Hypoxic stabilization and proteolytic degradation of erythroid-specific 5-aminolevulinate synthase
Eukaryotes have acquired a broad range of post-translational modifications to place controls and checks on metabolic pathways. Included among these is hydroxylation. Hydroxylases catalyze the oxygen-, iron (II)-, ascorbate- and 2-oxoglutarate-dependent hydroxylation of protein substrates. Until recently, few studies examined hydroxylation as a post-translational modification, focusing primarily on hydroxylation of structural proteins such as collagen and elastin. With the discovery of hydroxylase-dependent destabilization of transcription factors, the role of hydroxylation in gene expression has renewed the interest in these enzymes. The paramount example of this is the hydroxylation of the transcription factor involved in hypoxic-inducible gene expression, Hypoxia-Inducible Factor-1 (HIF-1). The possibility exists that other proteins are hydroxylated in a manner similar to HIF-1 and are degraded and/or have altered enzymatic activities. These proteins may be involved in pathways that maintain oxygen homeostasis. A database search of potential targets of HIF-1 prolyl hydroxylases has revealed erythroid-specific 5-aminolevulinate synthase (ALAS2). Here we provide evidence that ALAS2 is broken down under normoxic conditions by the proteosome and that the prolyl-4-hydroxylase/E3 ubiquitin ligase pathway may be involved. The implications to oxygen sensing are discussed.