Expression of human GLUD1 and GLUD2 glutamate dehydrogenases in steroid producing tissues

Spanaki, Cleanthe; Kotzamani, Dimitra; Petraki, Zoe; Δράκος, Ηλίας; Plaitakis, Andreas

doi:10.1016/j.mce.2015.07.020

Cited by 22 publications

(22 citation statements)

References 29 publications

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“…As noted above, steroid hormones interact with hGDH2 with a much greater affinity than with hGDH1 [51,56,57]. Thus, inhibitory assays, performed under baseline conditions, revealed that diethylstilbestrol (DES) (IC 50 = 0.08 ± 0.01 μM) and 17 beta-estradiol (IC 50 = 1.67 ± 0.06 μM) inhibit hGDH2 with ~ 18-fold higher affinity than hGDH1 (IC 50 = 1.53 ± 0.24 μM for DES and IC 50 = 26.94 ± 1.07 μM; p < 0.001 for 17 beta-estradiol) [56].…”

Section: Gdh Regulationmentioning

confidence: 99%

“…Also, estriol, progesterone, and pregnenolone (the precursor of all steroid hormones) inhibit hGDH2 with a 10-fold greater affinity than hGDH1 [56]. Similarly, the androgens DHEA and DHT interact with hGDH2 with a 10-fold and 25-fold greater affinity than with hGDH1 in the absence of ADP (baseline conditions) [57]. However, ADP at 0.1–1.0 mM attenuates this inhibitory effect [56,57].…”

Section: Gdh Regulationmentioning

confidence: 99%

“…Similarly, the androgens DHEA and DHT interact with hGDH2 with a 10-fold and 25-fold greater affinity than with hGDH1 in the absence of ADP (baseline conditions) [57]. However, ADP at 0.1–1.0 mM attenuates this inhibitory effect [56,57]. In contrast, corticosterone inhibits both human isoenzymes with a similar high potency [57].…”

Section: Gdh Regulationmentioning

confidence: 99%

See 2 more Smart Citations

The Glutamate Dehydrogenase Pathway and Its Roles in Cell and Tissue Biology in Health and Disease

Plaitakis

Kalef-Ezra

Kotzamani

et al. 2017

Biology

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145

113

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Glutamate dehydrogenase (GDH) is a hexameric enzyme that catalyzes the reversible conversion of glutamate to α-ketoglutarate and ammonia while reducing NAD(P)+ to NAD(P)H. It is found in all living organisms serving both catabolic and anabolic reactions. In mammalian tissues, oxidative deamination of glutamate via GDH generates α-ketoglutarate, which is metabolized by the Krebs cycle, leading to the synthesis of ATP. In addition, the GDH pathway is linked to diverse cellular processes, including ammonia metabolism, acid-base equilibrium, redox homeostasis (via formation of fumarate), lipid biosynthesis (via oxidative generation of citrate), and lactate production. While most mammals possess a single GDH1 protein (hGDH1 in the human) that is highly expressed in the liver, humans and other primates have acquired, via duplication, an hGDH2 isoenzyme with distinct functional properties and tissue expression profile. The novel hGDH2 underwent rapid evolutionary adaptation, acquiring unique properties that enable enhanced enzyme function under conditions inhibitory to its ancestor hGDH1. These are thought to provide a biological advantage to humans with hGDH2 evolution occurring concomitantly with human brain development. hGDH2 is co-expressed with hGDH1 in human brain, kidney, testis and steroidogenic organs, but not in the liver. In human cerebral cortex, hGDH1 and hGDH2 are expressed in astrocytes, the cells responsible for removing and metabolizing transmitter glutamate, and for supplying neurons with glutamine and lactate. In human testis, hGDH2 (but not hGDH1) is densely expressed in the Sertoli cells, known to provide the spermatids with lactate and other nutrients. In steroid producing cells, hGDH1/2 is thought to generate reducing equivalents (NADPH) in the mitochondria for the biosynthesis of steroidal hormones. Lastly, up-regulation of hGDH1/2 expression occurs in cancer, permitting neoplastic cells to utilize glutamine/glutamate for their growth. In addition, deregulation of hGDH1/2 is implicated in the pathogenesis of several human disorders.

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Section: Gdh Regulationmentioning

confidence: 99%

Section: Gdh Regulationmentioning

confidence: 99%

See 1 more Smart Citation

The Glutamate Dehydrogenase Pathway and Its Roles in Cell and Tissue Biology in Health and Disease

Plaitakis

Kalef-Ezra

Kotzamani

et al. 2017

Biology

Self Cite

145

113

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show abstract

“…Krebs originally suggested that these huge enzyme levels are needed for keeping its reactants in equilibrium [24]. While GDH levels are lower in non-hepatic tissues characterized by cellular heterogeneity (brain, kidney and steroidogenic organs) [25], the enzyme can attain high levels (∼10 mg/ml of mitochondrial matrix) within individual cells that express this protein [23]. To maintain such high intra-mitochondrial levels, GDH depends on a very efficient mitochondrial transport system.…”

Section: Introductionmentioning

confidence: 99%

Import of a major mitochondrial enzyme depends on synergy between two distinct helices of its presequence

Kalef-Ezra

Kotzamani

Zaganas

et al. 2016

Biochemical Journal

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Mammalian glutamate dehydrogenase (GDH), a nuclear-encoded enzyme central to cellular metabolism, is among the most abundant mitochondrial proteins (constituting up to 10% of matrix proteins). To attain such high levels, GDH depends on very efficient mitochondrial targeting that, for human isoenzymes hGDH1 and hGDH2, is mediated by an unusually long cleavable presequence (N53). Here, we studied the mitochondrial transport of these proteins using isolated yeast mitochondria and human cell lines. We found that both hGDHs were very rapidly imported and processed in isolated mitochondria, with their presequences (N53) alone being capable of directing non-mitochondrial proteins into mitochondria. These presequences were predicted to form two α helices (α1: N 1–10; α2: N 16–32) separated by loops. Selective deletion of the α1 helix abolished the mitochondrial import of hGDHs. While the α1 helix alone had a very weak hGDH mitochondrial import capacity, it could direct efficiently non-mitochondrial proteins into mitochondria. In contrast, the α2 helix had no autonomous mitochondrial-targeting capacity. A peptide consisting of α1 and α2 helices without intervening sequences had GDH transport efficiency comparable with that of N53. Mutagenesis of the cleavage site blocked the intra-mitochondrial processing of hGDHs, but did not affect their mitochondrial import. Replacement of all three positively charged N-terminal residues (Arg3, Lys7 and Arg13) by Ala abolished import. We conclude that the synergistic interaction of helices α1 and α2 is crucial for the highly efficient import of hGDHs into mitochondria.

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“…The collecting and analysis of saliva samples are suitable for rapid and simple application in clinical studies. In addition, it has been shown that saliva samples can be analyzed for amino acids accurately in real time [130][131][132]; there is considerable evidence for a GABAglutamate imbalance in ASD [17][18][19]133,134] and several neuroactive steroids act as strong modulators of receptors for GABA and glutamate [91][92][93]135,136]. Thus, it may be useful to employ saliva samples of ASD subjects routinely to determine levels of neuroactive steroids and amino acids in clinical practice.…”

Section: Discussionmentioning

confidence: 99%

Neuroactive Steroids and Related Steroids in Autism Spectrum Disorders

Zheng¹,

Wang²,

Li³

et al. 2018

Neuropsychiatry

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Neuroactive steroids (rapidly acting steroids that act as allosteric modulators of neurotransmitter receptors such as the ɣ-aminobutyric acid A (GABA A ) receptor and the NMDA glutamate receptor) are involved in brain development and have been proposed to be important in the etiology and/or pharmacotherapy of a number of psychiatric and neurologic disorders, but there is limited information available on their association with autism spectrum disorders (ASD). This paper reviews the possible involvement of neuroactive steroids (NASs) and some related steroids, including testosterone, androstenedione and estradiol steroids in the etiology of ASD. NASs include progesterone, pregnanolone, pregnenolone, pregnenolone sulfate, allopregnanolone, tetrahydrodeoxycorticosterone (THDOC), dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS). Studies on the levels of NASs and related steroids in blood, urine, saliva, and amniotic fluid in ASD are also reviewed. The results on plasma levels of NASs in ASD reported in the literature are generally inconclusive, probably because of differences among studies in terms of experimental design and factors such as age, gender, number of subjects, and medication being taken and differences in time of day at which samples are taken and storage conditions of samples. Future studies on levels of NASs in ASD should include careful consideration of the factors mentioned above, the possible advantages of saliva sampling and the use of assay procedures that provide simultaneous analysis of levels of a large number of these steroids.

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Expression of human GLUD1 and GLUD2 glutamate dehydrogenases in steroid producing tissues

Cited by 22 publications

References 29 publications

The Glutamate Dehydrogenase Pathway and Its Roles in Cell and Tissue Biology in Health and Disease

The Glutamate Dehydrogenase Pathway and Its Roles in Cell and Tissue Biology in Health and Disease

Import of a major mitochondrial enzyme depends on synergy between two distinct helices of its presequence

Neuroactive Steroids and Related Steroids in Autism Spectrum Disorders

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