Inverse solvent isotope effects arising from substrate triggering in the factor inhibiting hypoxia inducible factor.

ABSTRACT: Oxygen homeostasis plays a critical role in angiogenesis, erythropoiesis, and cell metabolism. Oxygen homeostasis is set by the hypoxia inducible factor-1α (HIF-1α) pathway, which is controlled by factor inhibiting HIF-1α (FIH). FIH is a non-heme Fe(II), α-ketoglutarate (αKG)-dependent dioxygenase that inhibits HIF-1α by hydroxylating the C-terminal transactivation domain (CTAD) of HIF-1α at HIF-Asn(803). A tight coupling between CTAD binding and O2 activation is essential for hypoxia sensing, making changes in the coordination geometry of Fe(II) upon CTAD encounter a crucial feature of this enzyme. Although the consensus chemical mechanism for FIH proposes that CTAD binding triggers O2 activation by causing the Fe(II) cofactor to release an aquo ligand, experimental evidence of this has b

SUBMITTER: Hangasky JA 

PROVIDER: S-EPMC4059518 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature