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PDBsum entry 2gfv

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protein links
Transferase PDB id
2gfv
Jmol
Contents
Protein chain
411 a.a. *
Waters ×269
* Residue conservation analysis
PDB id:
2gfv
Name: Transferase
Title: Structure of e. Coli fabf (kasii) c163q mutant
Structure: 3-oxoacyl-[acyl-carrier-protein] synthase 2. Chain: a. Synonym: 3-oxoacyl-[acyl-carrier-protein] synthase ii. Beta acp synthase ii. Kas ii. Fabf. Engineered: yes. Mutation: yes
Source: Escherichia coli. Organism_taxid: 562. Gene: fabf, fabj. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Dimer (from PDB file)
Resolution:
2.29Å     R-factor:   0.184     R-free:   0.247
Authors: S.M.Soisson,G Parthasarathy
Key ref:
J.Wang et al. (2006). Platensimycin is a selective FabF inhibitor with potent antibiotic properties. Nature, 441, 358-361. PubMed id: 16710421 DOI: 10.1038/nature04784
Date:
23-Mar-06     Release date:   23-May-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P0AAI5  (FABF_ECOLI) -  3-oxoacyl-[acyl-carrier-protein] synthase 2
Seq:
Struc:
413 a.a.
411 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.2.3.1.179  - Beta-ketoacyl-[acyl-carrier-protein] synthase Ii.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: (Z)-hexadec-11-enoyl-[acyl-carrier-protein] + malonyl-[acyl-carrier- protein] = (Z)-3-oxooctadec-13-enoyl-[acyl-carrier-protein] + CO2 + [acyl-carrier-protein]
(Z)-hexadec-11-enoyl-[acyl-carrier-protein]
+ malonyl-[acyl-carrier- protein]
= (Z)-3-oxooctadec-13-enoyl-[acyl-carrier-protein]
+ CO(2)
+ [acyl-carrier-protein]
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cytosol   1 term 
  Biological process     metabolic process   4 terms 
  Biochemical function     catalytic activity     7 terms  

 

 
    reference    
 
 
DOI no: 10.1038/nature04784 Nature 441:358-361 (2006)
PubMed id: 16710421  
 
 
Platensimycin is a selective FabF inhibitor with potent antibiotic properties.
J.Wang, S.M.Soisson, K.Young, W.Shoop, S.Kodali, A.Galgoci, R.Painter, G.Parthasarathy, Y.S.Tang, R.Cummings, S.Ha, K.Dorso, M.Motyl, H.Jayasuriya, J.Ondeyka, K.Herath, C.Zhang, L.Hernandez, J.Allocco, A.Basilio, J.R.Tormo, O.Genilloud, F.Vicente, F.Pelaez, L.Colwell, S.H.Lee, B.Michael, T.Felcetto, C.Gill, L.L.Silver, J.D.Hermes, K.Bartizal, J.Barrett, D.Schmatz, J.W.Becker, D.Cully, S.B.Singh.
 
  ABSTRACT  
 
Bacterial infection remains a serious threat to human lives because of emerging resistance to existing antibiotics. Although the scientific community has avidly pursued the discovery of new antibiotics that interact with new targets, these efforts have met with limited success since the early 1960s. Here we report the discovery of platensimycin, a previously unknown class of antibiotics produced by Streptomyces platensis. Platensimycin demonstrates strong, broad-spectrum Gram-positive antibacterial activity by selectively inhibiting cellular lipid biosynthesis. We show that this anti-bacterial effect is exerted through the selective targeting of beta-ketoacyl-(acyl-carrier-protein (ACP)) synthase I/II (FabF/B) in the synthetic pathway of fatty acids. Direct binding assays show that platensimycin interacts specifically with the acyl-enzyme intermediate of the target protein, and X-ray crystallographic studies reveal that a specific conformational change that occurs on acylation must take place before the inhibitor can bind. Treatment with platensimycin eradicates Staphylococcus aureus infection in mice. Because of its unique mode of action, platensimycin shows no cross-resistance to other key antibiotic-resistant strains tested, including methicillin-resistant S. aureus, vancomycin-intermediate S. aureus and vancomycin-resistant enterococci. Platensimycin is the most potent inhibitor reported for the FabF/B condensing enzymes, and is the only inhibitor of these targets that shows broad-spectrum activity, in vivo efficacy and no observed toxicity.
 
  Selected figure(s)  
 
Figure 1.
Figure 1: Characterization of platensimycin. a, Structure of platensimycin. b, In vivo studies on platensimycin. Dosing at 50 g h^-1 showed small decrease in viable S. aureus cells from the infected kidney. However, a 10^4–10^5 fold decrease (4 and 5 log reduction) were achieved with 100 and 150 g h^-1, respectively. Dosing at 150 g h^-1 showed 40% of the kidneys with no viable S. aureus, whereas dosing at 100 g h^-1 showed 20% of the kidneys without detectable viable S. aureus. Error bars indicate s.d. observed with five infected mice. The results were confirmed by a repeat experiment. c, Whole-cell labelling assay^16 with platensimycin. The assay was performed with a serial dilution of platensimycin, starting at 500 g ml^-1. Platensimycin showed no significant inhibition against syntheses of DNA (open circles), cell wall (filled triangles), protein (open squares) and RNA (open triangles) but greatly inhibited phospholipid synthesis (filled circles), providing an IC[50] value of 0.1 g ml^-1. Error bars indicate s.d. for three individual experiments. d, Direct binding assay results of [^3H]dihydroplatensimycin and E. coli FabF (ecFabF) in the presence and absence of n-dodecanoyl coenzyme A (lauroyl-CoA; C[12]-CoA) and the C163Q mutant protein. Error bars indicate s.d. observed with six replicate wells. Experimental details are given in Supplementary Information.
Figure 2.
Figure 2: Interactions of platensimycin with ecFabF(C163Q) and comparison with the apo structure. a, Superposition of platensimycin (yellow, thicker sticks) on ecFabF, with thiolactomycin (green) and cerulenin (cyan) shown for reference. Side chains discussed in the text are labelled and coloured as described above. The side chains from apo ecFabF are coloured magenta. b, Interactions between the benzoic acid ring of platensimycin (yellow) and ecFabF(C163Q). Side chains from the protein discussed in the text are labelled and coloured green. c, Interactions of ecFabF with the amide linker and ketolide of platensimycin. The colour scheme is the same as in b. d, The solvent-accessible surface area of FabF, coloured according to electrostatic potential. Platensimycin is depicted as a stick figure and coloured yellow, and is shown to be partly exposed to solvent. Platensimycin buries 345 Å^2 of solvent-accessible surface area on ecFabF, as calculated with areaimol^24,25. Of that surface area, 122 Å^2 is a direct result of the ketolide portion of the molecule, highlighting its important contribution to platensimycin binding. Significant interatomic distances (in ångströms) are marked in b and c with red dashed lines and numbers.
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (2006, 441, 358-361) copyright 2006.  

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PDB code: 1j3n
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PDB code: 2rjt
18442030 J.Krauss, V.Knorr, V.Manhardt, S.Scheffels, and F.Bracher (2008).
Synthesis of platensimycin analogues and their antibiotic potency.
  Arch Pharm (Weinheim), 341, 386-392.  
18221265 J.L.Guler, E.Kriegova, T.K.Smith, J.Lukes, and P.T.Englund (2008).
Mitochondrial fatty acid synthesis is required for normal mitochondrial morphology and function in Trypanosoma brucei.
  Mol Microbiol, 67, 1125-1142.  
18771264 K.C.Nicolaou, A.F.Stepan, T.Lister, A.Li, A.Montero, G.S.Tria, C.I.Turner, Y.Tang, J.Wang, R.M.Denton, and D.J.Edmonds (2008).
Design, synthesis, and biological evaluation of platensimycin analogues with varying degrees of molecular complexity.
  J Am Chem Soc, 130, 13110-13119.  
18662118 O.R.Sipahi (2008).
Economics of antibiotic resistance.
  Expert Rev Anti Infect Ther, 6, 523-539.  
18725634 P.Johansson, B.Wiltschi, P.Kumari, B.Kessler, C.Vonrhein, J.Vonck, D.Oesterhelt, and M.Grininger (2008).
Inhibition of the fungal fatty acid synthase type I multienzyme complex.
  Proc Natl Acad Sci U S A, 105, 12803-12808.
PDB code: 2vkz
19006597 P.L.Taylor, and G.D.Wright (2008).
Novel approaches to discovery of antibacterial agents.
  Anim Health Res Rev, 9, 237-246.  
18323848 R.L.Lock, and E.J.Harry (2008).
Cell-division inhibitors: new insights for future antibiotics.
  Nat Rev Drug Discov, 7, 324-338.  
18443624 R.Pathania, and E.D.Brown (2008).
Small and lethal: searching for new antibacterial compounds with novel modes of action.
  Biochem Cell Biol, 86, 111-115.  
17661706 A.Pantosti, A.Sanchini, and M.Monaco (2007).
Mechanisms of antibiotic resistance in Staphylococcus aureus.
  Future Microbiol, 2, 323-334.  
17704820 A.R.Coates, and Y.Hu (2007).
Novel approaches to developing new antibiotics for bacterial infections.
  Br J Pharmacol, 152, 1147-1154.  
17576425 B.Wilkinson, and J.Micklefield (2007).
Mining and engineering natural-product biosynthetic pathways.
  Nat Chem Biol, 3, 379-386.  
17242430 C.E.Christensen, B.B.Kragelund, P.von Wettstein-Knowles, and A.Henriksen (2007).
Structure of the human beta-ketoacyl [ACP] synthase from the mitochondrial type II fatty acid synthase.
  Protein Sci, 16, 261-272.
PDB codes: 2iwy 2iwz 2ix4
17584615 C.J.Balibar, S.Garneau-Tsodikova, and C.T.Walsh (2007).
Covalent CouN7 enzyme intermediate for acyl group shuttling in aminocoumarin biosynthesis.
  Chem Biol, 14, 679-690.  
17469819 C.Qiao, D.J.Wilson, E.M.Bennett, and C.C.Aldrich (2007).
A mechanism-based aryl carrier protein/thiolation domain affinity probe.
  J Am Chem Soc, 129, 6350-6351.  
17479086 D.Braaten (2007).
Bugs vs Drugs.
  Nat Med, 13, 522-523.  
18033577 D.D.Baker, M.Chu, U.Oza, and V.Rajgarhia (2007).
The value of natural products to future pharmaceutical discovery.
  Nat Prod Rep, 24, 1225-1244.  
18059524 D.M.Byers, and H.Gong (2007).
Acyl carrier protein: structure-function relationships in a conserved multifunctional protein family.
  Biochem Cell Biol, 85, 649-662.  
17339372 G.C.Kedar, V.Brown-Driver, D.R.Reyes, M.T.Hilgers, M.A.Stidham, K.J.Shaw, J.Finn, and R.J.Haselbeck (2007).
Evaluation of the metS and murB loci for antibiotic discovery using targeted antisense RNA expression analysis in Bacillus anthracis.
  Antimicrob Agents Chemother, 51, 1708-1718.  
17493872 G.D.Wright, and A.D.Sutherland (2007).
New strategies for combating multidrug-resistant bacteria.
  Trends Mol Med, 13, 260-267.  
18084068 G.Pappenberger, T.Schulz-Gasch, E.Kusznir, F.Müller, and M.Hennig (2007).
Structure-assisted discovery of an aminothiazole derivative as a lead molecule for inhibition of bacterial fatty-acid synthesis.
  Acta Crystallogr D Biol Crystallogr, 63, 1208-1216.
PDB codes: 2vb7 2vb8 2vb9 2vba
17917238 H.Jayasuriya, K.Herath, J.G.Ondeyka, C.Zhang, D.L.Zink, M.Brower, F.P.Gailliot, J.Greene, G.Birdsall, J.Venugopal, M.Ushio, B.Burgess, G.Russotti, A.Walker, M.Hesse, A.Seeley, B.Junker, N.Connors, O.Salazar, O.Genilloud, K.Liu, P.Masurekar, J.F.Barrett, and S.B.Singh (2007).
Isolation and structure elucidation of thiazomycin- a potent thiazolyl peptide antibiotic from Amycolatopsis fastidiosa.
  J Antibiot (Tokyo), 60, 554-564.  
17707686 H.T.Wright, and K.A.Reynolds (2007).
Antibacterial targets in fatty acid biosynthesis.
  Curr Opin Microbiol, 10, 447-453.  
17166831 J.L.Stephens, S.H.Lee, K.S.Paul, and P.T.Englund (2007).
Mitochondrial fatty acid synthesis in Trypanosoma brucei.
  J Biol Chem, 282, 4427-4436.  
17456595 J.Wang, S.Kodali, S.H.Lee, A.Galgoci, R.Painter, K.Dorso, F.Racine, M.Motyl, L.Hernandez, E.Tinney, S.L.Colletti, K.Herath, R.Cummings, O.Salazar, I.González, A.Basilio, F.Vicente, O.Genilloud, F.Pelaez, H.Jayasuriya, K.Young, D.F.Cully, and S.B.Singh (2007).
Discovery of platencin, a dual FabF and FabH inhibitor with in vivo antibiotic properties.
  Proc Natl Acad Sci U S A, 104, 7612-7616.  
  17697396 J.Z.Lu, S.P.Muench, M.Allary, S.Campbell, C.W.Roberts, E.Mui, R.L.McLeod, D.W.Rice, and S.T.Prigge (2007).
Type I and type II fatty acid biosynthesis in Eimeria tenella: enoyl reductase activity and structure.
  Parasitology, 134, 1949-1962.
PDB code: 2ptg
17695230 K.C.Nicolaou, Y.Tang, and J.Wang (2007).
Formal synthesis of (+/-)-platensimycin.
  Chem Commun (Camb), (), 1922-1923.  
17183501 K.L.Dormann, and R.Brückner (2007).
Variable synthesis of the optically active thiotetronic acid antibiotics thiolactomycin, thiotetromycin, and 834-B1.
  Angew Chem Int Ed Engl, 46, 1160-1163.  
18041906 K.Ohlsen, and U.Lorenz (2007).
Novel targets for antibiotics in Staphylococcus aureus.
  Future Microbiol, 2, 655-666.  
17433686 K.S.Lam (2007).
New aspects of natural products in drug discovery.
  Trends Microbiol, 15, 279-289.  
17692125 L.C.Rasmussen, H.U.Sperling-Petersen, and K.K.Mortensen (2007).
Hitting bacteria at the heart of the central dogma: sequence-specific inhibition.
  Microb Cell Fact, 6, 24.  
17988169 M.Casenghi, S.T.Cole, and C.F.Nathan (2007).
New approaches to filling the gap in tuberculosis drug discovery.
  PLoS Med, 4, e293.  
17767419 M.Dermyer, S.C.Wise, T.Braden, and T.P.Holler (2007).
Simultaneous screening of multiple bacterial tRNA synthetases using an Escherichia coli S30-based transcription and translation assay.
  Assay Drug Dev Technol, 5, 515-521.  
17617692 M.Iwatsuki, R.Uchida, Y.Takakusagi, A.Matsumoto, C.L.Jiang, Y.Takahashi, M.Arai, S.Kobayashi, M.Matsumoto, J.Inokoshi, H.Tomoda, and S.Omura (2007).
Lariatins, novel anti-mycobacterial peptides with a lasso structure, produced by Rhodococcus jostii K01-B0171.
  J Antibiot (Tokyo), 60, 357-363.  
17443473 M.J.Llewelyn, and J.Cohen (2007).
Tracking the microbes in sepsis: advancements in treatment bring challenges for microbial epidemiology.
  Clin Infect Dis, 44, 1343-1348.  
17596107 M.J.Pucci (2007).
Novel genetic techniques and approaches in the microbial genomics era: identification and/or validation of targets for the discovery of new antibacterial agents.
  Drugs R D, 8, 201-212.  
17524982 M.M.Alhamadsheh, F.Musayev, A.A.Komissarov, S.Sachdeva, H.T.Wright, N.Scarsdale, G.Florova, and K.A.Reynolds (2007).
Alkyl-CoA disulfides as inhibitors and mechanistic probes for FabH enzymes.
  Chem Biol, 14, 513-524.
PDB codes: 2eft 2gyo
18033580 N.Dixon, L.S.Wong, T.H.Geerlings, and J.Micklefield (2007).
Cellular targets of natural products.
  Nat Prod Rep, 24, 1288-1310.  
17630748 P.Li, J.N.Payette, and H.Yamamoto (2007).
Enantioselective route to platensimycin: an intramolecular Robinson annulation approach.
  J Am Chem Soc, 129, 9534-9535.  
17917239 S.B.Singh, J.Occi, H.Jayasuriya, K.Herath, M.Motyl, K.Dorso, C.Gill, E.Hickey, K.M.Overbye, J.F.Barrett, and P.Masurekar (2007).
Antibacterial evaluations of thiazomycin- a potent thiazolyl peptide antibiotic from Amycolatopsis fastidiosa.
  J Antibiot (Tokyo), 60, 565-571.  
17363967 S.H.Lee, J.L.Stephens, and P.T.Englund (2007).
A fatty-acid synthesis mechanism specialized for parasitism.
  Nat Rev Microbiol, 5, 287-297.  
17174327 S.Sridharan, L.Wang, A.K.Brown, L.G.Dover, L.Kremer, G.S.Besra, and J.C.Sacchettini (2007).
X-ray crystal structure of Mycobacterium tuberculosis beta-ketoacyl acyl carrier protein synthase II (mtKasB).
  J Mol Biol, 366, 469-480.
PDB code: 2gp6
17957681 U.Holzgrabe (2007).
[Two flies with one blow--platencin, an new antibiotic]
  Pharm Unserer Zeit, 36, 418-419.  
17407302 Y.Zou, C.H.Chen, C.D.Taylor, B.M.Foxman, and B.B.Snider (2007).
Formal synthesis of (+/-)-platensimycin.
  Org Lett, 9, 1825-1828.  
16964218 A.P.Bhavsar, and E.D.Brown (2006).
The worm turns for antimicrobial discovery.
  Nat Biotechnol, 24, 1098-1100.  
17160048 C.Sheridan (2006).
Antibiotics au naturel.
  Nat Biotechnol, 24, 1494-1496.  
16952137 D.Häbich, and F.von Nussbaum (2006).
Platensimycin, a new antibiotic and "superbug challenger" from nature.
  ChemMedChem, 1, 951-954.  
16890008 D.I.Andersson (2006).
The biological cost of mutational antibiotic resistance: any practical conclusions?
  Curr Opin Microbiol, 9, 461-465.  
16710404 E.D.Brown (2006).
Microbiology: antibiotic stops 'ping-pong' match.
  Nature, 441, 293-294.  
17049224 F.E.Koehn (2006).
Therapeutic potential of natural product signal transduction agents.
  Curr Opin Biotechnol, 17, 631-637.  
17160060 J.Clardy, M.A.Fischbach, and C.T.Walsh (2006).
New antibiotics from bacterial natural products.
  Nat Biotechnol, 24, 1541-1550.  
17013803 K.C.Nicolaou, A.Li, and D.J.Edmonds (2006).
Total synthesis of platensimycin.
  Angew Chem Int Ed Engl, 45, 7086-7090.  
17062631 N.Nakashima, T.Tamura, and L.Good (2006).
Paired termini stabilize antisense RNAs and enhance conditional gene silencing in Escherichia coli.
  Nucleic Acids Res, 34, e138.  
17160049 P.Fernandes (2006).
Antibacterial discovery and development--the failure of success?
  Nat Biotechnol, 24, 1497-1503.  
17009781 U.Holzgrabe, T.Dingermann, and I.Zündorf (2006).
[An old pathway to new antibiotics--platensimycin]
  Pharm Unserer Zeit, 35, 388-389.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.