PANB_MYCTU
ID PANB_MYCTU Reviewed; 281 AA.
AC P9WIL7; L0TAJ8; P0A5Q8; Q10505;
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=3-methyl-2-oxobutanoate hydroxymethyltransferase;
DE EC=2.1.2.11;
DE AltName: Full=Ketopantoate hydroxymethyltransferase;
DE Short=KPHMT;
GN Name=panB; OrderedLocusNames=Rv2225; ORFNames=MTCY427.06;
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 PROTEIN SEQUENCE OF 2-11, CATALYTIC ACTIVITY, FUNCTION, REACTION MECHANISM,
RP BIOPHYSICOCHEMICAL PROPERTIES, MASS SPECTROMETRY, AND COFACTOR.
RX PubMed=12515554; DOI=10.1021/bi020516q;
RA Sugantino M., Zheng R., Yu M., Blanchard J.S.;
RT "Mycobacterium tuberculosis ketopantoate hydroxymethyltransferase:
RT tetrahydrofolate-independent hydroxymethyltransferase and enolization
RT reactions with alpha-keto acids.";
RL Biochemistry 42:191-199(2003).
RN [3]
RP PROTEASOME SUBSTRATE.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=17082771; DOI=10.1038/sj.emboj.7601405;
RA Pearce M.J., Arora P., Festa R.A., Butler-Wu S.M., Gokhale R.S.,
RA Darwin K.H.;
RT "Identification of substrates of the Mycobacterium tuberculosis
RT proteasome.";
RL EMBO J. 25:5423-5432(2006).
RN [4]
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 [5]
RP PUPYLATION, AND NATURE OF THE CROSS-LINK.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=20355727; DOI=10.1021/ja910546x;
RA Sutter M., Damberger F.F., Imkamp F., Allain F.H., Weber-Ban E.;
RT "Prokaryotic ubiquitin-like protein (Pup) is coupled to substrates via the
RT side chain of its C-terminal glutamate.";
RL J. Am. Chem. Soc. 132:5610-5612(2010).
RN [6]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [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 [7]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) IN COMPLEX WITH MAGNESIUM IONS,
RP COFACTOR, AND SUBUNIT.
RX PubMed=12842039; DOI=10.1016/s0969-2126(03)00106-0;
RA Chaudhuri B.N., Sawaya M.R., Kim C.-Y., Waldo G.S., Park M.S.,
RA Terwilliger T.C., Yeates T.O.;
RT "The crystal structure of the first enzyme in the pantothenate biosynthetic
RT pathway, ketopantoate hydroxymethyltransferase, from M. tuberculosis.";
RL Structure 11:753-764(2003).
CC -!- FUNCTION: Catalyzes the reversible reaction in which hydroxymethyl
CC group from 5,10-methylenetetrahydrofolate is transferred onto alpha-
CC ketoisovalerate to form ketopantoate. {ECO:0000269|PubMed:12515554}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(6R)-5,10-methylene-5,6,7,8-tetrahydrofolate + 3-methyl-2-
CC oxobutanoate + H2O = (6S)-5,6,7,8-tetrahydrofolate + 2-
CC dehydropantoate; Xref=Rhea:RHEA:11824, ChEBI:CHEBI:11561,
CC ChEBI:CHEBI:11851, ChEBI:CHEBI:15377, ChEBI:CHEBI:15636,
CC ChEBI:CHEBI:57453; EC=2.1.2.11;
CC Evidence={ECO:0000269|PubMed:12515554};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:12515554, ECO:0000269|PubMed:12842039};
CC Name=Co(2+); Xref=ChEBI:CHEBI:48828;
CC Evidence={ECO:0000269|PubMed:12515554, ECO:0000269|PubMed:12842039};
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000269|PubMed:12515554, ECO:0000269|PubMed:12842039};
CC Name=Ni(2+); Xref=ChEBI:CHEBI:49786;
CC Evidence={ECO:0000269|PubMed:12515554, ECO:0000269|PubMed:12842039};
CC Name=Ca(2+); Xref=ChEBI:CHEBI:29108;
CC Evidence={ECO:0000269|PubMed:12515554, ECO:0000269|PubMed:12842039};
CC Note=Binds 1 Mg(2+) ion per subunit. Can also use Co(2+), Zn(2+),
CC Ni(2+) and Ca(2+) to a lesser extent. {ECO:0000269|PubMed:12515554,
CC ECO:0000269|PubMed:12842039};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=240 uM for alpha-ketoisovalerate (at 37 degrees Celsius and pH
CC 7.5) {ECO:0000269|PubMed:12515554};
CC KM=820 uM for 5,10-methylenetetrahydrofolate (at 37 degrees Celsius
CC and pH 7.5) {ECO:0000269|PubMed:12515554};
CC Vmax=1.6 umol/min/mg enzyme (at 37 degrees Celsius and pH 7.5)
CC {ECO:0000269|PubMed:12515554};
CC pH dependence:
CC Optimum pH is 7.0-7.5. {ECO:0000269|PubMed:12515554};
CC -!- PATHWAY: Cofactor biosynthesis; (R)-pantothenate biosynthesis; (R)-
CC pantoate from 3-methyl-2-oxobutanoate: step 1/2.
CC -!- SUBUNIT: Homodecamer; pentamer of dimers.
CC {ECO:0000269|PubMed:12842039}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000305}.
CC -!- PTM: Pupylated at an undetermined lysine residue by the prokaryotic
CC ubiquitin-like protein Pup with the help of the ligase PafA, which
CC leads to its degradation by the proteasome. The cross-link involves the
CC side-chain carboxylate of the C-terminal glutamate of Pup and the side-
CC chain amino group of a lysine in PanB. {ECO:0000269|PubMed:20355727}.
CC -!- MASS SPECTROMETRY: Mass=29202; Method=Electrospray;
CC Evidence={ECO:0000269|PubMed:12515554};
CC -!- MISCELLANEOUS: Was identified as a natural substrate of the
CC M.tuberculosis proteasome.
CC -!- MISCELLANEOUS: Was identified as a high-confidence drug target.
CC -!- SIMILARITY: Belongs to the PanB family. {ECO:0000305}.
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DR EMBL; AL123456; CCP45003.1; -; Genomic_DNA.
DR PIR; E70776; E70776.
DR RefSeq; NP_216741.1; NC_000962.3.
DR RefSeq; WP_003411489.1; NZ_NVQJ01000008.1.
DR PDB; 1OY0; X-ray; 2.80 A; A/B/C/D/E=1-281.
DR PDBsum; 1OY0; -.
DR AlphaFoldDB; P9WIL7; -.
DR SMR; P9WIL7; -.
DR STRING; 83332.Rv2225; -.
DR iPTMnet; P9WIL7; -.
DR PaxDb; P9WIL7; -.
DR DNASU; 887440; -.
DR GeneID; 887440; -.
DR KEGG; mtu:Rv2225; -.
DR TubercuList; Rv2225; -.
DR eggNOG; COG0413; Bacteria.
DR OMA; VLVWTDM; -.
DR PhylomeDB; P9WIL7; -.
DR UniPathway; UPA00028; UER00003.
DR Proteomes; UP000001584; Chromosome.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; HDA:MTBBASE.
DR GO; GO:0003864; F:3-methyl-2-oxobutanoate hydroxymethyltransferase activity; IDA:MTBBASE.
DR GO; GO:0000287; F:magnesium ion binding; IDA:MTBBASE.
DR GO; GO:0015940; P:pantothenate biosynthetic process; IDA:MTBBASE.
DR CDD; cd06557; KPHMT-like; 1.
DR Gene3D; 3.20.20.60; -; 1.
DR HAMAP; MF_00156; PanB; 1.
DR InterPro; IPR003700; Pantoate_hydroxy_MeTrfase.
DR InterPro; IPR015813; Pyrv/PenolPyrv_Kinase-like_dom.
DR InterPro; IPR040442; Pyrv_Kinase-like_dom_sf.
DR PANTHER; PTHR20881; PTHR20881; 1.
DR Pfam; PF02548; Pantoate_transf; 1.
DR PIRSF; PIRSF000388; Pantoate_hydroxy_MeTrfase; 1.
DR SUPFAM; SSF51621; SSF51621; 1.
DR TIGRFAMs; TIGR00222; panB; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Cytoplasm; Direct protein sequencing; Magnesium;
KW Metal-binding; Pantothenate biosynthesis; Reference proteome; Transferase;
KW Ubl conjugation.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000269|PubMed:12515554,
FT ECO:0007744|PubMed:21969609"
FT CHAIN 2..281
FT /note="3-methyl-2-oxobutanoate hydroxymethyltransferase"
FT /id="PRO_0000184864"
FT REGION 1..20
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 199
FT /note="Proton acceptor"
FT /evidence="ECO:0000250"
FT BINDING 62..63
FT /ligand="3-methyl-2-oxobutanoate"
FT /ligand_id="ChEBI:CHEBI:11851"
FT /evidence="ECO:0000250"
FT BINDING 62
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT BINDING 101
FT /ligand="3-methyl-2-oxobutanoate"
FT /ligand_id="ChEBI:CHEBI:11851"
FT /evidence="ECO:0000250"
FT BINDING 101
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250"
FT BINDING 131
FT /ligand="3-methyl-2-oxobutanoate"
FT /ligand_id="ChEBI:CHEBI:11851"
FT /evidence="ECO:0000250"
FT BINDING 133
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT MOD_RES 2
FT /note="N-acetylserine"
FT /evidence="ECO:0007744|PubMed:21969609"
FT HELIX 23..32
FT /evidence="ECO:0007829|PDB:1OY0"
FT STRAND 36..40
FT /evidence="ECO:0007829|PDB:1OY0"
FT HELIX 44..51
FT /evidence="ECO:0007829|PDB:1OY0"
FT TURN 52..54
FT /evidence="ECO:0007829|PDB:1OY0"
FT STRAND 57..60
FT /evidence="ECO:0007829|PDB:1OY0"
FT HELIX 64..67
FT /evidence="ECO:0007829|PDB:1OY0"
FT STRAND 72..76
FT /evidence="ECO:0007829|PDB:1OY0"
FT HELIX 79..81
FT /evidence="ECO:0007829|PDB:1OY0"
FT HELIX 83..92
FT /evidence="ECO:0007829|PDB:1OY0"
FT STRAND 96..101
FT /evidence="ECO:0007829|PDB:1OY0"
FT HELIX 111..123
FT /evidence="ECO:0007829|PDB:1OY0"
FT STRAND 128..135
FT /evidence="ECO:0007829|PDB:1OY0"
FT HELIX 136..138
FT /evidence="ECO:0007829|PDB:1OY0"
FT HELIX 139..148
FT /evidence="ECO:0007829|PDB:1OY0"
FT STRAND 152..157
FT /evidence="ECO:0007829|PDB:1OY0"
FT HELIX 176..191
FT /evidence="ECO:0007829|PDB:1OY0"
FT STRAND 194..200
FT /evidence="ECO:0007829|PDB:1OY0"
FT HELIX 203..212
FT /evidence="ECO:0007829|PDB:1OY0"
FT STRAND 217..222
FT /evidence="ECO:0007829|PDB:1OY0"
FT STRAND 226..231
FT /evidence="ECO:0007829|PDB:1OY0"
FT HELIX 233..236
FT /evidence="ECO:0007829|PDB:1OY0"
FT HELIX 254..270
FT /evidence="ECO:0007829|PDB:1OY0"
SQ SEQUENCE 281 AA; 29336 MW; E05CDDC5B7E80932 CRC64;
MSEQTIYGAN TPGGSGPRTK IRTHHLQRWK ADGHKWAMLT AYDYSTARIF DEAGIPVLLV
GDSAANVVYG YDTTVPISID ELIPLVRGVV RGAPHALVVA DLPFGSYEAG PTAALAAATR
FLKDGGAHAV KLEGGERVAE QIACLTAAGI PVMAHIGFTP QSVNTLGGFR VQGRGDAAEQ
TIADAIAVAE AGAFAVVMEM VPAELATQIT GKLTIPTVGI GAGPNCDGQV LVWQDMAGFS
GAKTARFVKR YADVGGELRR AAMQYAQEVA GGVFPADEHS F
