Y1264_MYCTU
ID Y1264_MYCTU Reviewed; 397 AA.
AC P9WMU9; L0T7S0; Q11055;
DT 16-APR-2014, integrated into UniProtKB/Swiss-Prot.
DT 16-APR-2014, sequence version 1.
DT 03-AUG-2022, entry version 40.
DE RecName: Full=pH-sensitive adenylate cyclase Rv1264;
DE EC=4.6.1.1;
DE AltName: Full=ATP pyrophosphate-lyase;
DE AltName: Full=Adenylyl cyclase;
GN OrderedLocusNames=Rv1264; ORFNames=MTCY50.18c;
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 INDUCTION BY HYPOXIA.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=11416222; DOI=10.1073/pnas.121172498;
RA Sherman D.R., Voskuil M., Schnappinger D., Liao R., Harrell M.I.,
RA Schoolnik G.K.;
RT "Regulation of the Mycobacterium tuberculosis hypoxic response gene
RT encoding alpha -crystallin.";
RL Proc. Natl. Acad. Sci. U.S.A. 98:7534-7539(2001).
RN [3]
RP CATALYTIC ACTIVITY, COFACTOR, SUBUNIT, AND MUTAGENESIS OF ASP-107; ARG-132;
RP ASP-222; LYS-261; ASP-265; ASP-312; ASN-319 AND ARG-323.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=11839758; DOI=10.1074/jbc.m200235200;
RA Linder J.U., Schultz A., Schultz J.E.;
RT "Adenylyl cyclase Rv1264 from Mycobacterium tuberculosis has an
RT autoinhibitory N-terminal domain.";
RL J. Biol. Chem. 277:15271-15276(2002).
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 DISRUPTION PHENOTYPE.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=17005450; DOI=10.1016/j.ijmm.2006.07.001;
RA Dittrich D., Keller C., Ehlers S., Schultz J.E., Sander P.;
RT "Characterization of a Mycobacterium tuberculosis mutant deficient in pH-
RT sensing adenylate cyclase Rv1264.";
RL Int. J. Med. Microbiol. 296:563-566(2006).
RN [6]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT THR-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 (2.3 ANGSTROMS) OF ACTIVE OR INACTIVE FORMS,
RP BIOPHYSICOCHEMICAL PROPERTIES, SUBUNIT, AND MUTAGENESIS OF HIS-192;
RP 193-MET--MET-194; GLU-195 AND ARG-309.
RX PubMed=15890882; DOI=10.1126/science.1107642;
RA Tews I., Findeisen F., Sinning I., Schultz A., Schultz J.E., Linder J.U.;
RT "The structure of a pH-sensing mycobacterial adenylyl cyclase holoenzyme.";
RL Science 308:1020-1023(2005).
RN [8]
RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 1-207, LINKER SEGMENT, FATTY ACID
RP BINDING, AND MUTAGENESIS.
RX PubMed=17482646; DOI=10.1016/j.jmb.2007.04.013;
RA Findeisen F., Linder J.U., Schultz A., Schultz J.E., Brugger B.,
RA Wieland F., Sinning I., Tews I.;
RT "The structure of the regulatory domain of the adenylyl cyclase Rv1264 from
RT Mycobacterium tuberculosis with bound oleic acid.";
RL J. Mol. Biol. 369:1282-1295(2007).
CC -!- FUNCTION: Catalyzes the formation of the second messenger cAMP.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP = 3',5'-cyclic AMP + diphosphate; Xref=Rhea:RHEA:15389,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:33019, ChEBI:CHEBI:58165; EC=4.6.1.1;
CC Evidence={ECO:0000269|PubMed:11839758};
CC -!- COFACTOR:
CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC Evidence={ECO:0000269|PubMed:11839758};
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:11839758};
CC Note=The isolated catalytic domain prefers Mn(2+) over Mg(2+) as a
CC cofactor. {ECO:0000269|PubMed:11839758};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC Vmax=420 nmol/min/mg enzyme {ECO:0000269|PubMed:15890882};
CC Note=At pH 6.0.;
CC pH dependence:
CC Optimum pH is 6.0. {ECO:0000269|PubMed:15890882};
CC -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:11839758,
CC ECO:0000269|PubMed:15890882}.
CC -!- INDUCTION: A possible member of the dormancy regulon. Induced in
CC response to reduced oxygen tension (hypoxia). It is hoped that this
CC regulon will give insight into the latent, or dormant phase of
CC infection. {ECO:0000269|PubMed:11416222}.
CC -!- DOMAIN: Consists of 3 structural domains. The pH-responsive N-terminus
CC inhibits the adenylyl cyclase (AC) activity of the C-terminal catalytic
CC domain. The length of the linker segment (aa 192-206) is decisive for
CC regulation.
CC -!- DISRUPTION PHENOTYPE: No visible phenotype following infection of SPF
CC C57BL/6 mice. {ECO:0000269|PubMed:17005450}.
CC -!- MISCELLANEOUS: Was identified as a high-confidence drug target.
CC -!- MISCELLANEOUS: Binds 1 C18:1 fatty acid per monomer.
CC -!- SIMILARITY: Belongs to the adenylyl cyclase class-4/guanylyl cyclase
CC family. {ECO:0000255|PROSITE-ProRule:PRU00099}.
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DR EMBL; AL123456; CCP44020.1; -; Genomic_DNA.
DR PIR; H70753; H70753.
DR RefSeq; NP_215780.1; NC_000962.3.
DR RefSeq; WP_003406372.1; NZ_NVQJ01000049.1.
DR PDB; 1Y10; X-ray; 2.30 A; A/B/C/D=1-397.
DR PDB; 1Y11; X-ray; 3.30 A; A=1-397.
DR PDB; 2EV1; X-ray; 1.60 A; A/B=1-207.
DR PDB; 2EV2; X-ray; 2.35 A; A/B=1-207.
DR PDB; 2EV3; X-ray; 2.68 A; A/B=1-207.
DR PDB; 2EV4; X-ray; 2.28 A; A/B=1-207.
DR PDBsum; 1Y10; -.
DR PDBsum; 1Y11; -.
DR PDBsum; 2EV1; -.
DR PDBsum; 2EV2; -.
DR PDBsum; 2EV3; -.
DR PDBsum; 2EV4; -.
DR AlphaFoldDB; P9WMU9; -.
DR SMR; P9WMU9; -.
DR STRING; 83332.Rv1264; -.
DR iPTMnet; P9WMU9; -.
DR PaxDb; P9WMU9; -.
DR GeneID; 887035; -.
DR KEGG; mtu:Rv1264; -.
DR TubercuList; Rv1264; -.
DR eggNOG; COG2114; Bacteria.
DR OMA; FEWSFAG; -.
DR PhylomeDB; P9WMU9; -.
DR Proteomes; UP000001584; Chromosome.
DR GO; GO:0004016; F:adenylate cyclase activity; IDA:MTBBASE.
DR GO; GO:0010855; F:adenylate cyclase inhibitor activity; IMP:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0008289; F:lipid binding; IEA:UniProtKB-KW.
DR GO; GO:0030145; F:manganese ion binding; IDA:MTBBASE.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0006171; P:cAMP biosynthetic process; IEA:UniProtKB-KW.
DR GO; GO:0035556; P:intracellular signal transduction; IEA:InterPro.
DR GO; GO:0009268; P:response to pH; IDA:MTBBASE.
DR Gene3D; 3.30.70.1230; -; 1.
DR InterPro; IPR001054; A/G_cyclase.
DR InterPro; IPR032026; Ad_Cy_reg.
DR InterPro; IPR029787; Nucleotide_cyclase.
DR Pfam; PF16701; Ad_Cy_reg; 1.
DR Pfam; PF00211; Guanylate_cyc; 1.
DR SMART; SM00044; CYCc; 1.
DR SUPFAM; SSF55073; SSF55073; 1.
DR PROSITE; PS50125; GUANYLATE_CYCLASE_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; ATP-binding; cAMP biosynthesis; Lipid-binding;
KW Lyase; Magnesium; Manganese; Metal-binding; Nucleotide-binding;
KW Reference proteome.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0007744|PubMed:21969609"
FT CHAIN 2..397
FT /note="pH-sensitive adenylate cyclase Rv1264"
FT /id="PRO_0000074131"
FT DOMAIN 217..325
FT /note="Guanylate cyclase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00099"
FT REGION 2..191
FT /note="Regulatory domain"
FT REGION 192..206
FT /note="Linker"
FT REGION 211..397
FT /note="Catalytic domain"
FT BINDING 222
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /evidence="ECO:0000305|PubMed:11839758"
FT BINDING 261
FT /ligand="substrate"
FT /evidence="ECO:0000305"
FT BINDING 265
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /evidence="ECO:0000305|PubMed:11839758"
FT BINDING 298
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000305"
FT BINDING 312
FT /ligand="substrate"
FT /evidence="ECO:0000305"
FT MOD_RES 2
FT /note="N-acetylthreonine"
FT /evidence="ECO:0007744|PubMed:21969609"
FT MUTAGEN 107
FT /note="D->A: 7-fold increase in holoenzyme adenylyl cyclase
FT activity at pH 8.0."
FT /evidence="ECO:0000269|PubMed:11839758"
FT MUTAGEN 132
FT /note="R->A: No change in holoenzyme activity."
FT /evidence="ECO:0000269|PubMed:11839758"
FT MUTAGEN 192
FT /note="H->A: Shifts activation towards acidic pH."
FT /evidence="ECO:0000269|PubMed:15890882"
FT MUTAGEN 192
FT /note="H->E: Higher activity above pH 7.0."
FT /evidence="ECO:0000269|PubMed:15890882"
FT MUTAGEN 193..194
FT /note="MM->PP: Loss of pH regulation."
FT /evidence="ECO:0000269|PubMed:15890882"
FT MUTAGEN 195
FT /note="E->A: Partially relieves high pH inhibition."
FT /evidence="ECO:0000269|PubMed:15890882"
FT MUTAGEN 222
FT /note="D->A: Loss of adenylyl cyclase activity in the
FT catalytic fragment."
FT /evidence="ECO:0000269|PubMed:11839758"
FT MUTAGEN 261
FT /note="K->A: Almost complete loss of adenylyl cyclase
FT activity in the catalytic fragment."
FT /evidence="ECO:0000269|PubMed:11839758"
FT MUTAGEN 265
FT /note="D->A: Loss of adenylyl cyclase activity in the
FT catalytic fragment."
FT /evidence="ECO:0000269|PubMed:11839758"
FT MUTAGEN 309
FT /note="R->A: Obviates pH regulation."
FT /evidence="ECO:0000269|PubMed:15890882"
FT MUTAGEN 312
FT /note="D->A: Loss of adenylyl cyclase activity in the
FT catalytic fragment."
FT /evidence="ECO:0000269|PubMed:11839758"
FT MUTAGEN 319
FT /note="N->A: Almost complete loss of adenylyl cyclase
FT activity in the catalytic fragment."
FT /evidence="ECO:0000269|PubMed:11839758"
FT MUTAGEN 323
FT /note="R->A: Retains 10% adenylyl cyclase activity in the
FT catalytic fragment."
FT /evidence="ECO:0000269|PubMed:11839758"
FT HELIX 13..17
FT /evidence="ECO:0007829|PDB:2EV1"
FT HELIX 22..37
FT /evidence="ECO:0007829|PDB:2EV1"
FT HELIX 42..47
FT /evidence="ECO:0007829|PDB:2EV1"
FT STRAND 48..50
FT /evidence="ECO:0007829|PDB:2EV1"
FT HELIX 51..53
FT /evidence="ECO:0007829|PDB:2EV2"
FT HELIX 54..59
FT /evidence="ECO:0007829|PDB:2EV1"
FT HELIX 69..76
FT /evidence="ECO:0007829|PDB:2EV1"
FT HELIX 80..90
FT /evidence="ECO:0007829|PDB:2EV1"
FT STRAND 93..95
FT /evidence="ECO:0007829|PDB:2EV4"
FT HELIX 105..111
FT /evidence="ECO:0007829|PDB:2EV1"
FT HELIX 114..119
FT /evidence="ECO:0007829|PDB:2EV1"
FT HELIX 124..153
FT /evidence="ECO:0007829|PDB:2EV1"
FT HELIX 160..194
FT /evidence="ECO:0007829|PDB:2EV1"
FT HELIX 201..205
FT /evidence="ECO:0007829|PDB:1Y11"
FT STRAND 214..223
FT /evidence="ECO:0007829|PDB:1Y10"
FT HELIX 226..229
FT /evidence="ECO:0007829|PDB:1Y11"
FT TURN 230..232
FT /evidence="ECO:0007829|PDB:1Y11"
FT HELIX 235..252
FT /evidence="ECO:0007829|PDB:1Y10"
FT STRAND 258..263
FT /evidence="ECO:0007829|PDB:1Y10"
FT STRAND 266..273
FT /evidence="ECO:0007829|PDB:1Y10"
FT HELIX 274..289
FT /evidence="ECO:0007829|PDB:1Y10"
FT STRAND 292..294
FT /evidence="ECO:0007829|PDB:1Y11"
FT STRAND 297..309
FT /evidence="ECO:0007829|PDB:1Y10"
FT STRAND 312..315
FT /evidence="ECO:0007829|PDB:1Y10"
FT HELIX 316..327
FT /evidence="ECO:0007829|PDB:1Y10"
FT STRAND 333..336
FT /evidence="ECO:0007829|PDB:1Y10"
FT HELIX 337..341
FT /evidence="ECO:0007829|PDB:1Y10"
FT STRAND 353..360
FT /evidence="ECO:0007829|PDB:1Y10"
FT STRAND 369..375
FT /evidence="ECO:0007829|PDB:1Y10"
SQ SEQUENCE 397 AA; 42232 MW; F6C212A181DB5AD3 CRC64;
MTDHVREADD ANIDDLLGDL GGTARAERAK LVEWLLEQGI TPDEIRATNP PLLLATRHLV
GDDGTYVSAR EISENYGVDL ELLQRVQRAV GLARVDDPDA VVHMRADGEA AARAQRFVEL
GLNPDQVVLV VRVLAEGLSH AAEAMRYTAL EAIMRPGATE LDIAKGSQAL VSQIVPLLGP
MIQDMLFMQL RHMMETEAVN AGERAAGKPL PGARQVTVAF ADLVGFTQLG EVVSAEELGH
LAGRLAGLAR DLTAPPVWFI KTIGDAVMLV CPDPAPLLDT VLKLVEVVDT DNNFPRLRAG
VASGMAVSRA GDWFGSPVNV ASRVTGVARP GAVLVADSVR EALGDAPEAD GFQWSFAGPR
RLRGIRGDVR LFRVRRGATR TGSGGAAQDD DLAGSSP
