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Increased Turnover at Limiting O2 Concentrations by the Thr(387) → Ala Variant of HIF-Prolyl Hydroxylase PHD2.

Abstract：

:PHD2 is a 2-oxoglutarate, non-heme Fe(2+)-dependent oxygenase that senses O2 levels in human cells by hydroxylating two prolyl residues in the oxygen-dependent degradation domain (ODD) of HIF1α. Identifying the active site contacts that determine the rate of reaction at limiting O2 concentrations is crucial for understanding how this enzyme senses pO2 and may suggest methods for chemically altering hypoxia responses. A hydrogen bonding network extends from the Fe(II) cofactor through ordered waters to the Thr(387) residue in the second coordination sphere. Here we tested the impact of the side chain of Thr(387) on the reactivity of PHD2 toward O2 through a combination of point mutagenesis, steady state kinetic experiments and {FeNO}(7) EPR spectroscopy. The steady state kinetic parameters for Thr(387) → Asn were very similar to those of wild-type (WT) PHD2, but kcat and kcat/KM(O2) for Thr(387) → Ala were increased by roughly 15-fold. X-Band electron paramagnetic resonance spectroscopy of the {FeNO}(7) centers of the (Fe+NO+2OG) enzyme forms showed the presence of a more rhombic line shape in Thr(387) → Ala than in WT PHD2, indicating an altered conformation for bound gas in this variant. Here we show that the side chain of residue Thr(387) plays a significant role in determining the rate of turnover by PHD2 at low O2 concentrations.

journal_name

Biochemistry

journal_title

Biochemistry

authors

Pektas S,Taabazuing CY,Knapp MJ

doi

10.1021/bi501540c

subject

Has Abstract

pub_date

2015-05-12 00:00:00

pages

2851-7

issue

18

eissn

0006-2960

issn

1520-4995

journal_volume

54

pub_type

杂志文章

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