Prolyl hydroxylases and therapeutics

Abstract

Prolyl hydroxylases are members of the iron- and 2-oxoglutarate-dependent dioxygenase enzyme family. Collagen prolyl hydroxylase is well known for its involvement in scurvy, in which ascorbate deficiency inhibits the enzyme and results in characteristic signs of the disease. Several distinct prolyl hydroxylases that hydroxylate (and thereby regulate) the hypoxia-inducible factor (HIF) transcription factors were discovered in 2001. These HIF prolyl hydroxylases, termed prolyl hydroxylase domain enzymes (PHDs), are the subject of this forum. HIF coordinates the cellular response to hypoxia, and the PHDs have attracted widespread interest as potential therapeutic targets in a wide range of diseases including anemia, ischemic heart disease, stroke, cancer, and pulmonary hypertension. Novel PHD-based pharmaceutical agents are now undergoing clinical trials. As well as original data, this forum includes reviews discussing recent advances in the biochemistry and therapeutic manipulation of PHDs, the potential role of PHD inhibitors in neuroprotection, and the involvement of PHDs in the complex interaction between oxygen homeostasis and iron homeostasis.