CYSH_MYCTU
ID CYSH_MYCTU Reviewed; 254 AA.
AC P9WIK3; L0T9P0; P65668; P71752;
DT 16-APR-2014, integrated into UniProtKB/Swiss-Prot.
DT 16-APR-2014, sequence version 1.
DT 03-AUG-2022, entry version 44.
DE RecName: Full=Adenosine 5'-phosphosulfate reductase {ECO:0000255|HAMAP-Rule:MF_00063, ECO:0000303|PubMed:12072441};
DE Short=APS reductase {ECO:0000255|HAMAP-Rule:MF_00063, ECO:0000303|PubMed:12072441};
DE EC=1.8.4.10 {ECO:0000255|HAMAP-Rule:MF_00063, ECO:0000269|PubMed:12072441, ECO:0000269|PubMed:19678707, ECO:0000269|PubMed:23711725};
DE AltName: Full=5'-adenylylsulfate reductase {ECO:0000255|HAMAP-Rule:MF_00063};
DE AltName: Full=Thioredoxin-dependent 5'-adenylylsulfate reductase {ECO:0000255|HAMAP-Rule:MF_00063};
GN Name=cysH {ECO:0000255|HAMAP-Rule:MF_00063, ECO:0000303|PubMed:12072441};
GN OrderedLocusNames=Rv2392; ORFNames=MTCY253.29c;
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, CATALYTIC ACTIVITY, AND PATHWAY.
RX PubMed=12072441; DOI=10.1074/jbc.m204613200;
RA Williams S.J., Senaratne R.H., Mougous J.D., Riley L.W., Bertozzi C.R.;
RT "5'-adenosinephosphosulfate lies at a metabolic branch point in
RT mycobacteria.";
RL J. Biol. Chem. 277:32606-32615(2002).
RN [3]
RP COFACTOR.
RX PubMed=17023175; DOI=10.1016/j.jasms.2006.08.010;
RA Gao H., Leary J., Carroll K.S., Bertozzi C.R., Chen H.;
RT "Noncovalent complexes of APS reductase from M. tuberculosis: delineating a
RT mechanistic model using ESI-FTICR MS.";
RL J. Am. Soc. Mass Spectrom. 18:167-178(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 FUNCTION, CATALYTIC ACTIVITY, AND IDENTIFICATION AS A DRUG TARGET.
RX PubMed=19678707; DOI=10.1021/jm900728u;
RA Hong J.A., Bhave D.P., Carroll K.S.;
RT "Identification of critical ligand binding determinants in Mycobacterium
RT tuberculosis adenosine-5'-phosphosulfate reductase.";
RL J. Med. Chem. 52:5485-5495(2009).
RN [6]
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 [7]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, AND BIOPHYSICOCHEMICAL
RP PROPERTIES.
RX PubMed=23711725; DOI=10.1016/j.ab.2013.05.007;
RA Paritala H., Carroll K.S.;
RT "A continuous spectrophotometric assay for adenosine 5'-phosphosulfate
RT reductase activity with sulfite-selective probes.";
RL Anal. Biochem. 440:32-39(2013).
RN [8]
RP IDENTIFICATION AS A DRUG TARGET.
RX PubMed=25710356; DOI=10.1080/15257770.2014.978012;
RA Paritala H., Suzuki Y., Carroll K.S.;
RT "Design, synthesis and evaluation of Fe-S targeted adenosine 5'-
RT phosphosulfate reductase inhibitors.";
RL Nucleosides Nucleotides Nucleic Acids 34:199-220(2015).
CC -!- FUNCTION: Catalyzes the formation of sulfite from adenosine 5'-
CC phosphosulfate (APS) using thioredoxin as an electron donor.
CC {ECO:0000255|HAMAP-Rule:MF_00063, ECO:0000269|PubMed:12072441,
CC ECO:0000269|PubMed:19678707, ECO:0000269|PubMed:23711725}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=[thioredoxin]-disulfide + AMP + 2 H(+) + sulfite =
CC [thioredoxin]-dithiol + adenosine 5'-phosphosulfate;
CC Xref=Rhea:RHEA:21976, Rhea:RHEA-COMP:10698, Rhea:RHEA-COMP:10700,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:17359, ChEBI:CHEBI:29950,
CC ChEBI:CHEBI:50058, ChEBI:CHEBI:58243, ChEBI:CHEBI:456215;
CC EC=1.8.4.10; Evidence={ECO:0000255|HAMAP-Rule:MF_00063,
CC ECO:0000269|PubMed:12072441, ECO:0000269|PubMed:19678707,
CC ECO:0000269|PubMed:23711725};
CC -!- COFACTOR:
CC Name=[4Fe-4S] cluster; Xref=ChEBI:CHEBI:49883;
CC Evidence={ECO:0000255|HAMAP-Rule:MF_00063,
CC ECO:0000269|PubMed:17023175};
CC Note=Binds 1 [4Fe-4S] cluster per subunit. {ECO:0000255|HAMAP-
CC Rule:MF_00063};
CC -!- ACTIVITY REGULATION: Inhibited by adenosine 5'-diphosphate (ADP).
CC {ECO:0000269|PubMed:23711725}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=24.3 uM for adenosine 5'-phosphosulfate
CC {ECO:0000269|PubMed:23711725};
CC Note=kcat is 7.8 min(-1). {ECO:0000269|PubMed:23711725};
CC -!- PATHWAY: Sulfur metabolism; hydrogen sulfide biosynthesis; sulfite from
CC sulfate. {ECO:0000255|HAMAP-Rule:MF_00063,
CC ECO:0000305|PubMed:12072441}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000255|HAMAP-Rule:MF_00063}.
CC -!- MISCELLANEOUS: Was identified as a high-confidence drug target
CC (PubMed:19099550, PubMed:19678707, PubMed:25710356). Inhibitors that
CC target the Fe-S cluster have been developed and studied
CC (PubMed:25710356). {ECO:0000269|PubMed:19099550,
CC ECO:0000269|PubMed:19678707, ECO:0000269|PubMed:25710356}.
CC -!- SIMILARITY: Belongs to the PAPS reductase family. CysH subfamily.
CC {ECO:0000255|HAMAP-Rule:MF_00063, ECO:0000305}.
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DR EMBL; AL123456; CCP45180.1; -; Genomic_DNA.
DR PIR; C70682; C70682.
DR RefSeq; NP_216908.1; NC_000962.3.
DR RefSeq; WP_003412303.1; NZ_NVQJ01000029.1.
DR PDB; 7LHR; X-ray; 3.11 A; A/B=1-254.
DR PDB; 7LHS; X-ray; 3.11 A; A/B=1-254.
DR PDB; 7LHU; X-ray; 3.09 A; A/B=1-254.
DR PDBsum; 7LHR; -.
DR PDBsum; 7LHS; -.
DR PDBsum; 7LHU; -.
DR AlphaFoldDB; P9WIK3; -.
DR SMR; P9WIK3; -.
DR STRING; 83332.Rv2392; -.
DR PaxDb; P9WIK3; -.
DR DNASU; 885250; -.
DR GeneID; 45426378; -.
DR GeneID; 885250; -.
DR KEGG; mtu:Rv2392; -.
DR TubercuList; Rv2392; -.
DR eggNOG; COG0175; Bacteria.
DR OMA; PIARWTQ; -.
DR PhylomeDB; P9WIK3; -.
DR Reactome; R-MTU-936721; Cysteine synthesis from O-acetylserine.
DR Proteomes; UP000001584; Chromosome.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005886; C:plasma membrane; HDA:MTBBASE.
DR GO; GO:0051539; F:4 iron, 4 sulfur cluster binding; IDA:MTBBASE.
DR GO; GO:0043866; F:adenylyl-sulfate reductase (thioredoxin) activity; IDA:MTBBASE.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0004604; F:phosphoadenylyl-sulfate reductase (thioredoxin) activity; IEA:UniProtKB-UniRule.
DR GO; GO:0019344; P:cysteine biosynthetic process; IEA:InterPro.
DR GO; GO:0019379; P:sulfate assimilation, phosphoadenylyl sulfate reduction by phosphoadenylyl-sulfate reductase (thioredoxin); IEA:UniProtKB-UniRule.
DR CDD; cd01713; PAPS_reductase; 1.
DR Gene3D; 3.40.50.620; -; 1.
DR HAMAP; MF_00063; CysH; 1.
DR InterPro; IPR011798; APS_reductase.
DR InterPro; IPR004511; PAPS/APS_Rdtase.
DR InterPro; IPR002500; PAPS_reduct.
DR InterPro; IPR014729; Rossmann-like_a/b/a_fold.
DR Pfam; PF01507; PAPS_reduct; 1.
DR PIRSF; PIRSF000857; PAPS_reductase; 1.
DR TIGRFAMs; TIGR02055; APS_reductase; 1.
DR TIGRFAMs; TIGR00434; cysH; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cytoplasm; Iron; Iron-sulfur; Metal-binding; Oxidoreductase;
KW Reference proteome.
FT CHAIN 1..254
FT /note="Adenosine 5'-phosphosulfate reductase"
FT /id="PRO_0000100633"
FT ACT_SITE 249
FT /note="Nucleophile; cysteine thiosulfonate intermediate"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_00063"
FT BINDING 140
FT /ligand="[4Fe-4S] cluster"
FT /ligand_id="ChEBI:CHEBI:49883"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_00063"
FT BINDING 141
FT /ligand="[4Fe-4S] cluster"
FT /ligand_id="ChEBI:CHEBI:49883"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_00063"
FT BINDING 223
FT /ligand="[4Fe-4S] cluster"
FT /ligand_id="ChEBI:CHEBI:49883"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_00063"
FT BINDING 226
FT /ligand="[4Fe-4S] cluster"
FT /ligand_id="ChEBI:CHEBI:49883"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_00063"
FT HELIX 10..23
FT /evidence="ECO:0007829|PDB:7LHU"
FT TURN 24..26
FT /evidence="ECO:0007829|PDB:7LHU"
FT HELIX 29..39
FT /evidence="ECO:0007829|PDB:7LHU"
FT STRAND 60..64
FT /evidence="ECO:0007829|PDB:7LHU"
FT STRAND 67..70
FT /evidence="ECO:0007829|PDB:7LHU"
FT HELIX 71..79
FT /evidence="ECO:0007829|PDB:7LHU"
FT STRAND 83..88
FT /evidence="ECO:0007829|PDB:7LHU"
FT HELIX 95..107
FT /evidence="ECO:0007829|PDB:7LHU"
FT STRAND 108..115
FT /evidence="ECO:0007829|PDB:7LHU"
FT HELIX 121..128
FT /evidence="ECO:0007829|PDB:7LHU"
FT HELIX 132..135
FT /evidence="ECO:0007829|PDB:7LHU"
FT HELIX 137..144
FT /evidence="ECO:0007829|PDB:7LHU"
FT HELIX 146..153
FT /evidence="ECO:0007829|PDB:7LHU"
FT STRAND 157..161
FT /evidence="ECO:0007829|PDB:7LHU"
FT HELIX 165..167
FT /evidence="ECO:0007829|PDB:7LHU"
FT HELIX 169..171
FT /evidence="ECO:0007829|PDB:7LHU"
FT STRAND 176..180
FT /evidence="ECO:0007829|PDB:7LHU"
FT TURN 181..184
FT /evidence="ECO:0007829|PDB:7LHU"
FT STRAND 185..188
FT /evidence="ECO:0007829|PDB:7LHU"
FT TURN 190..193
FT /evidence="ECO:0007829|PDB:7LHR"
FT HELIX 196..206
FT /evidence="ECO:0007829|PDB:7LHU"
FT HELIX 212..215
FT /evidence="ECO:0007829|PDB:7LHU"
FT HELIX 224..226
FT /evidence="ECO:0007829|PDB:7LHU"
SQ SEQUENCE 254 AA; 27423 MW; 554F2E3204452C55 CRC64;
MSGETTRLTE PQLRELAARG AAELDGATAT DMLRWTDETF GDIGGAGGGV SGHRGWTTCN
YVVASNMADA VLVDLAAKVR PGVPVIFLDT GYHFVETIGT RDAIESVYDV RVLNVTPEHT
VAEQDELLGK DLFARNPHEC CRLRKVVPLG KTLRGYSAWV TGLRRVDAPT RANAPLVSFD
ETFKLVKVNP LAAWTDQDVQ EYIADNDVLV NPLVREGYPS IGCAPCTAKP AEGADPRSGR
WQGLAKTECG LHAS
