PROTEINS 2015* Exploring the role of a dynamic accessory domain (#113)
Biomolecular Interaction Centre
and Department of Chemistry
University of Canterbury, Christchurch, New Zealand
Isopropylmalate synthase (IPMS) catalyses the first reaction in the leucine biosynthetic pathway in bacteria, fungi, and archaea. This enzyme is allosterically regulated by leucine. IPMS is a homodimer and each chain consists of a catalytic domain, two subdomains which act as a catalytic accessory unit, and a regulatory domain1. The binding site for leucine is located over 50 Å away from the active site of the enzyme. The mechanism of allosteric regulation is not fully understood. IPMS is closely related to homocitrate synthase (HCS), which functions in the lysine-producing α-aminoadipate pathway that is present in fungi and some archaea and bacteria2. HCS is structurally very similar to IPMS but lacks a regulatory domain and instead is competitively inhibited by lysine.
In our studies of the IPMS from Neisseria meningitidis, we have demonstrated that a functional, leucine-insensitive, enzyme can be created by removal of the regulatory domain as long as subdomain II of the catalytic accessory unit remains intact. This finding has allowed us to explore the roles of this catalytic accessory unit in both catalysis and allosteric regulation by leucine.
- Koon, N., Squire, C. J., & Baker, E. N. (2004). Crystal structure of LeuA from Mycobacterium tuberculosis, a key enzyme in leucine biosynthesis. Proceedings of the National Academy of Sciences of the United States of America, 101(22), 8295-8300. doi: 10.1073/pnas.0400820101
- Xu, Hengyu, Andi, Babak, Qian, Jinghua, West, Ann H., & Cook, Paul F. (2006). The alpha-aminoadipate pathway for lysine biosynthesis in fungi. Cell Biochemistry and Biophysics, 46(1), 43-64. doi: 10.1385/cbb:46:1:43