Structural basis of head to head polyketide fusion by CorB

Abstract

Corallopyronin A is a polyketide derived from the myxobacterium Corallococcus coralloides with potent antibiotic features.

Structural Insight into the Enzymatic Formation of Bacterial Stilbene

“…Thr96, Ile101 0 , Ala125, Glu154, Pro156, Leu193, Met231, and Ile262 are mainly involved in the construction of the short acyl-binding pocket, and the second binding pocket is formed with Leu269, Val273, Thr277, Phe308, Phe312, and Pro367 ( Figure 3A). In the crystal structure of StlD, the active site Cys126 was oxidized to cysteine sulfinic acid, as often observed with the catalytic center Cys residues in the previously reported crystal structures of b-ketosynthases (Jez et al, 2000;Satou et al, 2013;Sucipto et al, 2015;Zocher et al, 2015). This modification is either transient or a result of crystallization/ data collection, as discussed for the other b-ketosynthases (Sucipto et al, 2015;Zocher et al, 2015).…”

“…The monomers are nearly identical to each other, with root-meansquare deviations (RMSDs) of 0.1-0.2 Å . The overall structure of the homodimeric StlD revealed the conservation of the thiolase fold, observed in all of the structurally characterized b-ketosynthases ( Figures S5A-S5G) (Theisen et al, 2004;Gajiwala et al, 2009;Goblirsch et al, 2012;Sucipto et al, 2015;Zocher et al, 2015). In contrast, the overall structure of StlD exhibits low structural similarity with that of the type III PKS superfamily stilbene synthase from Pinus sylvestris (PDB: 1U0U; RMSD of 2.8 Å for 324 Ca-atoms).…”

“…Furthermore, recent studies demonstrated that MtxB from Myxococcus fulvus Mx f50 (Erol et al, 2010), CorB from Corallococcus coralloides (Sucipto et al, 2013), PpyS from P. luminescens (Kresovic et al, 2015), and CsyB from Aspergillus oryzae (Mori et al, 2015) also catalyze the condensation reactions of alkyl b-ketoacyl substrates to generate acylalkylpyrone scaffolds. The structural analyses of MxnB (Sucipto et al, 2015), CorB (Zocher et al, 2015), and CsyB (Mori et al, 2015) revealed the detailed enzyme reaction mechanisms for the formation of each pyrone derivative. However, while MtxB, CorB, PpyS, and CsyB catalyze the Claisen condensation and lactonization reactions, DarB catalyzes four chemical reactions: Claisen condensation (first C-C bond-forming reaction), Michael addition (second C-C bond-forming reaction), decarboxylation, and hydrolysis, to produce the dialkyl-CHD scaffold.…”

Biomimetic Thioesters as Probes for Enzymatic Assembly Lines: Synthesis, Applications, and Challenges

“…One central aim is to elucidate unknown biosynthetic steps and to identify and study the corresponding biocatalysts. Important examples include the identification of enzymes responsible for cyclocondensations to yield tetramate ring systems from one thioester-activated polyketide chain (Gui et al, 2015;Sims and Schmidt, 2008), or pyrone ring systems from two chains (Sucipto et al, 2015;Zocher et al, 2015). A tandem mass spectrometrybased analysis granted insight into a double-bond shift during corallopyronin biosynthesis (Lohr et al, 2013).…”

Toolbox for Antibiotics Discovery from Microorganisms

“…Usually KS domains catalyze the chain elongation by Claisen condensation reactions. However, for several BGCs it was shown that special KSs exist which interconnect two polyketide chains, e.g., in the bacterial BGCs for photopyrones , myxopyronins , and corallopyronins , as well as in the fungal csypyrones . It can be expected that many more clusters harboring such interconnecting enzymes will be described in the coming years.…”