The HAG Mechanism: A Molecular Rationale For The Therapeutic Application Of Iron Chelators In Human Diseases Involving the 2-Oxoacid Utilizing Dioxygenases

Hartmut   M.   Hanauske-Abel; Anthony   M.   Popowicz

Abstract

‘Iron chelation’ is widely understood as synonymous with non-specificity and viewed as a purely physicochemical mode of action, without any defined biomolecular target, broadly interfering with metalloenzymes. The 2-oxoacid-utilizing dioxygenases challenge this preconception. A family of non-heme iron enzymes that rely on chelation-dependent catalysis, they employ common molecules like Krebs cycle intermediates as endogenous iron chelators and consume atmospheric oxygen, inserting one of its atoms into cellular components. These enzymes control the adaptation of cells to hypoxia; the reversal of mutagenic DNA alkylations, the initiation of DNA replication, the translation of mRNAs; the production of extracellular matrix proteins like collagens and fibrillins; and numerous metabolic pathways: from the synthesis of the gibberellin growth hormones of plants, and the formation of carnitine, atropine, endotoxins, and cephalosporin antibiotics, to the breakdown of amino acids. Their pivotal roles in human pathology encompass oncogenesis and cancer angiogenesis, scarring and organ fibrosis, inherited diseases, and retroviral infections. Their unique catalysis, termed earlier the ‘HAG mechanism’ and known in subatomic detail, requires at least three different substrates to form three different products, and proceeds as a ligand reaction at the non-heme iron atom inside the active site pocket, without any direct involvement of apoenzyme residues. The apoenzyme sterically controls ligand access to the metal. The HAG mechanism-based concept of catalytic chelation directed by an apoenzyme, not merely by complexation parameters, has enabled knowledge-guided design of systemic and tissue-selective inhibitors, and of clinical trials. The HAG mechanism also lends itself to the development of novel, man-made biocatalysts.

Keywords: Non-heme iron, dioxygenase, drug design, prolyl 4-hydroxylase, cancer, fibrosis, hiv, cell cycle