2cgo: Difference between revisions
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==Overview== | ==Overview== | ||
In humans both the levels and activity of the alpha-subunit of the, hypoxia-inducible transcription factor (HIF-alpha) are regulated by its, post-translation hydroxylation as catalyzed by iron- and 2-oxoglutarate, (2OG)-dependent prolyl and asparaginyl hydroxylases (PHD1-3 and, factor-inhibiting HIF (FIH), respectively). One consequence of hypoxia is, the accumulation of tricarboxylic acid cycle intermediates (TCAIs). In, vitro assays were used to assess non-2OG TCAIs as inhibitors of purified, PHD2 and FIH. Under the assay conditions, no significant FIH inhibition, was observed by the TCAIs or pyruvate, but fumarate, succinate, and, isocitrate inhibited PHD2. Mass spectrometric analyses under nondenaturing, conditions were used to investigate the binding of TCAIs to PHD2 and, supported ... | In humans both the levels and activity of the alpha-subunit of the, hypoxia-inducible transcription factor (HIF-alpha) are regulated by its, post-translation hydroxylation as catalyzed by iron- and 2-oxoglutarate, (2OG)-dependent prolyl and asparaginyl hydroxylases (PHD1-3 and, factor-inhibiting HIF (FIH), respectively). One consequence of hypoxia is, the accumulation of tricarboxylic acid cycle intermediates (TCAIs). In, vitro assays were used to assess non-2OG TCAIs as inhibitors of purified, PHD2 and FIH. Under the assay conditions, no significant FIH inhibition, was observed by the TCAIs or pyruvate, but fumarate, succinate, and, isocitrate inhibited PHD2. Mass spectrometric analyses under nondenaturing, conditions were used to investigate the binding of TCAIs to PHD2 and, supported the solution studies. X-ray crystal structures of FIH in complex, with Fe(II) and fumarate or succinate revealed similar binding modes for, each in the 2OG co-substrate binding site. The in vitro results suggest, that the cellular inhibition of PHD2, but probably not FIH, by fumarate, and succinate may play a role in the Warburg effect providing that, appropriate relative concentrations of the components are achieved under, physiological conditions. | ||
==About this Structure== | ==About this Structure== | ||
2CGO is a | 2CGO is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with FE, SO4 and FMR as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Peptide-aspartate_beta-dioxygenase Peptide-aspartate beta-dioxygenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.11.16 1.14.11.16] Structure known Active Site: AC1. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2CGO OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: transcription regulation]] | [[Category: transcription regulation]] | ||
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 5 15:22:58 2007'' | ||
