Estrogen modification of human glutamate dehydrogenases is linked to enzyme activation state.

The Journal of Biological Chemistry
Nikolas BorompokasAndreas Plaitakis

Abstract

Mammalian glutamate dehydrogenase (GDH) is a housekeeping enzyme central to the metabolism of glutamate. Its activity is potently inhibited by GTP (IC(50) = 0.1-0.3 μM) and thought to be controlled by the need of the cell in ATP. Estrogens are also known to inhibit mammalian GDH, but at relatively high concentrations. Because, in addition to this housekeeping human (h) GDH1, humans have acquired via a duplication event an hGDH2 isoform expressed in human cortical astrocytes, we tested here the interaction of estrogens with the two human isoenzymes. The results showed that, under base-line conditions, diethylstilbestrol potently inhibited hGDH2 (IC(50) = 0.08 ± 0.01 μM) and with ∼18-fold lower affinity hGDH1 (IC(50) = 1.67 ± 0.06 μM; p < 0.001). Similarly, 17β-estradiol showed a ∼18-fold higher affinity for hGDH2 (IC(50) = 1.53 ± 0.24 μM) than for hGDH1 (IC(50) = 26.94 ± 1.07 μM; p < 0.001). Also, estriol and progesterone were more potent inhibitors of hGDH2 than hGDH1. Structure/function analyses revealed that the evolutionary R443S substitution, which confers low basal activity, was largely responsible for sensitivity of hGDH2 to estrogens. Inhibition of both human GDHs by estrogens was inversely related to their state of acti...Continue Reading

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Citations

Nov 1, 2011·Neurotoxicity Research·Cleanthe Spanaki, Andreas Plaitakis
Jan 18, 2014·Neurochemical Research·Cleanthe SpanakiAndreas Plaitakis
Dec 20, 2013·Neurochemical Research·Pullanipally Shashidharan, Andreas Plaitakis
Jun 20, 2012·Neurochemistry International·Ioannis ZaganasAndreas Plaitakis
Mar 23, 2011·Neurochemistry International·Andreas PlaitakisCleanthe Spanaki
Mar 7, 2013·Journal of Neuroscience Research·Andreas PlaitakisCleanthe Spanaki
Aug 5, 2015·Molecular and Cellular Endocrinology·Cleanthe SpanakiAndreas Plaitakis
Aug 28, 2012·Metabolism: Clinical and Experimental·Maria M AdevaCristóbal Donapetry
Nov 12, 2014·Biomedit︠s︡inskai︠a︡ khimii︠a︡·T N PogorelovaV A Linde

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