L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH

Intlekofer, Andrew M.; Wang, Bo; Liu, Hui; Shah, Hardik; Carmona‐Fontaine, Carlos; Rustenburg, Ariën S.; Salah, Salah; Gunner, M. R.; Chodera, John D.; Cross, Justin R.; Thompson, Craig B.

doi:10.1038/nchembio.2307

Cited by 198 publications

(231 citation statements)

References 63 publications

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“…Interestingly, recent work has identified that HIF stability may also be controlled by the lysosomal degradation pathway in an oxygen-independent manner 29–31 . Furthermore, it is also now clear that a number of the products of metabolism, including 2-oxoglutarate, 2-hydroxyglutarate, succinate and reactive oxygen species (ROS), can also exert control over the HIF pathway 32–36 (FIG. 3).…”

Section: Transcriptional Responses To Hypoxiamentioning

confidence: 99%

Regulation of immunity and inflammation by hypoxia in immunological niches

2017

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Immunological niches are focal sites of immune activity that can have varying microenvironmental features. Hypoxia is a feature of physiological and pathological immunological niches. The impact of hypoxia on immunity and inflammation can vary depending on the microenvironment and immune processes occurring in a given niche. In physiological immunological niches, such as the bone marrow, lymphoid tissue, placenta and intestinal mucosa, physiological hypoxia controls innate and adaptive immunity by modulating immune cell proliferation, development and effector function, largely via transcriptional changes driven by hypoxia-inducible factor (HIF). By contrast, in pathological immunological niches, such as tumours and chronically inflamed, infected or ischaemic tissues, pathological hypoxia can drive tissue dysfunction and disease development through immune cell dysregulation. Here, we differentiate between the effects of physiological and pathological hypoxia on immune cells and the consequences for immunity and inflammation in different immunological niches. Furthermore, we discuss the possibility of targeting hypoxia-sensitive pathways in immune cells for the treatment of inflammatory disease.

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Section: Transcriptional Responses To Hypoxiamentioning

confidence: 99%

Regulation of immunity and inflammation by hypoxia in immunological niches

2017

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“…Both have inhibitory activity against α-KG-dependent dioxygenases. l-2HG is generated from α-KG by LDHA or malate dehydrogenase in an IDH-independent manner in hypoxia or low pH conditions [65,66]. Mutation of genes encoding the TCA cycle enzymes FH1 or succinate dehydrogenase induces accumulation of fumarate or succinate, respectively.…”

Section: Epigenetic Regulation In Leukemic Cells By Oncometabolitesmentioning

confidence: 99%

Metabolic regulation of hematopoietic and leukemic stem/progenitor cells under homeostatic and stress conditions

Karigane

Takubo

2017

Int J Hematol

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organisms. HSPCs are composed of hematopoietic stem cells (HSCs) and several types of lineage-biased, but not fully committed, hematopoietic progenitor cells (HPCs). HSC capacities such as self-renewal and multilineage differentiation maintain the whole hematopoietic system over an organism's lifetime [1], and contribute to blood regeneration under stress condition, whereas HPCs reportedly function to maintain the supply of blood cells at steady state [2,3]. The surrounding BM microenvironment or "niche" determines HSC fate, namely its quiescence, symmetric/asymmetric division, differentiation, or migration potential, in both steady state and during stress. It is now evident that metabolic programs operating in HSCs play critical roles in maintaining hematopoietic homeostasis [4], often in response to BM niche signals [5]. Cellular pathways generate various metabolites through enzymatic activity that supplies material used as fuel, building blocks for other factors, or modulators of intra-or intercellular activities (Fig. 1). Despite the fact that numerous biochemical studies have addressed HSC metabolic regulation, numerous gaps in our knowledge of that regulation remain.Recently, novel means to fractionate metabolites using highly sensitive mass spectrometric technology [6] have dramatically facilitated metabolome analysis. These technologies reduce the need for high cell numbers and increase sensitivity of metabolite selection. As a result, metabolome analysis is feasible in rare cell populations such as HSCs. These analyses have revealed that metabolic programs play critical roles in maintaining stem cell "stemness" (Fig. 2). Here we review recent advances in the field of how metabolic changes regulate HSC dynamics under quiescence, proliferation, and differentiation from the viewpoint of each pathway. In addition to the normal HSC system, we also review activity of leukemia-related metabolic pathways, tumor-associated metabolites (oncometabolites), and Abstract Hematopoietic stem cells (HSCs) exhibit multilineage differentiation and self-renewal activities that maintain the entire hematopoietic system during an organism's lifetime. These abilities are sustained by intrinsic transcriptional programs and extrinsic cues from the microenvironment or niche. Recent studies using metabolomics technologies reveal that metabolic regulation plays an essential role in HSC maintenance. Metabolic pathways provide energy and building blocks for other factors functioning at steady state and in stress. Here we review recent advances in our understanding of metabolic regulation in HSCs relevant to cell cycle quiescence, symmetric/asymmetric division, and proliferation following stress and lineage commitment, and discuss the therapeutic potential of targeting metabolic factors or pathways to treat hematological malignancies.

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“…In addition, hypoxia [3–5] and acidic pH [6–8] trigger 2-HG production by MDH2 and LDH. Acidic pH is thought to protonate α-KG, enhancing its access to the substrate binding pocket of these enzymes [7]. However, it is unclear whether post-translational modification of these enzymes can also regulate 2-HG production.…”

Section: Introductionmentioning

confidence: 99%

Potential mechanisms linking SIRT activity and hypoxic 2-hydroxyglutarate generation: no role for direct enzyme (de)acetylation

Nadtochiy

Wang

Zhang

et al. 2017

Biochemical Journal

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2-hydroxyglutarate (2-HG) is a hypoxic metabolite with potentially important epigenetic signaling roles. The mechanisms underlying 2-HG generation are poorly understood, but evidence suggests a potential regulatory role for the sirtuin family of lysine deacetylases. Thus, we hypothesized that the acetylation status of the major 2-HG-generating enzymes (lactate dehydrogenase (LDH), isocitrate dehydrogenase (IDH) and malate dehydrogenase (MDH)) may govern their 2-HG generating activity. In-vitro acetylation of these enzymes, with confirmation by western blotting, mass spectrometry, reversibility by recombinant sirtuins, and an assay for global lysine occupancy, yielded no effect on 2-HG generating activity. In addition, while elevated 2-HG in hypoxia is associated with the activation of lysine deacetylases, we found that mice lacking mitochondrial SIRT3 exhibited hyperacetylation and elevated 2-HG. These data suggest there is no direct link between enzyme acetylation and 2-HG production. Furthermore, our observed effects of in-vitro acetylation on the canonical activities of IDH, MDH and LDH appeared to contrast with previous findings wherein acetyl-mimetic lysine mutations resulted in inhibition of these enzymes. Overall, these data suggest that a causal relationship should not be assumed between acetylation of metabolic enzymes and their activities, canonical or otherwise.

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L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH

Cited by 198 publications

References 63 publications

Regulation of immunity and inflammation by hypoxia in immunological niches

Regulation of immunity and inflammation by hypoxia in immunological niches

Metabolic regulation of hematopoietic and leukemic stem/progenitor cells under homeostatic and stress conditions

Potential mechanisms linking SIRT activity and hypoxic 2-hydroxyglutarate generation: no role for direct enzyme (de)acetylation

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