RISB_MYCTU
ID RISB_MYCTU Reviewed; 160 AA.
AC P9WHE9; L0T874; P66034; P71685;
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=6,7-dimethyl-8-ribityllumazine synthase;
DE Short=DMRL synthase;
DE Short=LS;
DE Short=Lumazine synthase;
DE EC=2.5.1.78;
GN Name=ribH; OrderedLocusNames=Rv1416; ORFNames=MTCY21B4.34;
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 ACTIVITY REGULATION.
RX PubMed=14750781; DOI=10.1021/jo030278k;
RA Cushman M., Sambaiah T., Jin G., Illarionov B., Fischer M., Bacher A.;
RT "Design, synthesis, and evaluation of 9-D-ribitylamino-1,3,7,9-tetrahydro-
RT 2,6,8-purinetriones bearing alkyl phosphate and alpha,alpha-
RT difluorophosphonate substituents as inhibitors of riboflavin synthase and
RT lumazine synthase.";
RL J. Org. Chem. 69:601-612(2004).
RN [3]
RP IDENTIFICATION BY MASS SPECTROMETRY, AND DETERMINATION OF TRANSLATIONAL
RP START SITE.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=17259624; DOI=10.1099/mic.0.2006/001537-0;
RA Rison S.C., Mattow J., Jungblut P.R., Stoker N.G.;
RT "Experimental determination of translational starts using peptide mass
RT mapping and tandem mass spectrometry within the proteome of Mycobacterium
RT tuberculosis.";
RL Microbiology 153:521-528(2007).
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 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 [6]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) IN COMPLEXES WITH PURINETRIONE
RP INHIBITORS, FUNCTION, AND SUBUNIT.
RX PubMed=15723519; DOI=10.1021/bi047848a;
RA Morgunova E., Meining W., Illarionov B., Haase I., Jin G., Bacher A.,
RA Cushman M., Fischer M., Ladenstein R.;
RT "Crystal structure of lumazine synthase from Mycobacterium tuberculosis as
RT a target for rational drug design: binding mode of a new class of
RT purinetrione inhibitors.";
RL Biochemistry 44:2746-2758(2005).
RN [7]
RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) IN COMPLEXES WITH PURINETRIONE AND
RP CHLOROPYRIMIDINE INHIBITORS.
RX PubMed=16984393; DOI=10.1111/j.1742-4658.2006.05481.x;
RA Morgunova E., Illarionov B., Sambaiah T., Haase I., Bacher A., Cushman M.,
RA Fischer M., Ladenstein R.;
RT "Structural and thermodynamic insights into the binding mode of five novel
RT inhibitors of lumazine synthase from Mycobacterium tuberculosis.";
RL FEBS J. 273:4790-4804(2006).
RN [8]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) IN COMPLEX WITH A REACTION
RP INTERMEDIATE ANALOG INHIBITOR AND PHOSPHATE, AND REACTION MECHANISM.
RX PubMed=18331058; DOI=10.1021/jo702631a;
RA Zhang Y., Illarionov B., Morgunova E., Jin G., Bacher A., Fischer M.,
RA Ladenstein R., Cushman M.;
RT "A new series of N-[2,4-dioxo-6-d-ribitylamino-1,2,3,4-tetrahydropyrimidin-
RT 5-yl]oxalamic acid derivatives as inhibitors of lumazine synthase and
RT riboflavin synthase: design, synthesis, biochemical evaluation,
RT crystallography, and mechanistic implications.";
RL J. Org. Chem. 73:2715-2724(2008).
CC -!- FUNCTION: Catalyzes the formation of 6,7-dimethyl-8-ribityllumazine by
CC condensation of 5-amino-6-(D-ribitylamino)uracil with 3,4-dihydroxy-2-
CC butanone 4-phosphate. This is the penultimate step in the biosynthesis
CC of riboflavin. {ECO:0000269|PubMed:15723519}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(2S)-2-hydroxy-3-oxobutyl phosphate + 5-amino-6-(D-
CC ribitylamino)uracil = 6,7-dimethyl-8-(1-D-ribityl)lumazine + H(+) + 2
CC H2O + phosphate; Xref=Rhea:RHEA:26152, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:15934, ChEBI:CHEBI:43474,
CC ChEBI:CHEBI:58201, ChEBI:CHEBI:58830; EC=2.5.1.78;
CC -!- ACTIVITY REGULATION: Activity is competitively inhibited by substituted
CC ribitylpurinetrione compounds such as 3-(1,3,7,9-tetrahydro-9-D-
CC ribityl-2,6,8-trioxopurin-7-yl)propane 1-phosphate, with inhibition
CC constants in the 4-5 nM range. {ECO:0000269|PubMed:14750781}.
CC -!- PATHWAY: Cofactor biosynthesis; riboflavin biosynthesis; riboflavin
CC from 2-hydroxy-3-oxobutyl phosphate and 5-amino-6-(D-
CC ribitylamino)uracil: step 1/2.
CC -!- SUBUNIT: Homopentamer. {ECO:0000269|PubMed:15723519,
CC ECO:0000269|PubMed:18331058}.
CC -!- MISCELLANEOUS: Was identified as a high-confidence drug target.
CC -!- SIMILARITY: Belongs to the DMRL synthase family. {ECO:0000305}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; AL123456; CCP44175.1; -; Genomic_DNA.
DR PIR; E70902; E70902.
DR RefSeq; NP_215932.2; NC_000962.3.
DR RefSeq; WP_003898872.1; NZ_NVQJ01000038.1.
DR PDB; 1W19; X-ray; 2.00 A; A/B/C/D/E=1-160.
DR PDB; 1W29; X-ray; 2.30 A; A/B/C/D/E=1-160.
DR PDB; 2C92; X-ray; 1.60 A; A/B/C/D/E=1-160.
DR PDB; 2C94; X-ray; 1.90 A; A/B/C/D/E=1-160.
DR PDB; 2C97; X-ray; 2.00 A; A/B/C/D/E=1-160.
DR PDB; 2C9B; X-ray; 2.75 A; A/B/C/D/E/F/G/H/I/J=1-160.
DR PDB; 2C9D; X-ray; 2.80 A; A/B/C/D/E/F/G/H/I/J=1-160.
DR PDB; 2VI5; X-ray; 2.30 A; A/B/C/D/E/F/G/H/I/J=1-160.
DR PDBsum; 1W19; -.
DR PDBsum; 1W29; -.
DR PDBsum; 2C92; -.
DR PDBsum; 2C94; -.
DR PDBsum; 2C97; -.
DR PDBsum; 2C9B; -.
DR PDBsum; 2C9D; -.
DR PDBsum; 2VI5; -.
DR AlphaFoldDB; P9WHE9; -.
DR SMR; P9WHE9; -.
DR STRING; 83332.Rv1416; -.
DR BindingDB; P9WHE9; -.
DR ChEMBL; CHEMBL1075177; -.
DR DrugBank; DB02693; (4S,5S)-1,2-dithiane-4,5-diol.
DR DrugBank; DB02135; 1-deoxy-1-{2,6,8-trioxo-7-[4-(phosphonooxy)butyl]-1,2,3,6,7,8-hexahydro-9H-purin-9-yl}-D-arabinitol.
DR DrugBank; DB03973; 3-[2,6,8-Trioxo-9-[(2R,3R,4R)-2,3,4,5-tetrahydroxypentyl]-3H-purin-7-yl]propyl dihydrogen phosphate.
DR DrugBank; DB03022; 3-[2,6,8-Trioxo-9-[(2R,3S,4R)-2,3,4,5-tetrahydroxypentyl]-3H-purin-7-yl]propyl dihydrogen phosphate.
DR DrugBank; DB03812; 3-{2,6,8-trioxo-9-[(2S,3R,4R)-2,3,4,5-tetrahydroxypentyl]-1,2,3,6,8,9-hexahydro-7H-purin-7-Yl}propyl dihydrogen phosphate.
DR DrugBank; DB02290; 3-{2,6,8-trioxo-9-[(2S,3S,4R)-2,3,4,5-tetrahydroxypentyl]-1,2,3,6,8,9-hexahydro-7H-purin-7-Yl}propyl dihydrogen phosphate.
DR DrugBank; DB08016; 4-(6-CHLORO-2,4-DIOXO-1,2,3,4-TETRAHYDROPYRIMIDIN-5-YL) BUTYL PHOSPHATE.
DR DrugBank; DB02711; 4-{2,6,8-Trioxo-9-[(2S,3R,4R)-2,3,4,5-Tetrahydroxypentyl]-1,2,3,6,8,9-Hexahydro-7h-Purin-7-Yl}Butyl Dihydrogen Phosphate.
DR DrugBank; DB02184; D-1,4-dithiothreitol.
DR DrugBank; DB01692; Dithioerythritol.
DR PaxDb; P9WHE9; -.
DR GeneID; 886681; -.
DR KEGG; mtu:Rv1416; -.
DR TubercuList; Rv1416; -.
DR eggNOG; COG0054; Bacteria.
DR OMA; CQGVTQG; -.
DR UniPathway; UPA00275; UER00404.
DR Proteomes; UP000001584; Chromosome.
DR GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR GO; GO:0009349; C:riboflavin synthase complex; IEA:InterPro.
DR GO; GO:0000906; F:6,7-dimethyl-8-ribityllumazine synthase activity; IBA:GO_Central.
DR GO; GO:0009231; P:riboflavin biosynthetic process; IBA:GO_Central.
DR CDD; cd09209; Lumazine_synthase-I; 1.
DR Gene3D; 3.40.50.960; -; 1.
DR HAMAP; MF_00178; Lumazine_synth; 1.
DR InterPro; IPR034964; LS.
DR InterPro; IPR002180; LS/RS.
DR InterPro; IPR036467; LS/RS_sf.
DR PANTHER; PTHR21058; PTHR21058; 1.
DR Pfam; PF00885; DMRL_synthase; 1.
DR SUPFAM; SSF52121; SSF52121; 1.
DR TIGRFAMs; TIGR00114; lumazine-synth; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Reference proteome; Riboflavin biosynthesis; Transferase.
FT CHAIN 1..160
FT /note="6,7-dimethyl-8-ribityllumazine synthase"
FT /id="PRO_0000134772"
FT ACT_SITE 89
FT /note="Proton donor"
FT /evidence="ECO:0000255"
FT BINDING 27
FT /ligand="5-amino-6-(D-ribitylamino)uracil"
FT /ligand_id="ChEBI:CHEBI:15934"
FT BINDING 59..61
FT /ligand="5-amino-6-(D-ribitylamino)uracil"
FT /ligand_id="ChEBI:CHEBI:15934"
FT BINDING 81..83
FT /ligand="5-amino-6-(D-ribitylamino)uracil"
FT /ligand_id="ChEBI:CHEBI:15934"
FT BINDING 86..87
FT /ligand="(2S)-2-hydroxy-3-oxobutyl phosphate"
FT /ligand_id="ChEBI:CHEBI:58830"
FT /evidence="ECO:0000305"
FT BINDING 114
FT /ligand="5-amino-6-(D-ribitylamino)uracil"
FT /ligand_id="ChEBI:CHEBI:15934"
FT BINDING 128
FT /ligand="(2S)-2-hydroxy-3-oxobutyl phosphate"
FT /ligand_id="ChEBI:CHEBI:58830"
FT /evidence="ECO:0000305"
FT STRAND 20..25
FT /evidence="ECO:0007829|PDB:2C92"
FT HELIX 29..45
FT /evidence="ECO:0007829|PDB:2C92"
FT STRAND 52..58
FT /evidence="ECO:0007829|PDB:2C92"
FT HELIX 59..61
FT /evidence="ECO:0007829|PDB:2C92"
FT HELIX 62..70
FT /evidence="ECO:0007829|PDB:2C92"
FT STRAND 74..83
FT /evidence="ECO:0007829|PDB:2C92"
FT HELIX 89..108
FT /evidence="ECO:0007829|PDB:2C92"
FT STRAND 112..121
FT /evidence="ECO:0007829|PDB:2C92"
FT HELIX 122..126
FT /evidence="ECO:0007829|PDB:2C92"
FT HELIX 138..156
FT /evidence="ECO:0007829|PDB:2C92"
SQ SEQUENCE 160 AA; 16371 MW; 20E837C273312E83 CRC64;
MKGGAGVPDL PSLDASGVRL AIVASSWHGK ICDALLDGAR KVAAGCGLDD PTVVRVLGAI
EIPVVAQELA RNHDAVVALG VVIRGQTPHF DYVCDAVTQG LTRVSLDSST PIANGVLTTN
TEEQALDRAG LPTSAEDKGA QATVAALATA LTLRELRAHS
