3IK9

Human GST A1-1-GIMF with GSDHN

Summary for 3IK9

• Entry DOI: 10.2210/pdb3ik9/pdb
• Related: 3IK7
• Descriptor: Glutathione S-transferase A1, (S)-2-amino-5-((R)-1-(carboxymethylamino)-3-((3S,4R)-1,4-dihydroxynonan-3-ylthio)-1-oxopropan-2-ylamino)-5-oxopentanoic acid (3 entities in total)
• Functional Keywords: human gst a1-1 gimf, enzyme, transferase, cytoplasm, polymorphism
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P08263
• Total number of polymer chains: 8
• Total formula weight: 209349.37

Authors

Balogh, L.M.,Le Trong, I.,Atkins, W.M.,Stenkamp, R.E. (deposition date: 2009-08-05, release date: 2010-06-23, Last modification date: 2023-09-06)

Primary citation

Balogh, L.M.,Le Trong, I.,Kripps, K.A.,Shireman, L.M.,Stenkamp, R.E.,Zhang, W.,Mannervik, B.,Atkins, W.M.
Substrate specificity combined with stereopromiscuity in glutathione transferase A4-4-dependent metabolism of 4-hydroxynonenal.
Biochemistry, 49:1541-1548, 2010

PubMed Abstract: Conjugation to glutathione (GSH) by glutathione transferase A4-4 (GSTA4-4) is a major route of elimination for the lipid peroxidation product 4-hydroxynonenal (HNE), a toxic compound that contributes to numerous diseases. Both enantiomers of HNE are presumed to be toxic, and GSTA4-4 has negligible stereoselectivity toward them, despite its high catalytic chemospecificity for alkenals. In contrast to the highly flexible, and substrate promiscuous, GSTA1-1 isoform that has poor catalytic efficiency with HNE, GSTA4-4 has been postulated to be a rigid template that is preorganized for HNE metabolism. However, the combination of high substrate chemoselectivity and low substrate stereoselectivity is intriguing. The mechanism by which GSTA4-4 achieves this combination is important, because it must metabolize both enantiomers of HNE to efficiently detoxify the biologically formed mixture. The crystal structures of GSTA4-4 and an engineered variant of GSTA1-1 with high catalytic efficiency toward HNE, cocrystallized with a GSH-HNE conjugate analogue, demonstrate that GSTA4-4 undergoes no enantiospecific induced fit; instead, the active site residue Arg15 is ideally located to interact with the 4-hydroxyl group of either HNE enantiomer. The results reveal an evolutionary strategy for achieving biologically useful stereopromiscuity toward a toxic racemate, concomitant with high catalytic efficiency and substrate specificity toward an endogenously formed toxin.

PubMed: 20085333
DOI: 10.1021/bi902038u

Experimental method

X-RAY DIFFRACTION (2.2 Å)