Prolyl hydroxylases as regulators of cell metabolism
Abstract
Cellular response to oxygen depletion is mediated by HIF (hypoxia-inducible factor). HIF is a heterodimer consisting of a constitutively expressed subunit (HIFβ) and an oxygen-regulated subunit (HIFα). HIFα stability is regulated by prolyl hydroxylation by PHD (prolyl hydroxylase domain-containing protein) family members. PHD activity depends on the availability of molecular oxygen, making PHDs the oxygen-sensing system in animal cells. However, PHDs have recently been shown to respond to stimuli other than oxygen, such as 2-oxoglutarate (α-ketoglutarate), succinate or fumarate, as illustrated by the pseudo-hypoxic response in succinate dehydrogenase- or fumarate dehydrogenase-deficient tumours. Moreover, HIFα is not the sole PHD effector, suggesting that PHDs have functions that extend beyond oxygen sensing. Currently, we are investigating the role of PHDs in the cellular response to amino acid deprivation, a process regulated by mTOR (mammalian target of rapamycin). The precise mechanism whereby amino acids are signalling to mTOR is not fully understood. Given that 2-oxoglutarate is a limiting co-substrate for PHD activity during normoxia and that 2-oxoglutarate levels depend on amino acid availability, it is possible that PHD activity depends not only on oxygen, but also on amino acid availability, suggesting a global metabolic sensor function for PHDs which could be signalling not only to HIF, but also to mTOR.
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Non-hypoxic stimuli that disrupt the PHD/VHL/HIF proteolytic cascade can induce accumulation of HIF.
“non-hypoxic stimuli that disrupt the PHD/VHL/HIF proteolytic cascade can also induce accumulation of HIF.”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [61]
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“Since HIF1 α is known to promote the expression of several key glycolytic enzymes and α -KG could affect HIF1 α stability via prolyl hydroxylase domain-containing protein 27 – 29 , we hypothesized that IDH2 might impact HIF1 α and glycolysis by altering α -KG level inTNBC cells.”
BackgroundNeomorphic mutations create therapeutic challenges in cancer
Takiar, V., Ip, C. K. M., Gao, M., Mills, G. B., & Cheung, L. W. T. (2016) · Oncogene · doi:10.1038/onc.2016.312 · Cited by 31 · see citing works
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“PHD post‑translationally modifies multiple proteins to exert broad effects on cellular metabolism (28-30).”
Metabolic Regulation in Mitochondria and Drug Resistance
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“Under normoxic conditions inmost tissues, HIF-1 is hydroxylated on proline residues by prolyl hydroxylase domain-containing proteins (PHD1–3; also known as Egln2, Egln1, and Egln3, respectively), which facilitate its binding to the pVHL (von Hippel-Lindau protein)-ubiquitin E3 ligase, resulting in its rapid degradatio…”
BackgroundmTOR: dissecting regulation and mechanism of action to understand human disease
Goberdhan, D. C. I., & Boyd, C. A. R. (2009) · Biochemical Society Transactions · doi:10.1042/bst0370213 · Cited by 27 · see citing works
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Metabolic Reprogramming of Mouse Bone Marrow Derived Macrophages Following Erythrophagocytosis
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“Other metabolites that influence prolyl hydroxylases to regulate HIF1α stability include αKG (the precursor to succinate) and fumarate (Boulahbel et al., 2009).”
BackgroundBelaïdi, E., Béguin, P. C., Levy, P. A., Ribuot, C., & Godin‐Ribuot, D. (2011) · Fundamental and Clinical Pharmacology · doi:10.1111/j.1472-8206.2011.00940.x · Cited by 26 · see citing works
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“Thiamine pyrophosphate is a cofactor in the rate limiting step of alpha-ketoglutarate (oxo-glutarate) dehydrogenase, an enzyme at the crossroads of energy metabolism, nitrogen assimilation and ROS signaling [85], with a possible role inmodulation of the activity of HIF-1 [86], all aspects that are deregulated in tumor…”
BackgroundMetabolic sensors and their interplay with cell signalling and transcription
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Ascorbate antagonizes nickel ion to regulate JMJD1A expression in kidney cancer cells
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“In addition to oxygen, several TCA cycle intermediates are also essential regulators of PHD activity, especially under normoxia.(46,50,92) Rodent and human β-cells express high levels of the anaplerotic mitochondrial enzyme pyruvate carboxylase (PC) that plays a crucial role in generating TCA intermediates, including…”
BackgroundGlutaminase - A potential target for cancer treatment
Josephine, A., Varalakshmi, S., Sekar, A. K., Devarajan, N., Janakiraman, B., & Rajendran, P. (2024) · Biomedicine · doi:10.37796/2211-8039.1445 · Cited by 17 · see citing works
“Apart from the role of RRAGB, EGLNs/prolyl hydroxylases play a critical role and constitute a mechanistic link in a -ketoglutarate mediated activation of mTORC1 [35].”
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“Such an unusual rate of proline hydroxylationmight compromise hydroxylation of other known protein substrates of PHD, such as hypoxia-inducible factor, leading to its stabilization in the cytosol [24,25].”
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“On the contrary, at lower oxygen concentrationWDR83 expressiondecreases andEGLN3 activity is reduced with the consequence of a higher stability of HIF1AmRNA allowing the activation of downstreammetabolic processes essentials to reduce the effect of low oxygen level in tissues [19,20] as angiogenesis, erythropoiesis, i…”
BackgroundProlyl-4-hydroxylase 3 maintains β cell glucose metabolism during fatty acid excess in mice
Nasteska, D., Cuozzo, F., Viloria, K., Johnson, E. M., Thakker, A., Bakar, R. B., Westbrook, R. L., Barlow, J. P., Hoang, M., Joseph, J. W., et al. (2021) · JCI Insight · doi:10.1172/jci.insight.140288 · Cited by 8 · see citing works
“Due to the dependence of PHD3 on alpha71 ketoglutarate and oxygen for its activity (18), many of these actions are likely to be mediated 72 through alterations in cell metabolism (19).”
Isoform-specific Roles of Prolyl Hydroxylases in the Regulation of Pancreatic β-Cell Function
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“The long-term hypoxia leads to PHD inhibition which allows for HIF1α stabilization and activates target genes involved in the switch to anaerobic metabolism and angiogenesis to increase oxygen supply (14-17, 26, 29, 54-56).”
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“It has repeatedly been shown that HIF-1 stabilization can, in addition to optimizing mitochondrial function [4], induce a metabolic shi resulting in a decreased aerobic, mitochondrial ATPproduction via TCA and an increased nonmitochondrial, anaerobic ATP-production via glycolysis, which reduces the oxygen and glucose…”
BackgroundUnlocking the Role of Metabolic Pathways in Brain Metastatic Disease
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“However, HIF1 α can be activated in normoxic environments due to VHL mutations or the accumulation of metabolites such as fumarate and succinate from the TCA cycle [43].”
Prolyl hydroxylase and hypoxia inducible factor: potential targets for cancer therapy
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“Hypoxia acts as a strong inducer of PHD-2 expression which plays important role in oncologic event.((18)) The expression and nuclear translocalization of PHD-2 is strongly increased in more aggressive proliferating and less differentiated carcinomas which alter the expression that depends upon growth promoting events.”
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Guest editorial: hypoxia biology in health and disease
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“metabolism, and oxidative stress [8].”
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A big picture of the mitochondria-mediated signals: From mitochondria to organism
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Regulation of vitamin C transport in brain
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mTOR Signalling, Nutrients and Disease
Goberdhan, D. C. I., Boyd, R. S., & Lamb, R. F. (2008)
Yamakura, M. U. F. (2012)
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The prolyl hydroxylase PHD3 maintains β-cell glucose metabolism during fatty acid excessPreprint
Nasteska, D., Cuozzo, F., Thakker, A., Bakar, R. B., Westbrook, R. L., Akerman, I., Cantley, J., Tennant, D., & Hodson, D. (2020) · bioRxiv · doi:10.1101/2020.04.30.068106
“Due to the dependence of PHD3 on alpha-ketoglutarate and oxygen for its activity (18), many of these actions are likely to be mediated through alterations in cell metabolism (19).”
BackgroundMetabolic Regulation of Inflammation
Siddiqui, S. I., Chowdhury, S., & Trivedi, A. K. (2024) · Springer eBooks · doi:10.1007/978-981-97-0157-5_8
BindingDB (2022) · UC San Diego · doi:10.7270/q2br8wwr
- Authors
- Boulahbel, H., Durán, R. V., & Gottlieb, E.
- Affiliations
- Cancer Research UK (GB)
- Venue
- Biochemical Society Transactions
- Publisher
- Portland Press Ltd.
- Published
- 2009-01-20
- Volume
- 37
- Issue
- 1
- Pages
- 291-294
- ISSN
- 0300-5127 (ISSN-L)
- 1470-8752
- OpenAlex
- W2031638748
- Cited by
- 82
- References
- 33
- Citations by year
- 2025: 2 · 2024: 5 · 2023: 1 · 2022: 1 · 2021: 3 · 2020: 3 · 2019: 3 · 2018: 3 · 2017: 5 · 2016: 10 · 2015: 2 · 2014: 5 · 2013: 9 · 2012: 12
- FWCI
- 0.61
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical Society Transactions (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- prolyl hydroxylase, hypoxia-inducible factor, oxygen sensing, alpha-ketoglutarate, succinic acid, fumarate, succinate dehydrogenase deficiency, amino acid starvation, mTOR signaling, cellular metabolism, metabolic sensing
- MeSH terms
- Animals, Cells, Humans, Procollagen-Proline Dioxygenase, Protein Kinases, Cell Hypoxia, Hypoxia-Inducible Factor 1, TOR Serine-Threonine Kinases
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