The human GLUD2 glutamate dehydrogenase: Localization and functional aspects

In all mammals, glutamate dehydrogenase (GDH), an enzyme central to the metabolism of glutamate, is encoded by a single gene (GLUD1 in humans) which is expressed widely (housekeeping). Humans and other primates also possess a second gene, GLUD2, which encodes a highly homologous GDH isoenzyme (hGDH2) expressed predominantly in retina, brain and testis. There is evidence that GLUD1 was retro-posed <23 million years ago to the X chromosome, where it gave rise to GLUD2 through random mutations and natural selection. These mutations provided the novel enzyme with unique properties thought to facilitate its function in the particular milieu of the nervous system. hGDH2, having been dissociated from GTP control (through the Gly456Ala change), is mainly regulated by rising levels of ADP/l-leucine. To achieve full-range regulation by these activators, hGDH2 needs to set its basal activity at low levels (<10% of full capacity), a property largely conferred by the evolutionary Arg443Ser change. Studies of structure/function relationships have identified residues in the regulatory domain of hGDH2 that modify basal catalytic activity and regulation. In addition, enzyme concentration and buffer ionic strength can influence basal enzyme activity. While mature hGDH1 and hGDH2 isoproteins are highly homologous, their predicted leader peptide sequences show a greater degree of divergence. Study of the subcellular sites targeted by hGDH2 in three different cultured cell lines using a GLUD2/EGFP construct revealed that hGDH2 localizes mainly to mitochondria and to a lesser extent to the endoplasmic reticulum of these cells. The implications of these findings for the potential role of this enzyme in the biology of the nervous system in health and disease are discussed.