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PDBsum entry 1mo2
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protein Protein-protein interface(s) links
Transferase PDB id
1mo2

 

 

 

 

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JSmol PyMol  
Contents
Protein chains
251 a.a. *
Waters ×56
* Residue conservation analysis
PDB id:
1mo2
Name: Transferase
Title: Thioesterase domain from 6-deoxyerythronolide synthase (debs te), ph 8.5
Structure: Erythronolide synthase, modules 5 and 6. Chain: a, b. Fragment: thioesterase domain. Synonym: 6-deoxyerythronolide b synthase iii. Debs 3. Debs te. Erythronolide synthase iii. Engineered: yes
Source: Saccharopolyspora erythraea. Organism_taxid: 1836. Gene: erya. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Biol. unit: Dimer (from PQS)
Resolution:
3.00Å     R-factor:   0.244     R-free:   0.287
Authors: S.-C.Tsai,H.Lu,D.E.Cane,C.Khosla,R.M.Stroud
Key ref:
S.C.Tsai et al. (2002). Insights into channel architecture and substrate specificity from crystal structures of two macrocycle-forming thioesterases of modular polyketide synthases. Biochemistry, 41, 12598-12606. PubMed id: 12379102 DOI: 10.1021/bi0260177
Date:
05-Sep-02     Release date:   04-Feb-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q03133  (ERYA3_SACER) -  Erythronolide synthase EryA3 from Saccharopolyspora erythraea
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		3172 a.a.
251 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.2.3.1.94  - 6-deoxyerythronolide-B synthase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: 6 (S)-methylmalonyl-CoA + propanoyl-CoA + 6 NADPH + 12 H+ = 6-deoxyerythronolide B + 6 CO2 + 6 NADP+ + 7 CoA + H2O
6 × (S)-methylmalonyl-CoA
 + propanoyl-CoA
 + 6 × NADPH
 + 12 × H(+)
 = 6-deoxyerythronolide B
 + 6 × CO2
 + 6 × NADP(+)
 + 7 × CoA
 + H2O
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    reference    
 
 
DOI no: 10.1021/bi0260177 Biochemistry 41:12598-12606 (2002)
PubMed id: 12379102  
 
 
Insights into channel architecture and substrate specificity from crystal structures of two macrocycle-forming thioesterases of modular polyketide synthases.
S.C.Tsai, H.Lu, D.E.Cane, C.Khosla, R.M.Stroud.
 
  ABSTRACT  
 
Modular polyketide synthases (PKSs) synthesize the polyketide cores of pharmacologically important natural products such as erythromycin and picromycin. Understanding PKSs at high resolution could present new opportunities for chemoenzymatic synthesis of complex molecules. The crystal structures of macrocycle-forming thioesterase (TE) domains from the picromycin synthase (PICS) and 6-deoxyerythronolide B synthase (DEBS) were determined to 1.8-3.0 A with an R(crys) of 19.2-24.4%, including three structures of PICS TE (crystallized at pH 7.6, 8.0, and 8.4) and a second crystal form of DEBS TE. As predicted by the previous work on DEBS TE [Tsai, S. C., et al. (2001) Proc. Natl. Acad. Sci. U.S.A. 98, 14808-14813], PICS TE contains an open substrate channel and a hydrophobic dimer interface. Notwithstanding their similarity, the dimer interfaces and substrate channels of DEBS TE and PICS TE reveal key differences. The structural basis for the divergent substrate specificities of DEBS TE and PICS TE is analyzed. The size of the substrate channel increases with increasing pH, presumably due to electrostatic repulsion in the channel at elevated pH. Together, these structures support previous predictions that macrocycle-forming thioesterases from PKSs share the same protein fold, an open substrate channel, a similar catalytic mechanism, and a hydrophobic dimer interface. They also provide a basis for the design of enzymes capable of catalyzing regioselective macrocyclization of natural or synthetic substrates. A series of high-resolution snapshots of a protein channel at different pHs is presented alongside analysis of channel residues, which could help in the redesign of the protein channel architecture.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20506386 D.C.Cantu, Y.Chen, and P.J.Reilly (2010).
Thioesterases: a new perspective based on their primary and tertiary structures.
  Protein Sci, 19, 1281-1295.  
20152156 D.L.Akey, J.R.Razelun, J.Tehranisa, D.H.Sherman, W.H.Gerwick, and J.L.Smith (2010).
Crystal structures of dehydratase domains from the curacin polyketide biosynthetic pathway.
  Structure, 18, 94.
PDB codes: 3kg6 3kg7 3kg8 3kg9
20432424 K.Buntin, K.J.Weissman, and R.Müller (2010).
An unusual thioesterase promotes isochromanone ring formation in ajudazol biosynthesis.
  Chembiochem, 11, 1137-1146.  
20111804 L.Du, and L.Lou (2010).
PKS and NRPS release mechanisms.
  Nat Prod Rep, 27, 255-278.  
20659683 L.Tran, R.W.Broadhurst, M.Tosin, A.Cavalli, and K.J.Weissman (2010).
Insights into protein-protein and enzyme-substrate interactions in modular polyketide synthases.
  Chem Biol, 17, 705-716.  
20332208 T.P.Korman, J.M.Crawford, J.W.Labonte, A.G.Newman, J.Wong, C.A.Townsend, and S.C.Tsai (2010).
Structure and function of an iterative polyketide synthase thioesterase domain catalyzing Claisen cyclization in aflatoxin biosynthesis.
  Proc Natl Acad Sci U S A, 107, 6246-6251.
PDB code: 3ils
19636447 A.Koglin, and C.T.Walsh (2009).
Structural insights into nonribosomal peptide enzymatic assembly lines.
  Nat Prod Rep, 26, 987.  
19103602 H.B.Claxton, D.L.Akey, M.K.Silver, S.J.Admiraal, and J.L.Smith (2009).
Structure and Functional Analysis of RifR, the Type II Thioesterase from the Rifamycin Biosynthetic Pathway.
  J Biol Chem, 284, 5021-5029.
PDB codes: 3fla 3flb
19027305 J.D.Kittendorf, and D.H.Sherman (2009).
The methymycin/pikromycin pathway: a model for metabolic diversity in natural product biosynthesis.
  Bioorg Med Chem, 17, 2137-2146.  
19551180 J.L.Meier, and M.D.Burkart (2009).
The chemical biology of modular biosynthetic enzymes.
  Chem Soc Rev, 38, 2012-2045.  
19074611 M.Kotowska, K.Pawlik, A.Smulczyk-Krawczyszyn, H.Bartosz-Bechowski, and K.Kuczek (2009).
Type II thioesterase ScoT, associated with Streptomyces coelicolor A3(2) modular polyketide synthase Cpk, hydrolyzes acyl residues and has a preference for propionate.
  Appl Environ Microbiol, 75, 887-896.  
19362634 S.C.Tsai, and B.D.Ames (2009).
Structural enzymology of polyketide synthases.
  Methods Enzymol, 459, 17-47.  
18427109 H.Zhou, J.Zhan, K.Watanabe, X.Xie, and Y.Tang (2008).
A polyketide macrolactone synthase from the filamentous fungus Gibberella zeae.
  Proc Natl Acad Sci U S A, 105, 6249-6254.  
18493665 J.L.Meier, T.Barrows-Yano, T.L.Foley, C.L.Wike, and M.D.Burkart (2008).
The unusual macrocycle forming thioesterase of mycolactone.
  Mol Biosyst, 4, 663-671.  
18357594 K.J.Weissman, and R.Müller (2008).
Protein-protein interactions in multienzyme megasynthetases.
  Chembiochem, 9, 826-848.  
19021139 L.Betancor, M.J.Fernández, K.J.Weissman, and P.F.Leadlay (2008).
Improved catalytic activity of a purified multienzyme from a modular polyketide synthase after coexpression with Streptomyces chaperonins in Escherichia coli.
  Chembiochem, 9, 2962-2966.  
18972512 S.C.Wenzel, H.B.Bode, I.Kochems, and R.Müller (2008).
A type I/type III polyketide synthase hybrid biosynthetic pathway for the structurally unique ansa compound kendomycin.
  Chembiochem, 9, 2711-2721.  
18482697 T.Liu, X.Lin, X.Zhou, Z.Deng, and D.E.Cane (2008).
Mechanism of thioesterase-catalyzed chain release in the biosynthesis of the polyether antibiotic nanchangmycin.
  Chem Biol, 15, 449-458.  
17328673 C.Khosla, Y.Tang, A.Y.Chen, N.A.Schnarr, and D.E.Cane (2007).
Structure and mechanism of the 6-deoxyerythronolide B synthase.
  Annu Rev Biochem, 76, 195-221.  
17653357 F.Kopp, and M.A.Marahiel (2007).
Macrocyclization strategies in polyketide and nonribosomal peptide biosynthesis.
  Nat Prod Rep, 24, 735-749.  
17704771 N.Kadi, D.Oves-Costales, F.Barona-Gomez, and G.L.Challis (2007).
A new family of ATP-dependent oligomerization-macrocyclization biocatalysts.
  Nat Chem Biol, 3, 652-656.  
17466016 S.M.Ma, and Y.Tang (2007).
Biochemical characterization of the minimal polyketide synthase domains in the lovastatin nonaketide synthase LovB.
  FEBS J, 274, 2854-2864.  
17898897 S.Smith, and S.C.Tsai (2007).
The type I fatty acid and polyketide synthases: a tale of two megasynthases.
  Nat Prod Rep, 24, 1041-1072.  
16572230 A.M.Hill (2006).
The biosynthesis, molecular genetics and enzymology of the polyketide-derived metabolites.
  Nat Prod Rep, 23, 256-320.  
16897798 B.M.Harvey, H.Hong, M.A.Jones, Z.A.Hughes-Thomas, R.M.Goss, M.L.Heathcote, V.M.Bolanos-Garcia, W.Kroutil, J.Staunton, P.F.Leadlay, and J.B.Spencer (2006).
Evidence that a novel thioesterase is responsible for polyketide chain release during biosynthesis of the polyether ionophore monensin.
  Chembiochem, 7, 1435-1442.  
16969372 D.L.Akey, J.D.Kittendorf, J.W.Giraldes, R.A.Fecik, D.H.Sherman, and J.L.Smith (2006).
Structural basis for macrolactonization by the pikromycin thioesterase.
  Nat Chem Biol, 2, 537-542.
PDB codes: 2hfj 2hfk
17046237 J.D.Kittendorf, and D.H.Sherman (2006).
Developing tools for engineering hybrid polyketide synthetic pathways.
  Curr Opin Biotechnol, 17, 597-605.  
16969373 J.W.Giraldes, D.L.Akey, J.D.Kittendorf, D.H.Sherman, J.L.Smith, and R.A.Fecik (2006).
Structural and mechanistic insights into polyketide macrolactonization from polyketide-based affinity labels.
  Nat Chem Biol, 2, 531-536.
PDB codes: 2h7x 2h7y
16609856 M.Ghatge, N.Palaniappan, S.Das Choudhuri, and K.Reynolds (2006).
Genetic manipulation of the biosynthetic process leading to phoslactomycins, potent protein phosphatase 2A inhibitors.
  J Ind Microbiol Biotechnol, 33, 589-599.  
16567627 T.H.Davis, and R.M.Stroud (2006).
Profile of Robert M. Stroud.
  Proc Natl Acad Sci U S A, 103, 5256-5258.  
16322741 K.J.Weissman, and P.F.Leadlay (2005).
Combinatorial biosynthesis of reduced polyketides.
  Nat Rev Microbiol, 3, 925-936.  
  12889743 C.D.Reeves (2003).
The enzymology of combinatorial biosynthesis.
  Crit Rev Biotechnol, 23, 95.  
12923197 K.Watanabe, C.C.Wang, C.N.Boddy, D.E.Cane, and C.Khosla (2003).
Understanding substrate specificity of polyketide synthase modules by generating hybrid multimodular synthases.
  J Biol Chem, 278, 42020-42026.  
12819191 N.Palaniappan, B.S.Kim, Y.Sekiyama, H.Osada, and K.A.Reynolds (2003).
Enhancement and selective production of phoslactomycin B, a protein phosphatase IIa inhibitor, through identification and engineering of the corresponding biosynthetic gene cluster.
  J Biol Chem, 278, 35552-35557.  
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.

 

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