THCL_STRAJ
ID THCL_STRAJ Reviewed; 72 AA.
AC P0C8P8; C4NCM0;
DT 10-FEB-2009, integrated into UniProtKB/Swiss-Prot.
DT 14-DEC-2011, sequence version 2.
DT 25-MAY-2022, entry version 40.
DE RecName: Full=Thiostrepton;
DE AltName: Full=Alaninamide;
DE AltName: Full=Bryamycin;
DE AltName: Full=Gargon;
DE AltName: Full=Thiactin;
DE Flags: Precursor;
GN Name=tpdA;
OS Streptomyces azureus.
OC Bacteria; Actinobacteria; Streptomycetales; Streptomycetaceae;
OC Streptomyces.
OX NCBI_TaxID=146537;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND HYDROXYLATION AT ILE-65.
RC STRAIN=ATCC 14921 / DSM 40106 / CBS 467.68 / ETH 28555 / JCM 4564 / NBRC
RC 12744 / NRRL B-2655 / VKM Ac-719;
RX PubMed=19338336; DOI=10.1021/ja900488a;
RA Morris R.P., Leeds J.A., Naegeli H.U., Oberer L., Memmert K., Weber E.,
RA LaMarche M.J., Parker C.N., Burrer N., Esterow S., Hein A.E., Schmitt E.K.,
RA Krastel P.;
RT "Ribosomally synthesized thiopeptide antibiotics targeting elongation
RT factor Tu.";
RL J. Am. Chem. Soc. 131:5946-5955(2009).
RN [2]
RP CHARACTERIZATION.
RX PubMed=13355325;
RA Donovick R., Pagano J.F., Stout H.A., Weinstein M.J.;
RT "Thiostrepton, a new antibiotic. I. In vitro studies.";
RL Antibiot. Annu. 3:554-559(1955).
RN [3]
RP CHARACTERIZATION.
RX PubMed=13355326;
RA Dutcher J.D., Vandeputte J.;
RT "Thiostrepton, a new antibiotic. II. Isolation and chemical
RT characterization.";
RL Antibiot. Annu. 3:560-561(1955).
RN [4]
RP CHARACTERIZATION.
RX PubMed=13355327;
RA Jambor W.P., Steinberg B.A., Suydam L.O.;
RT "Thiostrepton, a new antibiotic. III. In vivo studies.";
RL Antibiot. Annu. 3:562-565(1955).
RN [5]
RP BIOSYNTHESIS OF THE QUINOLINE MOIETY.
RX PubMed=8831986; DOI=10.1016/0968-0896(96)00126-5;
RA Priestley N.D., Smith T.M., Shipley P.R., Floss H.G.;
RT "Studies on the biosynthesis of thiostrepton: 4-(1-hydroxyethyl)quinoline-
RT 2-carboxylate as a free intermediate on the pathway to the quinaldic acid
RT moiety.";
RL Bioorg. Med. Chem. 4:1135-1147(1996).
RN [6]
RP STRUCTURE VERIFICATION BY CHEMICAL SYNTHESIS.
RX PubMed=16076224; DOI=10.1021/ja0529337;
RA Nicolaou K.C., Safina B.S., Zak M., Lee S.H., Nevalainen M., Bella M.,
RA Estrada A.A., Funke C., Zecri F.J., Bulat S.;
RT "Total synthesis of thiostrepton. Retrosynthetic analysis and construction
RT of key building blocks.";
RL J. Am. Chem. Soc. 127:11159-11175(2005).
RN [7]
RP STRUCTURE VERIFICATION BY CHEMICAL SYNTHESIS.
RX PubMed=16076225; DOI=10.1021/ja052934z;
RA Nicolaou K.C., Zak M., Safina B.S., Estrada A.A., Lee S.H., Nevalainen M.;
RT "Total synthesis of thiostrepton. Assembly of key building blocks and
RT completion of the synthesis.";
RL J. Am. Chem. Soc. 127:11176-11183(2005).
RN [8]
RP STRUCTURE BY NMR OF 56-72, AMIDATION AT SER-72, AND DEHYDRATION AT SER-58;
RP THR-63; SER-71 AND SER-72.
RX PubMed=6885635; DOI=10.7164/antibiotics.36.799;
RA Hensens O.D., Albers-Schonberg G., Anderson B.F.;
RT "The solution conformation of the peptide antibiotic thiostrepton: a 1H NMR
RT study.";
RL J. Antibiot. 36:799-813(1983).
RN [9]
RP STRUCTURE BY NMR OF 56-72.
RX PubMed=6885637; DOI=10.7164/antibiotics.36.832;
RA Hensens O.D., Albers-Schonberg G.;
RT "13C NMR study of thiostrepton and thiopeptin components.";
RL J. Antibiot. 36:832-845(1983).
RN [10]
RP X-RAY CRYSTALLOGRAPHY (1.02 ANGSTROMS) OF 56-72.
RX PubMed=11320328; DOI=10.1107/s0907444901003134;
RA Bond C.S., Shaw M.P., Alphey M.S., Hunter W.N.;
RT "Structure of the macrocycle thiostrepton solved using the anomalous
RT dispersion contribution of sulfur.";
RL Acta Crystallogr. D 57:755-758(2001).
CC -!- FUNCTION: Has bacteriocidal activity. Inhibits bacterial protein
CC biosynthesis by acting on the elongation factor Tu (EF-Tu) (By
CC similarity). {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250}.
CC -!- PTM: Maturation of thiazole and oxazole containing antibiotics involves
CC the enzymatic condensation of a Cys, Ser or Thr with the alpha-carbonyl
CC of the preceding amino acid to form a thioether or ether bond, then
CC dehydration to form a double bond with the alpha-amino nitrogen.
CC Thiazoline or oxazoline ring are dehydrogenated to form thiazole or
CC oxazole rings.
CC -!- PTM: Maturation of pyridinyl containing antibiotics involves the cross-
CC linking of a Ser and a Cys-Ser pair usually separated by 7 or 8
CC residues along the peptide chain. The Ser residues are dehydrated to
CC didehydroalanines, then bonded between their beta carbons. The alpha
CC carbonyl of the Cys condenses with alpha carbon of the first Ser to
CC form a pyridinyl ring. The ring may be multiply dehydrogenated to form
CC a pyridine ring with loss of the amino nitrogen of the first Ser.
CC -!- PTM: The amidation of Ser-72 probably does not occur by the same
CC mechanism, oxidative cleavage of glycine, as in eukaryotes.
CC {ECO:0000305}.
CC -!- PTM: The structure of the 2,3-didehydrobutyrin is shown to be Z-isomer
CC (PubMed:6885635 and PubMed:11320328).
CC -!- PHARMACEUTICAL: Available under the names Animax (Dechra) and Panolog
CC (Fort Dodge), that combine thiostrepton with nystatin (antifungal),
CC neomycin (antibiotic) and triamcinolone (corticosteroid). Used to treat
CC cat and dog skin and ear disorders caused by allergies, or bacterial as
CC well as yeast infections. It is also used for infections of the anal
CC gland and interdigital cysts.
CC -!- SIMILARITY: Belongs to the thiocillin family. {ECO:0000305}.
CC -!- CAUTION: Thiostrepton is produced by Streptomyces azureus ATCC 14921,
CC S.hawaiiensis ATCC 12236, and by S.laurentii ATCC 31255. The species
CC used as a thiostrepton producer in all studies is uncertain.
CC {ECO:0000305}.
CC -!- CAUTION: It is uncertain whether Met-1 or Met-13 is the initiator.
CC {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Thiostrepton entry;
CC URL="https://en.wikipedia.org/wiki/Thiostrepton";
CC -!- WEB RESOURCE: Name=Fermentek Biotechnologies; Note=Thiostrepton notice;
CC URL="https://www.fermentek.com/product/thiostrepton";
CC -!- WEB RESOURCE: Name=Merck Millipore; Note=Thiostrepton notice;
CC URL="https://www.merckmillipore.com/CH/en/product/Thiostrepton-CAS-1393-48-2-Calbiochem,EMD_BIO-598226";
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DR EMBL; FJ494914; ACR15111.1; -; Genomic_DNA.
DR PDB; 1E9W; X-ray; 1.02 A; A=56-72.
DR PDB; 1OLN; Other; -; B=56-72.
DR PDB; 2JQ7; NMR; -; C=56-72.
DR PDB; 2L2W; NMR; -; A=56-72.
DR PDB; 2L2X; NMR; -; A=56-71.
DR PDB; 2L2Y; NMR; -; A=56-71.
DR PDB; 2L2Z; NMR; -; A=56-72.
DR PDB; 3CF5; X-ray; 3.30 A; 5=56-72.
DR PDB; 4HP2; X-ray; 0.64 A; A/B=56-72.
DR PDB; 5D8H; X-ray; 2.80 A; D=56-72.
DR PDB; 6MXF; EM; 1.91 A; A=56-72.
DR PDBsum; 1E9W; -.
DR PDBsum; 1OLN; -.
DR PDBsum; 2JQ7; -.
DR PDBsum; 2L2W; -.
DR PDBsum; 2L2X; -.
DR PDBsum; 2L2Y; -.
DR PDBsum; 2L2Z; -.
DR PDBsum; 3CF5; -.
DR PDBsum; 4HP2; -.
DR PDBsum; 5D8H; -.
DR PDBsum; 6MXF; -.
DR AlphaFoldDB; P0C8P8; -.
DR SMR; P0C8P8; -.
DR DrugBank; DB02940; (4s)-2-[(1e)-1-Aminoprop-1-Enyl]-4,5-Dihydro-1,3-Thiazole-4-Carboxylic Acid.
DR DrugBank; DB02566; 8-Hydroxy-4-(1-Hydroxyethyl)Quinoline-2-Carboxylic Acid.
DR EvolutionaryTrace; P0C8P8; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0042742; P:defense response to bacterium; IEA:UniProtKB-KW.
DR InterPro; IPR023895; Thiopep_bacteriocin_prcur.
DR TIGRFAMs; TIGR03892; thiopep_precurs; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Amidation; Antibiotic; Antimicrobial; Hydroxylation;
KW Methylation; Pharmaceutical; Secreted; Thioether bond.
FT PROPEP 1..55
FT /id="PRO_0000414718"
FT PEPTIDE 56..72
FT /note="Thiostrepton"
FT /id="PRO_0000363170"
FT MOD_RES 58
FT /note="2,3-didehydroalanine (Ser)"
FT /evidence="ECO:0000269|PubMed:6885635"
FT MOD_RES 63
FT /note="(Z)-2,3-didehydrobutyrine"
FT /evidence="ECO:0000269|PubMed:6885635"
FT MOD_RES 65
FT /note="(3S,4R)-3,4-dihydroxyisoleucine"
FT /evidence="ECO:0000269|PubMed:19338336"
FT MOD_RES 71
FT /note="2,3-didehydroalanine (Ser)"
FT /evidence="ECO:0000269|PubMed:6885635"
FT MOD_RES 72
FT /note="2,3-didehydroalanine (Ser)"
FT /evidence="ECO:0000269|PubMed:6885635"
FT MOD_RES 72
FT /note="Serine amide"
FT /evidence="ECO:0000269|PubMed:6885635"
FT CROSSLNK 56..67
FT /note="4-(1-hydroxyethyl)-7-isoleucino-2-(threonin-O3-
FT ylcarbonyl)-7,8-dihydroquinolin-8-ol (Ile-Thr)"
FT CROSSLNK 60..69
FT /note="5-amino-piperideine-2,5-dicarboxylic acid (Ser-Ser)
FT (with C-68)"
FT CROSSLNK 60..68
FT /note="5-amino-piperideine-2,5-dicarboxylic acid (Ser-Cys)
FT (with S-69)"
FT CROSSLNK 60..61
FT /note="Thiazole-4-carboxylic acid (Ser-Cys)"
FT CROSSLNK 63..64
FT /note="(4S)-thiazoline-4-carboxylic acid (Thr-Cys)"
FT CROSSLNK 65..66
FT /note="Thiazole-4-carboxylic acid (Ile-Cys)"
FT CROSSLNK 67..68
FT /note="Thiazole-4-carboxylic acid (Thr-Cys)"
FT CROSSLNK 69..70
FT /note="Thiazole-4-carboxylic acid (Ser-Cys)"
SQ SEQUENCE 72 AA; 7550 MW; 064299CF4257AB5F CRC64;
MDATAIHERW SVMSNASIGQ EIGVEGLTGL DVDALEISDY VDETLLDGED LTVTMIASAS
CTTCICTCSC SS
