Figure 4. Interconnection of the GABA shunt and polyamine degradation (PA) pathway in metabolic regulation.

Orange arrows indicate the GABA shunt; Green arrows indicate the PA pathway. GABA shunt: GABA biosynthesis begins with the transamination of α-ketoglutarate (α-KG), catalyzed by glutamate dehydrogenase (GDH), to produce glutamate. Subsequently, the irreversible decarboxylation at the α- carbon of glutamate, catalyzed by glutamic acid decarboxylase (GAD), yields GABA. This reaction consumes a proton and releases carbon dioxide and can occur in both the mitochondria and the cytoplasm. GABA catabolism is then catalyzed by GABA transaminase (GABA-T), converting GABA into succinic semialdehyde (SSA). SSA is subsequently oxidized by succinate-semialdehyde dehydrogenase (SSADH) and enters the tricarboxylic acid (TCA) cycle as succinate. PA pathway: In this pathway, glutamate is converted to α-KG by GABA-T. This α-KG then undergoes a series of enzymatic reactions to produce glutathione and, ultimately, ornithine. Ornithine is transported to the cytoplasm, where it is converted into putrescine by ornithine decarboxylase (ODC). Through further enzymatic reactions, putrescine is converted to spermidine and spermine. Putrescine, spermidine, and spermine are then converted by diamine oxidase (DAO) and polyamine oxidase (PAO), respectively, to produce 4-aminobutyraldehyde. This 4-aminobutyraldehyde is dehydrogenated by 4-aminobutyraldehyde dehydrogenase (AMADH) to form GABA. The PA pathway intersects with the GABA shunt, and their metabolites eventually enter the TCA cycle.