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 22-JUL-2015, entry version 14. 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., RA Harris D.E., Gordon S.V., Eiglmeier K., Gas S., Barry C.E. III, RA Tekaia F., Badcock K., Basham D., Brown D., Chillingworth T., RA Connor R., Davies R.M., Devlin K., Feltwell T., Gentles S., Hamlin N., RA Holroyd S., Hornsby T., Jagels K., Krogh A., McLean J., Moule S., RA Murphy L.D., Oliver S., Osborne J., Quail M.A., Rajandream M.A., RA Rogers J., Rutter S., Seeger K., Skelton S., Squares S., Squares R., RA Sulston J.E., Taylor K., Whitehead S., Barrell B.G.; RT "Deciphering the biology of Mycobacterium tuberculosis from the RT complete 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; RP ARG-132; 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 RT tuberculosis through an interactome, reactome and genome-scale RT 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 RT pH-sensing adenylate cyclase Rv1264."; RL Int. J. Med. Microbiol. 296:563-566(2006). RN [6] RP ACETYLATION [LARGE SCALE ANALYSIS] AT THR-2, IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS], AND CLEAVAGE OF INITIATOR RP METHIONINE [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., RA Yadav A.K., Shrivastava P., Marimuthu A., Anand S., Sundaram H., RA Kingsbury R., Harsha H.C., Nair B., Prasad T.S., Chauhan D.S., RA Katoch K., Katoch V.M., Kumar P., Chaerkady R., Ramachandran S., RA Dash D., Pandey A.; RT "Proteogenomic analysis of Mycobacterium tuberculosis by high RT resolution 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., RA Linder J.U.; RT "The structure of a pH-sensing mycobacterial adenylyl cyclase RT holoenzyme."; RL Science 308:1020-1023(2005). RN [8] RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 1-207, LINKER SEGMENT, FATTY RP ACID 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 RT from 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: ATP = 3',5'-cyclic AMP + diphosphate. CC {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 CC this regulon will give insight into the latent, or dormant phase CC of infection. {ECO:0000269|PubMed:11416222}. CC -!- DOMAIN: Consists of 3 structural domains. The pH-responsive N- CC terminus inhibits the adenylyl cyclase (AC) activity of the C- CC terminal catalytic domain. The length of the linker segment (aa CC 192-206) is decisive for regulation. CC -!- DISRUPTION PHENOTYPE: No visible phenotype following infection of CC SPF 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 CC cyclase family. {ECO:0000255|PROSITE-ProRule:PRU00099}. CC -!- SIMILARITY: Contains 1 guanylate cyclase domain. CC {ECO:0000255|PROSITE-ProRule:PRU00099}. 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; CCP44020.1; -; Genomic_DNA. DR PIR; H70753; H70753. DR RefSeq; NP_215780.1; NC_000962.3. DR RefSeq; WP_003406372.1; NZ_KK339370.1. 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 ProteinModelPortal; P9WMU9; -. DR SMR; P9WMU9; 14-377. DR STRING; 83332.Rv1264; -. DR EnsemblBacteria; CCP44020; CCP44020; Rv1264. DR GeneID; 887035; -. DR KEGG; mtu:Rv1264; -. DR KEGG; mtv:RVBD_1264; -. DR TubercuList; Rv1264; -. DR KO; K01768; -. DR OMA; PVRFIKT; -. DR PhylomeDB; P9WMU9; -. DR Proteomes; UP000001584; Chromosome. DR GO; GO:0005622; C:intracellular; IEA:GOC. DR GO; GO:0004016; F:adenylate cyclase activity; IDA:MTBBASE. 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: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; IPR029787; Nucleotide_cyclase. 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; KW Complete proteome; Lipid-binding; Lyase; Magnesium; Manganese; KW Metal-binding; Nucleotide-binding; Reference proteome. FT INIT_MET 1 1 Removed. {ECO:0000269|PubMed:21969609}. FT CHAIN 2 397 pH-sensitive adenylate cyclase Rv1264. FT /FTId=PRO_0000074131. FT DOMAIN 217 325 Guanylate cyclase. {ECO:0000255|PROSITE- FT ProRule:PRU00099}. FT REGION 2 191 Regulatory domain. FT REGION 192 206 Linker. FT REGION 211 397 Catalytic domain. FT METAL 222 222 Manganese or magnesium. {ECO:0000305}. FT METAL 265 265 Manganese or magnesium. {ECO:0000305}. FT BINDING 261 261 Substrate. {ECO:0000305}. FT BINDING 298 298 ATP. {ECO:0000305}. FT BINDING 312 312 Substrate. {ECO:0000305}. FT MOD_RES 2 2 N-acetylthreonine. FT {ECO:0000269|PubMed:21969609}. FT MUTAGEN 107 107 D->A: 7-fold increase in holoenzyme FT adenylyl cyclase activity at pH 8.0. FT {ECO:0000269|PubMed:11839758}. FT MUTAGEN 132 132 R->A: No change in holoenzyme activity. FT {ECO:0000269|PubMed:11839758}. FT MUTAGEN 192 192 H->A: Shifts activation towards acidic FT pH. {ECO:0000269|PubMed:15890882}. FT MUTAGEN 192 192 H->E: Higher activity above pH 7.0. FT {ECO:0000269|PubMed:15890882}. FT MUTAGEN 193 194 MM->PP: Loss of pH regulation. FT {ECO:0000269|PubMed:15890882}. FT MUTAGEN 195 195 E->A: Partially relieves high pH FT inhibition. FT {ECO:0000269|PubMed:15890882}. FT MUTAGEN 222 222 D->A: Loss of adenylyl cyclase activity FT in the catalytic fragment. FT {ECO:0000269|PubMed:11839758}. FT MUTAGEN 261 261 K->A: Almost complete loss of adenylyl FT cyclase activity in the catalytic FT fragment. {ECO:0000269|PubMed:11839758}. FT MUTAGEN 265 265 D->A: Loss of adenylyl cyclase activity FT in the catalytic fragment. FT {ECO:0000269|PubMed:11839758}. FT MUTAGEN 309 309 R->A: Obviates pH regulation. FT {ECO:0000269|PubMed:15890882}. FT MUTAGEN 312 312 D->A: Loss of adenylyl cyclase activity FT in the catalytic fragment. FT {ECO:0000269|PubMed:11839758}. FT MUTAGEN 319 319 N->A: Almost complete loss of adenylyl FT cyclase activity in the catalytic FT fragment. {ECO:0000269|PubMed:11839758}. FT MUTAGEN 323 323 R->A: Retains 10% adenylyl cyclase FT activity in the catalytic fragment. FT {ECO:0000269|PubMed:11839758}. FT HELIX 13 17 {ECO:0000244|PDB:2EV1}. FT HELIX 22 37 {ECO:0000244|PDB:2EV1}. FT HELIX 42 47 {ECO:0000244|PDB:2EV1}. FT STRAND 48 50 {ECO:0000244|PDB:2EV1}. FT HELIX 51 53 {ECO:0000244|PDB:2EV2}. FT HELIX 54 59 {ECO:0000244|PDB:2EV1}. FT HELIX 69 76 {ECO:0000244|PDB:2EV1}. FT HELIX 80 90 {ECO:0000244|PDB:2EV1}. FT STRAND 93 95 {ECO:0000244|PDB:2EV4}. FT HELIX 105 111 {ECO:0000244|PDB:2EV1}. FT HELIX 114 119 {ECO:0000244|PDB:2EV1}. FT HELIX 124 153 {ECO:0000244|PDB:2EV1}. FT HELIX 160 194 {ECO:0000244|PDB:2EV1}. FT HELIX 201 205 {ECO:0000244|PDB:1Y11}. FT STRAND 214 223 {ECO:0000244|PDB:1Y10}. FT HELIX 226 229 {ECO:0000244|PDB:1Y11}. FT TURN 230 232 {ECO:0000244|PDB:1Y11}. FT HELIX 235 252 {ECO:0000244|PDB:1Y10}. FT STRAND 258 263 {ECO:0000244|PDB:1Y10}. FT STRAND 266 273 {ECO:0000244|PDB:1Y10}. FT HELIX 274 289 {ECO:0000244|PDB:1Y10}. FT STRAND 292 294 {ECO:0000244|PDB:1Y11}. FT STRAND 297 309 {ECO:0000244|PDB:1Y10}. FT STRAND 312 315 {ECO:0000244|PDB:1Y10}. FT HELIX 316 327 {ECO:0000244|PDB:1Y10}. FT STRAND 333 336 {ECO:0000244|PDB:1Y10}. FT HELIX 337 341 {ECO:0000244|PDB:1Y10}. FT STRAND 353 360 {ECO:0000244|PDB:1Y10}. FT STRAND 369 375 {ECO:0000244|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 //