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| Figure 4:Proposed metabolic ratchet model for polyamine flux. Increased SSAT initiates polyamine flux by acetylation of polyamines, which facilitates their export from the cell. Acetylation eliminates the ability of polyamines to repress biosynthetic enzymes (ODC and SAMDC), which leads to a compensatory increase in polyamine biosynthesis. The restored polyamine pools are then available for SSAT acetylation and continuation of the cycle. When flux increases, substrate utilization (such as acetyl-CoA) and product accumulation (such as acetylated polyamines) also increase but the levels of polyamines do not change. Our results show that induction of SSAT in astrocytes by HIV Tat leads to depletion of acetyl-CoA pools and accumulation of acetylated polyamines, a critical consequence of increased cycling. Abbreviations: ODC, Ornithine Decarboxylase; SAMDC, S-Adenosylmethionine Decarboxylase; PAO, Polyamine Oxidase. |
