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PDBsum entry 1u0m

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protein ligands Protein-protein interface(s) links
Biosynthetic protein PDB id
1u0m
Jmol
Contents
Protein chains
348 a.a. *
Ligands
15P ×2
GOL ×2
Waters ×148
* Residue conservation analysis
PDB id:
1u0m
Name: Biosynthetic protein
Title: Crystal structure of 1,3,6,8-tetrahydroxynaphthalene synthas from streptomyces coelicolor a3(2): a bacterial type iii po synthase (pks) provides insights into enzymatic control of polyketide intermediates
Structure: Putative polyketide synthase. Chain: a, b. Engineered: yes
Source: Streptomyces coelicolor. Organism_taxid: 100226. Strain: a3(2). Gene: sco1206. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693.
Biol. unit: Dimer (from PQS)
Resolution:
2.22Å     R-factor:   0.253     R-free:   0.292
Authors: M.B.Austin,M.Izumikawa,M.E.Bowman,D.W.Udwary,J.L.Ferrer,B.S. J.P.Noel
Key ref:
M.B.Austin et al. (2004). Crystal structure of a bacterial type III polyketide synthase and enzymatic control of reactive polyketide intermediates. J Biol Chem, 279, 45162-45174. PubMed id: 15265863 DOI: 10.1074/jbc.M406567200
Date:
13-Jul-04     Release date:   14-Sep-04    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q9FCA7  (Q9FCA7_STRCO) -  Putative polyketide synthase
Seq:
Struc:
374 a.a.
348 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     metabolic process   2 terms 
  Biochemical function     catalytic activity     3 terms  

 

 
DOI no: 10.1074/jbc.M406567200 J Biol Chem 279:45162-45174 (2004)
PubMed id: 15265863  
 
 
Crystal structure of a bacterial type III polyketide synthase and enzymatic control of reactive polyketide intermediates.
M.B.Austin, M.Izumikawa, M.E.Bowman, D.W.Udwary, J.L.Ferrer, B.S.Moore, J.P.Noel.
 
  ABSTRACT  
 
In bacteria, a structurally simple type III polyketide synthase (PKS) known as 1,3,6,8-tetrahydroxynaphthlene synthase (THNS) catalyzes the iterative condensation of five CoA-linked malonyl units to form a pentaketide intermediate. THNS subsequently catalyzes dual intramolecular Claisen and aldol condensations of this linear intermediate to produce the fused ring tetrahydroxynaphthalene (THN) skeleton. The type III PKS-catalyzed polyketide extension mechanism, utilizing a conserved Cys-His-Asn catalytic triad in an internal active site cavity, is fairly well understood. However, the mechanistic basis for the unusual production of THN and dual cyclization of its malonyl-primed pentaketide is obscure. Here we present the first bacterial type III PKS crystal structure, that of Streptomyces coelicolor THNS, and identify by mutagenesis, structural modeling, and chemical analysis the unexpected catalytic participation of an additional THNS-conserved cysteine residue in facilitating malonyl-primed polyketide extension beyond the triketide stage. The resulting new mechanistic model, involving the use of additional cysteines to alter and steer polyketide reactivity, may generally apply to other PKS reaction mechanisms, including those catalyzed by iterative type I and II PKS enzymes. Our crystal structure also reveals an unanticipated novel cavity extending into the "floor" of the traditional active site cavity, providing the first plausible structural and mechanistic explanation for yet another unusual THNS catalytic activity: its previously inexplicable extra polyketide extension step when primed with a long acyl starter. This tunnel allows for selective expansion of available active site cavity volume by sequestration of aliphatic starter-derived polyketide tails, and further suggests another distinct protection mechanism involving maintenance of a linear polyketide conformation.
 
  Selected figure(s)  
 
Figure 1.
FIG. 1. Known and possible reactions catalyzed by THNS. A, overall reaction catalyzed by THNS. Portions of the linear pentaketide derived from the starter (first) malonyl unit loaded are pink. B, conserved type III PKS catalytic triad and reaction mechanism for starter loading and polyketide chain extension by iterative Claisen condensations. The starter moiety is pink, whereas the first acetyl extension is green. C, all plausible Claisen and aldol condensation cyclization routes to THN of the fully elongated linear intermediate of THNS are shown. The most favorable initial condensations are green, and secondary cyclizations leading to S- or U-shaped THN cyclization patterns (see "Results") are depicted in red and blue, respectively. Predicted substrate labeling patterns are indicated by boldface bonds on the hypothetical monocyclic intermediates and resulting THN.
Figure 4.
FIG. 4. In vivo THN labeling experiment using heterologously expressed S. coelicolor THNS to determine the S- or U-shaped THN cyclization pattern (see Fig. 1C). The expected effects of the symmetric THN product's spontaneous oxidation to flaviolin upon label distribution are depicted, as is our result: the observation of U-THN-derived flaviolin.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2004, 279, 45162-45174) copyright 2004.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21521637 Y.Khatri, F.Hannemann, O.Perlova, R.Müller, and R.Bernhardt (2011).
Investigation of cytochromes P450 in myxobacteria: Excavation of cytochromes P450 from the genome of Sorangium cellulosum So ce56.
  FEBS Lett, 585, 1506-1513.  
20348430 D.Cook, A.M.Rimando, T.E.Clemente, J.Schröder, F.E.Dayan, N.P.Nanayakkara, Z.Pan, B.P.Noonan, M.Fishbein, I.Abe, S.O.Duke, and S.R.Baerson (2010).
Alkylresorcinol synthases expressed in Sorghum bicolor root hairs play an essential role in the biosynthesis of the allelopathic benzoquinone sorgoleone.
  Plant Cell, 22, 867-887.  
21041675 H.Morita, K.Wanibuchi, H.Nii, R.Kato, S.Sugio, and I.Abe (2010).
Structural basis for the one-pot formation of the diarylheptanoid scaffold by curcuminoid synthase from Oryza sativa.
  Proc Natl Acad Sci U S A, 107, 19778-19783.
PDB code: 3ale
20080733 H.Morita, Y.Shimokawa, M.Tanio, R.Kato, H.Noguchi, S.Sugio, T.Kohno, and I.Abe (2010).
A structure-based mechanism for benzalacetone synthase from Rheum palmatum.
  Proc Natl Acad Sci U S A, 107, 669-673.
PDB codes: 3a5q 3a5r 3a5s
20358042 H.Zhou, Y.Li, and Y.Tang (2010).
Cyclization of aromatic polyketides from bacteria and fungi.
  Nat Prod Rep, 27, 839-868.  
20358127 I.Abe, and H.Morita (2010).
Structure and function of the chalcone synthase superfamily of plant type III polyketide synthases.
  Nat Prod Rep, 27, 809-838.  
21079635 J.M.Crawford, and C.A.Townsend (2010).
New insights into the formation of fungal aromatic polyketides.
  Nat Rev Microbiol, 8, 879-889.  
20693992 S.Lin, R.E.Hanson, and J.E.Cronan (2010).
Biotin synthesis begins by hijacking the fatty acid synthetic pathway.
  Nat Chem Biol, 6, 682-688.  
19177221 I.Fujii (2009).
Heterologous expression systems for polyketide synthases.
  Nat Prod Rep, 26, 155-169.  
19844637 M.Nett, H.Ikeda, and B.S.Moore (2009).
Genomic basis for natural product biosynthetic diversity in the actinomycetes.
  Nat Prod Rep, 26, 1362-1384.  
18476861 B.J.Nikolau, M.A.Perera, L.Brachova, and B.Shanks (2008).
Platform biochemicals for a biorenewable chemical industry.
  Plant J, 54, 536-545.  
18981598 I.Abe (2008).
Engineering of plant polyketide biosynthesis.
  Chem Pharm Bull (Tokyo), 56, 1505-1514.  
18347585 M.B.Austin, P.E.O'Maille, and J.P.Noel (2008).
Evolving biosynthetic tangos negotiate mechanistic landscapes.
  Nat Chem Biol, 4, 217-222.  
18940668 S.B.Rubin-Pitel, H.Zhang, T.Vu, J.S.Brunzelle, H.Zhao, and S.K.Nair (2008).
Distinct structural elements dictate the specificity of the type III pentaketide synthase from Neurospora crassa.
  Chem Biol, 15, 1079-1090.
PDB codes: 3euo 3euq 3eut
18412189 T.Moriguchi, Y.Ebizuka, and I.Fujii (2008).
Domain-domain interactions in the iterative type I polyketide synthase ATX from Aspergillus terreus.
  Chembiochem, 9, 1207-1212.  
17109150 B.Liu, T.Raeth, T.Beuerle, and L.Beerhues (2007).
Biphenyl synthase, a novel type III polyketide synthase.
  Planta, 225, 1495-1503.  
  17620714 H.Morita, S.Kondo, R.Kato, K.Wanibuchi, H.Noguchi, S.Sugio, I.Abe, and T.Kohno (2007).
Crystallization and preliminary crystallographic analysis of an acridone-producing novel multifunctional type III polyketide synthase from Huperzia serrata.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 63, 576-578.  
17462571 H.Morita, S.Kondo, S.Oguro, H.Noguchi, S.Sugio, I.Abe, and T.Kohno (2007).
Structural insight into chain-length control and product specificity of pentaketide chromone synthase from Aloe arborescens.
  Chem Biol, 14, 359-369.
PDB codes: 2d3m 2d51 2d52
17229146 K.Springob, S.Samappito, A.Jindaprasert, J.Schmidt, J.E.Page, W.De-Eknamkul, and T.M.Kutchan (2007).
A polyketide synthase of Plumbago indica that catalyzes the formation of hexaketide pyrones.
  FEBS J, 274, 406-417.  
17482864 K.Watanabe, A.P.Praseuth, and C.C.Wang (2007).
A comprehensive and engaging overview of the type III family of polyketide synthases.
  Curr Opin Chem Biol, 11, 279-286.  
17440908 S.Grüschow, T.J.Buchholz, W.Seufert, J.S.Dordick, and D.H.Sherman (2007).
Substrate profile analysis and ACP-mediated acyl transfer in Streptomyces coelicolor Type III polyketide synthases.
  Chembiochem, 8, 863-868.  
16356722 A.M.Haapalainen, G.Meriläinen, and R.K.Wierenga (2006).
The thiolase superfamily: condensing enzymes with diverse reaction specificities.
  Trends Biochem Sci, 31, 64-71.  
16395556 F.Gross, N.Luniak, O.Perlova, N.Gaitatzis, H.Jenke-Kodama, K.Gerth, D.Gottschalk, E.Dittmann, and R.Müller (2006).
Bacterial type III polyketide synthases: phylogenetic analysis and potential for the production of novel secondary metabolites by heterologous expression in pseudomonads.
  Arch Microbiol, 185, 28-38.  
  16946474 H.Morita, S.Kondo, T.Abe, H.Noguchi, S.Sugio, I.Abe, and T.Kohno (2006).
Crystallization and preliminary crystallographic analysis of a novel plant type III polyketide synthase that produces pentaketide chromone.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 62, 899-901.  
16367761 I.Abe, T.Watanabe, W.Lou, and H.Noguchi (2006).
Active site residues governing substrate selectivity and polyketide chain length in aloesone synthase.
  FEBS J, 273, 208-218.  
16906151 M.B.Austin, T.Saito, M.E.Bowman, S.Haydock, A.Kato, B.S.Moore, R.R.Kay, and J.P.Noel (2006).
Biosynthesis of Dictyostelium discoideum differentiation-inducing factor by a hybrid type I fatty acid-type III polyketide synthase.
  Nat Chem Biol, 2, 494-502.
PDB code: 2h84
16496097 S.Brand, D.Hölscher, A.Schierhorn, A.Svatos, J.Schröder, and B.Schneider (2006).
A type III polyketide synthase from Wachendorfia thyrsiflora and its role in diarylheptanoid and phenylphenalenone biosynthesis.
  Planta, 224, 413-428.  
17004275 T.Moriguchi, Y.Ebizuka, and I.Fujii (2006).
Analysis of subunit interactions in the iterative type I polyketide synthase ATX from Aspergillus terreus.
  Chembiochem, 7, 1869-1874.  
17103476 Y.Haagen, K.Glück, K.Fay, B.Kammerer, B.Gust, and L.Heide (2006).
A gene cluster for prenylated naphthoquinone and prenylated phenazine biosynthesis in Streptomyces cinnamonensis DSM 1042.
  Chembiochem, 7, 2016-2027.  
15860421 J.P.Noel, M.B.Austin, and E.K.Bomati (2005).
Structure-function relationships in plant phenylpropanoid biosynthesis.
  Curr Opin Plant Biol, 8, 249-253.  
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 code is shown on the right.