GLUD2 encodes glutamate dehydrogenase 2 (hGDH2), an X-linked enzyme expressed in testicular Sertoli cells and cerebral cortical astrocytes 1. Unlike the ubiquitously expressed GLUD1, GLUD2 arose through retroposition in primates during enhanced brain development 2. hGDH2 catalyzes bidirectional glutamate metabolism, converting glutamate to α-ketoglutarate to facilitate metabolic recycling essential for glutamatergic neurotransmission 1. Critically, hGDH2 dissociated from GTP inhibition, enabling glutamate oxidation independent of cellular energy status—an adaptation allowing astrocytes to handle increased transmitter loads during intense synaptic activity 2. During postnatal brain development, GLUD2 expression affects carbon flux through the tricarboxylic acid cycle, potentially supporting lipid biosynthesis 3. Disease relevance includes a rare T1492G variant (Ser445Ala) that enhances catalytic activity and is resistant to GTP modulation; hemizygous males carrying this variant developed Parkinson's disease 6-13 years earlier than unaffected genotypes, while heterozygous females were protected by estrogen-mediated inhibition 1. Additionally, pathogenic GLUD2 variants have been linked to primary spermatogenic failure and male infertility 4. The evolutionary acquisition of GLUD2's unique regulatory properties renders it a selective target for neuroactive steroids and antipsychotic drugs, offering therapeutic intervention opportunities in neurodegeneration 1.