Oral Presentation The 46th Lorne Conference on Protein Structure and Function 2021

Structure and Function of Fungal and Plant Acetohydroxyacid Synthase (#23)

Luke W Guddat 1
  1. The University of Queensland, Brisbane, QLD, Australia

Acetohydroxyacid synthase (AHAS) also known as acetolactate synthase is a FAD and ThDP-Mg2+-dependent enzyme that catalyses the first step in the biosynthesis of the branched chain amino acids (BCAAs). It is the target for over 50 commercial herbicides [1-3]. AHAS requires both catalytic and regulatory subunits for maximal activity and functionality. Here we present our structures of the hexadecameric Saccharomyces cerevisiae and dodecameric Arabidopsis thaliana AHAS complexes demonstrate that the regulatory subunits form a core upon which the catalytic subunit dimers are attached, adopting the shape of a “Maltese Cross” [4]. The structures show how the catalytic and regulatory subunits communicate with each other to provide a pathway for activation and for feedback inhibition by the BCAAs. We also show that Mycobacterium tuberculosis AHAS adopts a similar structure, thus demonstrating that the overall AHAS architecture is conserved across kingdoms [4].

 

 

  1. 1. Garcia, M. D., Nouwens, A., Lonhienne, T. G. & Guddat, L. W. (2017) Comprehensive understanding of acetohydroxyacid synthase inhibition by different herbicide families, Proc Natl Acad Sci USA. 114, E1091-E1100.
  2. 2. Lonhienne, T., Garcia, M. D., Pierens, G., Mobli, M., Nouwens, A. & Guddat, L. W. (2018) Structural insights into the mechanism of inhibition of AHAS by herbicides, Proc Natl Acad Sci USA. 115, E1945-E1954.
  3. 3. Garcia, M. D., Chua, S. M. H., Low, Y. S., Lee, Y. T., Agnew-Francis, K., Wang, J. G., Nouwens, A., Lonhienne, T., Williams, C. M., Fraser, J. A. & Guddat, L. W. (2018) Commercial AHAS-inhibiting herbicides are promising drug leads for the treatment of human fungal pathogenic infections, Proc Natl Acad Sci USA. 115, E9649-E9658.
  4. 4. Lonhienne, T., Low, Y. S., Garcia, M. D., Croll, T., Gao, Y., Wang, Q., Brillault, L., Williams, C. M., Fraser, J. A., McGeary, R. P., West, N. P., Landsberg, M. J., Rao, Z., Schenk, G. & Guddat, L. W. (2020) Structures of fungal and plant acetohydroxyacid synthases, Nature. 586, 317-321.