2ZTJ

Crystal structure of homocitrate synthase from Thermus thermophilus complexed with alpha-ketoglutarate

Summary for 2ZTJ

• Entry DOI: 10.2210/pdb2ztj/pdb
• Related: 2ZJK
• Descriptor: Homocitrate synthase, 2-OXOGLUTARIC ACID, COPPER (II) ION, ... (4 entities in total)
• Functional Keywords: (beta/alpha)8 tim barrel, substrate complex, amino-acid biosynthesis, lysine biosynthesis, transferase
• Biological source: Thermus thermophilus
• Cellular location: Cytoplasm (Potential): O87198
• Total number of polymer chains: 1
• Total formula weight: 43283.70

Authors

Okada, T.,Tomita, T.,Kuzuyama, T.,Nishiyama, M. (deposition date: 2008-10-06, release date: 2009-10-13, Last modification date: 2024-03-13)

Primary citation

Okada, T.,Tomita, T.,Wulandari, A.P.,Kuzuyama, T.,Nishiyama, M.
Mechanism of substrate recognition and insight into feedback inhibition of homocitrate synthase from Thermus thermophilus
J.Biol.Chem., 285:4195-4205, 2010

PubMed Abstract: Homocitrate synthase (HCS) catalyzes aldol-type condensation of acetyl coenzyme A (acetyl-CoA) and alpha-ketoglutarate (alpha-KG) to synthesize homocitrate (HC), which is the first and committed step in the lysine biosynthetic pathway through alpha-aminoadipate. As known in most enzymes catalyzing the first reactions in amino acid biosynthetic pathways, HCS is regulated via feedback inhibition by the end product, lysine. Here, we determined the crystal structures of HCS from Thermus thermophilus complexed with alpha-KG, HC, or lysine. In the HC complex, the C1-carboxyl group of HC, which is derived from acetyl-CoA, is hydrogen-bonded with His-292* from another subunit (indicated by the asterisk), indicating direct involvement of this residue in the catalytic mechanism of HCS. The crystal structure of HCS complexed with lysine showed that lysine is bound to the active site with rearrangement of amino acid residues in the substrate-binding site, which accounts for the competitive inhibition by lysine with alpha-KG. Comparison between the structures suggests that His-72, which is conserved in lysine-sensitive HCSs and binds the C5-carboxyl group of alpha-KG, serves as a switch for the conformational change. Replacement of His-72 by leucine made HCS resistant to lysine inhibition, demonstrating the regulatory role of this conserved residue.

PubMed: 19996101
DOI: 10.1074/jbc.M109.086330

Experimental method

X-RAY DIFFRACTION (1.8 Å)