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Your search keyword '"collagen prolyl-4-hydroxylase"' showing total 2 results
Start Over Descriptor "collagen prolyl-4-hydroxylase" Topic hypoxia inducible factor
2 results on '"collagen prolyl-4-hydroxylase"'

1. Mannose binding lectin is hydroxylated by collagen prolyl-4-hydroxylase and inhibited by some PHD inhibitors

Author

Maxwell, Patrick, Bhute, Vijesh, Harte, James, Houghton, Jack, Maxwell, Patrick [0000-0002-0338-2679], and Apollo - University of Cambridge Repository

Subjects
hypoxia inducible factor, mannose binding lectin, post-translational, collagen prolyl-4-hydroxylase, Procollagen-Proline Dioxygenase, protein processing, chemical and pharmacologic phenomena, Prolyl-Hydroxylase Inhibitors, bacterial infections and mycoses, Prolyl Hydroxylases, PHD inhibitors, Hypoxia-Inducible Factor-Proline Dioxygenases, HEK293 cells, Collagen, FG-4592, chronic kidney disease, renal anemia, vadadustat, molidustat
Abstract

Background Mannose binding lectin (MBL) is an important component of innate immune defence. MBL undergoes oligomerization to generate high molecular weight (HMW) forms which act as pattern recognition molecules to detect and opsonize various microorganisms. Several post-translational modifications including prolyl hydroxylation are known to affect the oligomerization of MBL. Yet, the enzyme(s) which hydroxylate proline in the collagen-like domain residues have not been identified and the significance of prolyl hydroxylation is incompletely understood. Methods To investigate post-translational modifications of MBL, we stably expressed Myc-DDK tagged MBL in HEK293S cells. We used pharmacological and genetic inhibition of 2-oxoglutarate dependent dioxygenases (2OGDD) to identify the enzyme required for prolyl hydroxylation of MBL. We performed mass spectrometry to determine the effects of various inhibitors on MBL modifications. Results Secretion of HMW MBL was impaired by inhibitors of the superfamily of 2OGDD, and was dependent on prolyl-4-hydroxylase subunit alpha 1. Roxadustat and vadadustat, but not molidustat, led to significant suppression of hydroxylation and secretion of HMW forms of MBL. Conclusions These data suggest that prolyl hydroxylation in the collagen-like domain of MBL is mediated by collagen prolyl 4 hydroxylase. Reduced MBL activity is likely to be an off-target effect of some, but not all PHD inhibitors. There may be advantages in selective PHD inhibitors that would not interfere with MBL production.

Published
2020

2. Hyperoxia attenuates the inhibitory effect of nitric oxide donors on HIF prolyl-4-hydroxylase-2: Implication on discriminative effect of nitric oxide on HIF prolyl-4-hydroxylase-2 and collagen prolyl-4-hydroxylase

Author

Yum, Soohwan, Choi, Jeongyoun, Hong, Sungchae, Park, Myung Hee, Lee, Jaewon, Ha, Nam-Chul, and Jung, Yunjin

Subjects
*HYPEROXIA, *ENZYME regulation, *NITRIC oxide, *COLLAGEN, *NITROSO compounds, *PHENETHYLAMINES, *GLUTATHIONE, *TRANSCRIPTION factors
Abstract

Abstract: Prolyl 4-hydroxylases (P4Hs), such as collagen prolyl-4-hydroxylases (CPHs) and hypoxia inducible factor prolyl-4-hydroxylases (HPHs), have recently been recognized as promising drug targets for the treatment of fibrotic and ischemic diseases. CPHs and HPHs catalyze identical metabolic reactions, yet lead to quite different physiological consequences, collagen synthesis and the regulation of oxygen homeostasis. Selective modulation of the two enzymes should provide a therapeutic benefit upon pharmacotherapy. In an in vitro VHL capture assay, hydroxylation of the 19mer HIF peptide (corresponding to HIF-1α residues 556–574) by HPH-2 was effectively prevented by nitric oxide (NO) donors, (±)-S-nitroso-N-acetylpenicillamine (SNAP) and S-nitrosoglutathione. The NO donors also caused inhibition of HPHs and accumulation of nonhydroxylated HIF-1α protein in A549 human lung adenocarcinoma cells. Hyperoxia (100% O2) attenuated both NO donor-induced accumulation of HIF-1α and inhibition of HPH-mediated hydroxylation. In the presence of a proteasome inhibitor, MG132, the hyperoxia-mediated degradation of HIF-1α was deterred and hydroxylated HIF-1α was detected. SNAP, while being an effective inhibitor of proline 4-hydroxylation of HIF-1α by HPH-2, did not diminish proline hydroxylation of collagen by CPHs. Our data suggest that NO inhibits HPH-2 via competing with dioxygen and that the discriminative effect of NO on CPHs and HPH-2 is attributable to the difference in the affinity of the two enzymes toward dioxygen. [Copyright &y& Elsevier]

Published
2011
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