PMID- 22687491
OWN - NLM
STAT- MEDLINE
DCOM- 20121105
LR  - 20211021
IS  - 1873-3344 (Electronic)
IS  - 0162-0134 (Print)
IS  - 0162-0134 (Linking)
VI  - 113
DP  - 2012 Aug
TI  - Screening chelating inhibitors of HIF-prolyl hydroxylase domain 2 (PHD2) and 
      factor inhibiting HIF (FIH).
PG  - 25-30
LID - 10.1016/j.jinorgbio.2012.03.002 [doi]
AB  - Two primary O(2)-sensors for humans are the HIF-hydroxylases, enzymes that 
      hydroxylate specific residues of the hypoxia inducible factor-alpha (HIF). These 
      enzymes are factor inhibiting HIF (FIH) and prolyl hydroxylase-2 (PHD2), each an 
      alpha-ketoglutarate (alphaKG) dependent, non-heme Fe(II) dioxygenase. Although the two 
      enzymes have similar active sites, FIH hydroxylates Asn(803) of HIF-1alpha while PHD2 
      hydroxylates Pro(402) and/or Pro(564) of HIF-1alpha. The similar structures but 
      unique functions of FIH and PHD2 make them prime targets for selective inhibition 
      leading to regulatory control of diseases such as cancer and stroke. Three 
      classes of iron chelators were tested as inhibitors for FIH and PHD2: pyridines, 
      hydroxypyrones/hydroxypyridinones and catechols. An initial screen of the ten 
      small molecule inhibitors at varied [alphaKG] revealed a non-overlapping set of 
      inhibitors for PHD2 and FIH. Dose response curves at moderate [alphaKG] ([alphaKG]~K(M)) 
      showed that the hydroxypyrones/hydroxypyridinones were selective inhibitors, with 
      IC(50) in the muM range, and that the catechols were generally strong inhibitors 
      of both FIH and PHD2, with IC(50) in the low muM range. As support for binding at 
      the active site of each enzyme as the mode of inhibition, electron paramagnetic 
      resonance (EPR) spectroscopy were used to demonstrate inhibitor binding to the 
      metal center of each enzyme. This work shows some selective inhibition between 
      FIH and PHD2, primarily through the use of simple aromatic or pseudo-aromatic 
      chelators, and suggests that hydroxypyrones and hydroxypyridones may be promising 
      chelates for FIH or PHD2 inhibition.
CI  - Copyright (c) 2012 Elsevier Inc. All rights reserved.
FAU - Flagg, Shannon C
AU  - Flagg SC
AD  - Department of Chemistry, University of Massachusetts, Amherst, MA 01003, USA.
FAU - Martin, Cristina B
AU  - Martin CB
FAU - Taabazuing, Cornelius Y
AU  - Taabazuing CY
FAU - Holmes, Breanne E
AU  - Holmes BE
FAU - Knapp, Michael J
AU  - Knapp MJ
LA  - eng
GR  - R01 GM077413/GM/NIGMS NIH HHS/United States
GR  - T32 GM008515/GM/NIGMS NIH HHS/United States
GR  - R01-GM077413/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20120317
PL  - United States
TA  - J Inorg Biochem
JT  - Journal of inorganic biochemistry
JID - 7905788
RN  - 0 (Catechols)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Iron Chelating Agents)
RN  - 0 (Ketoglutaric Acids)
RN  - 0 (Pyridines)
RN  - 0 (Pyridones)
RN  - 0 (Pyrones)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Repressor Proteins)
RN  - E1UOL152H7 (Iron)
RN  - EC 1.- (Mixed Function Oxygenases)
RN  - EC 1.14.11.- (HIF1AN protein, human)
RN  - EC 1.14.11.2 (EGLN1 protein, human)
RN  - EC 1.14.11.2 (Procollagen-Proline Dioxygenase)
RN  - EC 1.14.11.29 (Hypoxia-Inducible Factor-Proline Dioxygenases)
SB  - IM
MH  - Amino Acid Sequence
MH  - Binding Sites
MH  - Catechols/chemistry
MH  - Electron Spin Resonance Spectroscopy
MH  - Escherichia coli
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/chemistry
MH  - Hypoxia-Inducible Factor-Proline Dioxygenases
MH  - Iron/*chemistry
MH  - Iron Chelating Agents/*chemistry
MH  - Ketoglutaric Acids/chemistry
MH  - Kinetics
MH  - Mixed Function Oxygenases/antagonists & inhibitors/*chemistry
MH  - Molecular Sequence Data
MH  - Procollagen-Proline Dioxygenase/antagonists & inhibitors/*chemistry
MH  - Protein Binding
MH  - Pyridines/chemistry
MH  - Pyridones/chemistry
MH  - Pyrones/chemistry
MH  - Recombinant Proteins/antagonists & inhibitors/chemistry
MH  - Repressor Proteins/antagonists & inhibitors/*chemistry
MH  - Substrate Specificity
PMC - PMC3525482
MID - NIHMS384362
EDAT- 2012/06/13 06:00
MHDA- 2012/11/06 06:00
PMCR- 2013/08/01
CRDT- 2012/06/13 06:00
PHST- 2011/07/01 00:00 [received]
PHST- 2012/02/04 00:00 [revised]
PHST- 2012/03/09 00:00 [accepted]
PHST- 2012/06/13 06:00 [entrez]
PHST- 2012/06/13 06:00 [pubmed]
PHST- 2012/11/06 06:00 [medline]
PHST- 2013/08/01 00:00 [pmc-release]
AID - S0162-0134(12)00081-5 [pii]
AID - 10.1016/j.jinorgbio.2012.03.002 [doi]
PST - ppublish
SO  - J Inorg Biochem. 2012 Aug;113:25-30. doi: 10.1016/j.jinorgbio.2012.03.002. Epub 
      2012 Mar 17.