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PDBsum entry 2zyf
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References listed in PDB file
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Key reference
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Title
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Mechanism of substrate recognition and insight into feedback inhibition of homocitrate synthase from thermus thermophilus.
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Authors
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T.Okada,
T.Tomita,
A.P.Wulandari,
T.Kuzuyama,
M.Nishiyama.
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Ref.
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J Biol Chem, 2010,
285,
4195-4205.
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PubMed id
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Abstract
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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.
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