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Published on: March 11, 2020
The human GLUD2 glutamate dehydrogenase: localization and functional aspects
Ioannis Zaganas1, Konstantinos Kanavouras, Vasileios Mastorodemos
1Department of Neurology, Medical School, University of Crete, Heraklion, Crete, Greece.
Neurochemistry International
|May 12, 2009
Summary
Humans possess two glutamate dehydrogenase (GDH) genes: GLUD1 and GLUD2. The GLUD2 gene evolved unique properties for nervous system function, with distinct regulation and cellular localization.
Area of Science:
- Biochemistry
- Evolutionary Biology
- Neuroscience
Background:
- Mammals typically have one glutamate dehydrogenase (GDH) gene (GLUD1), a housekeeping enzyme.
- Humans and primates have a second, homologous gene (GLUD2) encoding GDH isoenzyme hGDH2, primarily in the retina, brain, and testes.
- GLUD2 likely arose from a retroposed GLUD1 on the X chromosome, acquiring unique properties through mutation and selection.
Purpose of the Study:
- To investigate the evolutionary origins and functional adaptations of the human GLUD2 gene and its encoded hGDH2 enzyme.
- To understand the regulatory mechanisms and cellular localization of hGDH2, particularly in the context of nervous system function.
- To explore the structure-function relationships influencing hGDH2's catalytic activity and regulation.
Main Methods:
- Comparative gene analysis and evolutionary studies to trace the origin of GLUD2.
- Biochemical assays to determine the regulatory properties of hGDH2, including its response to ADP/l-leucine and dissociation from GTP control.
- Structure-function relationship studies to identify key residues affecting enzyme activity.
- Subcellular localization studies using a GLUD2/EGFP construct in cultured cell lines.
Main Results:
- GLUD2 evolved from GLUD1 on the X chromosome, with mutations conferring distinct regulatory properties, notably reduced GTP sensitivity and enhanced ADP/l-leucine regulation.
- Key mutations (Gly456Ala and Arg443Ser) contribute to hGDH2's unique regulatory profile and low basal activity.
- hGDH2 localizes primarily to mitochondria and secondarily to the endoplasmic reticulum in cultured cells.
- Leader peptide sequences of hGDH1 and hGDH2 show significant divergence, suggesting differential targeting.
Conclusions:
- The GLUD2 gene provides a specialized GDH enzyme (hGDH2) adapted for the nervous system's unique environment.
- hGDH2's altered regulation and subcellular localization are critical for its proposed roles in neural function.
- Further research is needed to fully elucidate the implications of hGDH2 in neurological health and disease.
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