICITY.
RX PubMed=21290071; DOI=10.1039/c0ob00884b;
RA Hoshino T., Nakano C., Ootsuka T., Shinohara Y., Hara T.;
RT "Substrate specificity of Rv3378c, an enzyme from Mycobacterium
RT tuberculosis, and the inhibitory activity of the bicyclic diterpenoids
RT against macrophage phagocytosis.";
RL Org. Biomol. Chem. 9:2156-2165(2011).
RN [5]
RP FUNCTION IN VIRULENCE, DISRUPTION PHENOTYPE, AND CATALYTIC ACTIVITY.
RX PubMed=31427817; DOI=10.1038/s41589-019-0336-0;
RA Buter J., Cheng T.Y., Ghanem M., Grootemaat A.E., Raman S., Feng X.,
RA Plantijn A.R., Ennis T., Wang J., Cotton R.N., Layre E., Ramnarine A.K.,
RA Mayfield J.A., Young D.C., Jezek Martinot A., Siddiqi N., Wakabayashi S.,
RA Botella H., Calderon R., Murray M., Ehrt S., Snider B.B., Reed M.B.,
RA Oldfield E., Tan S., Rubin E.J., Behr M.A., van der Wel N.N.,
RA Minnaard A.J., Moody D.B.;
RT "Mycobacterium tuberculosis releases an antacid that remodels phagosomes.";
RL Nat. Chem. Biol. 15:889-899(2019).
RN [6] {ECO:0007744|PDB:3WQK, ECO:0007744|PDB:3WQL, ECO:0007744|PDB:3WQM, ECO:0007744|PDB:3WQN, ECO:0007744|PDB:4KT8}
RP X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) OF APOENZYME; IN COMPLEX WITH
RP BPH-629 INHIBITOR AND OF INACTIVE MUTANTS IN COMPLEXES WITH TUBERCULOSINOL,
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, SUBUNIT, AND MUTAGENESIS
RP OF ASP-34; ARG-38; TYR-51 AND TYR-90.
RX PubMed=24475925; DOI=10.1021/ja413127v;
RA Chan H.C., Feng X., Ko T.P., Huang C.H., Hu Y., Zheng Y., Bogue S.,
RA Nakano C., Hoshino T., Zhang L., Lv P., Liu W., Crick D.C., Liang P.H.,
RA Wang A.H., Oldfield E., Guo R.T.;
RT "Structure and inhibition of tuberculosinol synthase and decaprenyl
RT diphosphate synthase from Mycobacterium tuberculosis.";
RL J. Am. Chem. Soc. 136:2892-2896(2014).
RN [7] {ECO:0007744|PDB:4CMW, ECO:0007744|PDB:4CMX}
RP X-RAY CRYSTALLOGRAPHY (2.21 ANGSTROMS), FUNCTION, CATALYTIC ACTIVITY,
RP SUBUNIT, AND MUTAGENESIS OF ASP-34.
RX PubMed=24516143; DOI=10.1073/pnas.1315883111;
RA Layre E., Lee H.J., Young D.C., Martinot A.J., Buter J., Minnaard A.J.,
RA Annand J.W., Fortune S.M., Snider B.B., Matsunaga I., Rubin E.J., Alber T.,
RA Moody D.B.;
RT "Molecular profiling of Mycobacterium tuberculosis identifies
RT tuberculosinyl nucleoside products of the virulence-associated enzyme
RT Rv3378c.";
RL Proc. Natl. Acad. Sci. U.S.A. 111:2978-2983(2014).
CC -!- FUNCTION: Tuberculosinyl transferase that catalyzes the condensation of
CC adenosine and tuberculosinyl diphosphate (TbPP) to generate 1-
CC tuberculosinyladenosine (1-TbAd), which acts as an antiacid that
CC directly protects M.tuberculosis from acid pH and physically remodels
CC M.tuberculosis phagolysosomes (PubMed:24516143, PubMed:31427817). In
CC addition, acts as a phosphatase that catalyzes the diphosphate-removal
CC from TbPP to produce both tuberculosinol (TOH) and isotuberculosinol
CC (iso-TOH) (PubMed:21228491, PubMed:24475925). Has broad substrate
CC specificity, and can also use the 3 labdadienyl diphosphates, copalyl
CC diphosphate (CDP), ent-CDP and syn-CDP in vitro (PubMed:21290071).
CC {ECO:0000269|PubMed:21228491, ECO:0000269|PubMed:21290071,
CC ECO:0000269|PubMed:24475925, ECO:0000269|PubMed:24516143,
CC ECO:0000269|PubMed:31427817}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=adenosine + H(+) + tuberculosinyl diphosphate = 1-
CC tuberculosinyladenosine + diphosphate; Xref=Rhea:RHEA:46000,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:16335, ChEBI:CHEBI:33019,
CC ChEBI:CHEBI:58822, ChEBI:CHEBI:85603; EC=2.5.1.153;
CC Evidence={ECO:0000269|PubMed:24516143};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + tuberculosinyl diphosphate = diphosphate +
CC tuberculosinol; Xref=Rhea:RHEA:31783, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:33019, ChEBI:CHEBI:50387, ChEBI:CHEBI:58822;
CC Evidence={ECO:0000269|PubMed:21228491, ECO:0000269|PubMed:24475925};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + tuberculosinyl diphosphate = (13R)-edaxadiene +
CC diphosphate; Xref=Rhea:RHEA:31787, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:33019, ChEBI:CHEBI:58822, ChEBI:CHEBI:63178;
CC Evidence={ECO:0000269|PubMed:21228491, ECO:0000269|PubMed:24475925};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + tuberculosinyl diphosphate = (13S)-edaxadiene +
CC diphosphate; Xref=Rhea:RHEA:31791, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:33019, ChEBI:CHEBI:58822, ChEBI:CHEBI:63180;
CC Evidence={ECO:0000269|PubMed:21228491, ECO:0000269|PubMed:24475925};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(+)-copalyl diphosphate + H2O = (+)-copalol + diphosphate;
CC Xref=Rhea:RHEA:40007, ChEBI:CHEBI:15377, ChEBI:CHEBI:33019,
CC ChEBI:CHEBI:58635, ChEBI:CHEBI:76943;
CC Evidence={ECO:0000269|PubMed:21290071};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(+)-copalyl diphosphate + H2O = diphosphate + manool;
CC Xref=Rhea:RHEA:40011, ChEBI:CHEBI:15377, ChEBI:CHEBI:33019,
CC ChEBI:CHEBI:58635, ChEBI:CHEBI:76945;
CC Evidence={ECO:0000269|PubMed:21290071};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(+)-copalyl diphosphate + H2O = 13-epi-manool + diphosphate;
CC Xref=Rhea:RHEA:40015, ChEBI:CHEBI:15377, ChEBI:CHEBI:33019,
CC ChEBI:CHEBI:58635, ChEBI:CHEBI:76944;
CC Evidence={ECO:0000269|PubMed:21290071};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ent-copalyl diphosphate + H2O = (-)-ent-copalol + diphosphate;
CC Xref=Rhea:RHEA:40019, ChEBI:CHEBI:15377, ChEBI:CHEBI:33019,
CC ChEBI:CHEBI:58553, ChEBI:CHEBI:76950;
CC Evidence={ECO:0000269|PubMed:21290071};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ent-copalyl diphosphate + H2O = diphosphate + ent-manool;
CC Xref=Rhea:RHEA:40031, ChEBI:CHEBI:15377, ChEBI:CHEBI:33019,
CC ChEBI:CHEBI:58553, ChEBI:CHEBI:76948;
CC Evidence={ECO:0000269|PubMed:21290071};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=9alpha-copalyl diphosphate + H2O = diphosphate + syn-copalol;
CC Xref=Rhea:RHEA:40023, ChEBI:CHEBI:15377, ChEBI:CHEBI:33019,
CC ChEBI:CHEBI:58622, ChEBI:CHEBI:76952;
CC Evidence={ECO:0000269|PubMed:21290071};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=9alpha-copalyl diphosphate + H2O = (13S)-vitexifolin A +
CC diphosphate; Xref=Rhea:RHEA:40027, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:33019, ChEBI:CHEBI:58622, ChEBI:CHEBI:76954;
CC Evidence={ECO:0000269|PubMed:21290071};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:21228491};
CC Note=Can also use Fe(2+), Cu(2+), Mn(2+), Zn(2+) and Ni(2+).
CC {ECO:0000269|PubMed:21228491};
CC -!- ACTIVITY REGULATION: Inhibited by the bisphosphonate inhibitor BPH-629.
CC {ECO:0000269|PubMed:24475925}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=27.1 uM for tuberculosinyl diphosphate (at 45 degrees Celsius and
CC pH 7) {ECO:0000269|PubMed:21228491};
CC Note=kcat is 0.031 min(-1) with tuberculosinyl diphosphate as
CC substrate. {ECO:0000269|PubMed:21228491};
CC pH dependence:
CC Optimum pH is 7. It is active in a pH range of 5.5-9.0.
CC {ECO:0000269|PubMed:21228491};
CC Temperature dependence:
CC Optimum temperature is 45 degrees Celsius. No activity is detected
CC above 50 degrees Celsius. {ECO:0000269|PubMed:21228491};
CC -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:21228491,
CC ECO:0000269|PubMed:24475925, ECO:0000269|PubMed:24516143}.
CC -!- DISRUPTION PHENOTYPE: Deletion of the gene abolishes 1-TbAd
CC biosynthesis and decreases the formation of swollen phagosomes.
CC {ECO:0000269|PubMed:31427817}.
CC -!- MISCELLANEOUS: 1-TbAd is highly prevalent among patient-derived
CC M.tuberculosis strains, where it is among the most abundant lipids
CC produced. {ECO:0000305|PubMed:31427817}.
CC -!- SIMILARITY: Belongs to the diterpene synthase family. {ECO:0000305}.
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DR EMBL; AL123456; CCP46199.1; -; Genomic_DNA.
DR PIR; A70973; A70973.
DR RefSeq; NP_217895.1; NC_000962.3.
DR RefSeq; WP_003417908.1; NZ_NVQJ01000052.1.
DR PDB; 3WQK; X-ray; 2.30 A; A=1-296.
DR PDB; 3WQL; X-ray; 2.10 A; A/B/C/D=1-296.
DR PDB; 3WQM; X-ray; 2.10 A; A=1-296.
DR PDB; 3WQN; X-ray; 2.70 A; A=1-296.
DR PDB; 4CMV; X-ray; 2.31 A; A/B=1-296.
DR PDB; 4CMW; X-ray; 2.21 A; A/B=1-296.
DR PDB; 4CMX; X-ray; 2.36 A; A/B=1-296.
DR PDB; 4KT8; X-ray; 2.40 A; A=1-296.
DR PDBsum; 3WQK; -.
DR PDBsum; 3WQL; -.
DR PDBsum; 3WQM; -.
DR PDBsum; 3WQN; -.
DR PDBsum; 4CMV; -.
DR PDBsum; 4CMW; -.
DR PDBsum; 4CMX; -.
DR PDBsum; 4KT8; -.
DR AlphaFoldDB; P9WJ61; -.
DR SMR; P9WJ61; -.
DR STRING; 83332.Rv3378c; -.
DR SwissLipids; SLP:000001168; -.
DR PaxDb; P9WJ61; -.
DR DNASU; 888075; -.
DR GeneID; 888075; -.
DR KEGG; mtu:Rv3378c; -.
DR TubercuList; Rv3378c; -.
DR eggNOG; ENOG502ZJEY; Bacteria.
DR OMA; FYGEWRE; -.
DR BioCyc; MetaCyc:G185E-7654-MON; -.
DR BRENDA; 2.5.1.153; 3445.
DR BRENDA; 4.2.3.B30; 3445.
DR BRENDA; 4.2.3.B31; 3445.
DR BRENDA; 4.2.3.B32; 3445.
DR BRENDA; 4.2.3.B33; 3445.
DR BRENDA; 4.2.3.B34; 3445.
DR BRENDA; 4.2.3.B35; 3445.
DR BRENDA; 4.2.3.B36; 3445.
DR Proteomes; UP000001584; Chromosome.
DR GO; GO:0062204; F:(13S)-vitexifolin A synthase activity; IEA:RHEA.
DR GO; GO:0016791; F:phosphatase activity; IDA:MTBBASE.
DR GO; GO:0016765; F:transferase activity, transferring alkyl or aryl (other than methyl) groups; IEA:InterPro.
DR GO; GO:0016102; P:diterpenoid biosynthetic process; IDA:MTBBASE.
DR GO; GO:0052572; P:response to host immune response; IMP:MTBBASE.
DR GO; GO:0035440; P:tuberculosinol biosynthetic process; IDA:UniProtKB.
DR Gene3D; 3.40.1180.10; -; 1.
DR InterPro; IPR036424; UPP_synth-like_sf.
PE 1: Evidence at protein level;
KW 3D-structure; Reference proteome; Transferase; Virulence.
FT CHAIN 1..296
FT /note="Tuberculosinyl adenosine transferase"
FT /id="PRO_0000416456"
FT MUTAGEN 34
FT /note="D->A: Abolishes transferase activity. Decrease in
FT TOH production. Almost loss of iso-TOH production."
FT /evidence="ECO:0000269|PubMed:24475925,
FT ECO:0000269|PubMed:24516143"
FT MUTAGEN 34
FT /note="D->N: Abolishes transferase activity."
FT /evidence="ECO:0000269|PubMed:24516143"
FT MUTAGEN 38
FT /note="R->A: Does not affect TOH production. Strong
FT decrease in iso-TOH production."
FT /evidence="ECO:0000269|PubMed:24475925"
FT MUTAGEN 51
FT /note="Y->F: Strong decrease in TOH and iso-TOH production.
FT Almost loss of TOH and TOH production; when associated with
FT F-90."
FT /evidence="ECO:0000269|PubMed:24475925"
FT MUTAGEN 81
FT /note="D->N: Significant decrease in phosphatase activity.
FT Loss of phosphatase activity; when associated with N-82 or
FT N-85."
FT /evidence="ECO:0000269|PubMed:21228491"
FT MUTAGEN 82
FT /note="D->N: Significant decrease in phosphatase activity.
FT Loss of phosphatase activity; when associated with N-81 or
FT N-85."
FT /evidence="ECO:0000269|PubMed:21228491"
FT MUTAGEN 85
FT /note="D->N: Significant decrease in phosphatase activity.
FT Loss of phosphatase activity; when associated with N-81 or
FT N-82."
FT /evidence="ECO:0000269|PubMed:21228491"
FT MUTAGEN 90
FT /note="Y->F: Decrease in TOH production and almost loss of
FT iso-TOH production. Almost loss of TOH and TOH production;
FT when associated with F-51."
FT /evidence="ECO:0000269|PubMed:24475925"
FT HELIX 6..11
FT /evidence="ECO:0007829|PDB:3WQL"
FT HELIX 14..24
FT /evidence="ECO:0007829|PDB:3WQL"
FT STRAND 27..30
FT /evidence="ECO:0007829|PDB:3WQL"
FT HELIX 36..43
FT /evidence="ECO:0007829|PDB:3WQL"
FT TURN 46..48
FT /evidence="ECO:0007829|PDB:3WQL"
FT HELIX 51..68
FT /evidence="ECO:0007829|PDB:3WQL"
FT STRAND 73..79
FT /evidence="ECO:0007829|PDB:3WQL"
FT HELIX 81..85
FT /evidence="ECO:0007829|PDB:3WQM"
FT HELIX 92..101
FT /evidence="ECO:0007829|PDB:3WQL"
FT HELIX 105..113
FT /evidence="ECO:0007829|PDB:3WQL"
FT STRAND 116..123
FT /evidence="ECO:0007829|PDB:3WQL"
FT HELIX 124..127
FT /evidence="ECO:0007829|PDB:3WQL"
FT HELIX 132..147
FT /evidence="ECO:0007829|PDB:3WQL"
FT TURN 148..150
FT /evidence="ECO:0007829|PDB:3WQL"
FT STRAND 153..161
FT /evidence="ECO:0007829|PDB:3WQL"
FT HELIX 166..180
FT /evidence="ECO:0007829|PDB:3WQL"
FT HELIX 186..194
FT /evidence="ECO:0007829|PDB:3WQL"
FT STRAND 202..210
FT /evidence="ECO:0007829|PDB:3WQL"
FT STRAND 224..230
FT /evidence="ECO:0007829|PDB:3WQL"
FT HELIX 232..234
FT /evidence="ECO:0007829|PDB:3WQL"
FT HELIX 237..249
FT /evidence="ECO:0007829|PDB:3WQL"
FT TURN 250..252
FT /evidence="ECO:0007829|PDB:3WQL"
FT HELIX 259..261
FT /evidence="ECO:0007829|PDB:3WQL"
FT HELIX 264..276
FT /evidence="ECO:0007829|PDB:3WQL"
FT STRAND 286..288
FT /evidence="ECO:0007829|PDB:3WQL"
FT STRAND 291..293
FT /evidence="ECO:0007829|PDB:3WQL"
SQ SEQUENCE 296 AA; 34031 MW; D79E55CFDE338E07 CRC64;
MNLVSEKEFL DLPLVSVAEI VRCRGPKVSV FPFDGTRRWF HLECNPQYDD YQQAALRQSI
RILKMLFEHG IETVISPIFS DDLLDRGDRY IVQALEGMAL LANDEEILSF YKEHEVHVLF
YGDYKKRLPS TAQGAAVVKS FDDLTISTSS NTEHRLCFGV FGNDAAESVA QFSISWNETH
GKPPTRREII EGYYGEYVDK ADMFIGFGRF STFDFPLLSS GKTSLYFTVA PSYYMTETTL
RRILYDHIYL RHFRPKPDYS AMSADQLNVL RNRYRAQPDR VFGVGCVHDG IWFAEG
