Human aspartyl (asparaginyl) hydroxylase. A multifaceted enzyme with broad intra- and extra-cellular activity

Human aspartyl (asparaginyl) β-hydroxylase (HAAH), a unique iron and 2-oxoglutarate dependent oxygenase, has shown increased importance as a suspected oncogenic protein. HAAH and its associated mRNA are upregulated in a wide variety of cancer types, however, the current role of HAAH in the malignant transformation of cells is unknown. HAAH is suspected to play an important role in NOTCH signaling via selective hydroxylation of aspartic acid and asparagine residues of epidermal growth factor (EGF)-like domains. HAAH hydroxylation also potentially mediates calcium signaling and oxygen sensing. In this review, we summarize the current state of understanding of the biochemistry and chemical biology of this enzyme, identify key differences from other family members, outline its broader intra- and extra-cellular roles, and identify the most promising areas for future research efforts.