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496 a.a.
 L-glutamate |
+ |
H(2)O |
+ |
 NAD(P)(+) |
= |
 2-oxoglutarate |
+ |
NH(3) |
+ |
 NAD(P)H |
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Key reference
DOI no: 10.1021/bi0206917 Biochemistry 42:3446-3456 (2003) PubMed id: 12653548
Structural studies on ADP activation of mammalian glutamate dehydrogenase and the evolution of regulation. S.Banerjee, T.Schmidt, J.Fang, C.A.Stanley, T.J.Smith. ABSTRACT
Glutamate dehydrogenase (GDH) is found in all organisms and catalyzes the reversible oxidative deamination of L-glutamate to 2-oxoglutarate. Unlike GDH from bacteria, mammalian GDH exhibits negative cooperativity with respect to coenzyme, activation by ADP, and inhibition by GTP. Presented here are the structures of apo bovine GDH, bovine GDH complexed with ADP, and the R463A mutant form of human GDH (huGDH) that is insensitive to ADP activation. In the absence of active site ligands, the catalytic cleft is in the open conformation, and the hexamers form long polymers in the crystal cell with more interactions than found in the abortive complex crystals. This is consistent with the fact that ADP promotes aggregation in solution. ADP is shown to bind to the second, inhibitory, NADH site yet causes activation. The beta-phosphates of the bound ADP interact with R459 (R463 in huGDH) on the pivot helix. The structure of the ADP-resistant, R463A mutant of human GDH is identical to native GDH with the exception of the truncated side chain on the pivot helix. Together, these results strongly suggest that ADP activates by facilitating the opening of the catalytic cleft. From alignment of GDH from various sources, it is likely that the antenna evolved in the protista prior to the formation of purine regulatory sites. This suggests that there was some selective advantage of the antenna itself and that animals evolved new functions for GDH through the addition of allosteric regulation.
Literature references that cite this PDB file's key reference
PubMed id Reference
19393024 K.Kanavouras, N.Borompokas, H.Latsoudis, A.Stagourakis, I.Zaganas, and A.Plaitakis (2009).
Mutations in human GLUD2 glutamate dehydrogenase affecting basal activity and regulation.J Neurochem, 109, 167-173.
18467497 J.B.Carrigan, and P.C.Engel (2008).
The structural basis of proteolytic activation of bovine glutamate dehydrogenase.Protein Sci, 17, 1346-1353.
18710941 L.Li, E.A.Monckton, and R.Godbout (2008).
A role for DEAD box 1 at DNA double-strand breaks.Mol Cell Biol, 28, 6413-6425.
18078298 S.Bigdeli, A.H.Talasaz, P.Ståhl, H.H.Persson, M.Ronaghi, R.W.Davis, and M.Nemat-Gorgani (2008).
Conformational flexibility of a model protein upon immobilization on self-assembled monolayers.Biotechnol Bioeng, 100, 19-27.
17253646 K.Kanavouras, V.Mastorodemos, N.Borompokas, C.Spanaki, and A.Plaitakis (2007).
Properties and molecular evolution of human GLUD2 (neural and testicular tissue-specific) glutamate dehydrogenase.J Neurosci Res, 85, 1101-1109.
17924438 K.Kanavouras, V.Mastorodemos, N.Borompokas, C.Spanaki, and A.Plaitakis (2007).
Properties and molecular evolution of human GLUD2 (neural and testicular tissue-specific) glutamate dehydrogenase.J Neurosci Res, 85, 3398-3406.
17949437 M.Hamelin, J.Mary, M.Vostry, B.Friguet, and H.Bakala (2007).
Glycation damage targets glutamate dehydrogenase in the rat liver mitochondrial matrix during aging.FEBS J, 274, 5949-5961.
17507377 M.M.Choi, E.A.Kim, S.J.Yang, S.Y.Choi, S.W.Cho, and J.W.Huh (2007).
Amino acid changes within antenna helix are responsible for different regulatory preferences of human glutamate dehydrogenase isozymes.J Biol Chem, 282, 19510-19517.
17173671 E.Jaspard (2006).
A computational analysis of the three isoforms of glutamate dehydrogenase reveals structural features of the isoform EC 1.4.1.4 supporting a key role in ammonium assimilation by plants.Biol Direct, 1, 38.
15578726 V.Mastorodemos, I.Zaganas, C.Spanaki, M.Bessa, and A.Plaitakis (2005).
Molecular basis of human glutamate dehydrogenase regulation under changing energy demands.J Neurosci Res, 79, 65-73. The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time.
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