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Scientific Highlight
Khosla Research

 




19 December 2006

  High Resolution Structural Study of a Modular Polyketide Synthase Didomain

summary written by Rachel Courtland, SLAC Communication Office

 
 


Researchers have obtained the highest-resolution image of a didomain structure in a modular polyketide synthase (PKS), revealing new structural features. PKS enzymes catalyze the synthesis of polyketides, which include a number of antibiotics, anticancer agents, antiparasitics, and immunosuppressants. The researchers solved the x-ray crystal structure of a didomain of 6-deoxyerythronolide B synthase (DEBS), a model PKS using data measured at SSRL Structural Molecular Biology Beam Line 11-1. They imaged a 194-kDA fragment of module 5 of the enzyme with multiwavelength anomalous dispersion (MAD). The fragment contained full-length ketosythase (KS) and acyl transferase (AT) domains, and the linkers that are part of the polyketide chain elongation process. With 40,908 atoms (582 kDa) per asymmetric unit, this structure represents the largest unique crystal structure to be solved using MAD. The 2.7- resolution image showed that the active site residues of the KS and AT domains, Cys199 and Ser642, respectively, were more than 80 apart. The distance is too large to be traversed by the long arm of a statically positioned acyl carrier protein, needed to ferry growing polyketides along the synthase backbone. The unexpected feature suggests substantial domain reorganization may be needed for the synthase module to function. The didomain structure also revealed a novel protein fold for the KS-to-AT linker.

Principal investigator Chaitan Khosla of Stanford University was recently elected a fellow to the American Association for the Advancement of Science for his contributions to the field of metabolic chemistry and engineering, particularly to the biosynthesis of polyketide antibiotics.

To learn more about this research see the full scientific highlight at:
http://www-ssrl.slac.stanford.edu/research/highlights_archive/PKS.html

Tang, Y., Kim, C.-Y., Mathews, I. I., Cane, D. E., Khosla, C. (2006) The 2.7- Crystal Structure of a 194-kDa Homodimeric Fragment of the 6-Deoxyerythronolide B Synthase. PNAS, 103, 11124-11129.