Non-enzymatic Lysine Lactoylation of Glycolytic Enzymes

Gaffney, Dominique O.; Jennings, Erin Q.; Anderson, Colin C.; Marentette, John; Shi, Taoda; Oxvig, Anne Mette Schou; Streeter, Matthew D.; Johannsen, Mogens; Spiegel, David A.; Chapman, Eli; Roede, James R.; Galligan, James J.

doi:10.1016/j.chembiol.2019.11.005

Cited by 154 publications

(210 citation statements)

References 28 publications

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“…Besides the important functions of lysine ERPs and the growth-halting effects of lysine deprivation discussed above, lysine is also a versatile AA modified by various modifications including methylation, acetylation, phosphorylation, malonylation, O-GlcNAcylation, SUMOylation, ubiquitination and lactoylation, especially those lysine residues in histones [34][35][36]. These post-translational modifications of lysine and its ERPs regulate the structures and functions of enzymes to expand the functional proteome [36], represent the crosstalk between metabolism and epignome [37], and also link cell signaling and metabolic reconfiguration to cell proliferation and differentiation [38]. Thus, all these support that lysine is an important EAA, its ERPs and their modifications play indispensable roles in homeostasis, proliferation, differentiation and diseases including malnutrition and cancer.…”

Section: Glycine Restriction and Supplementmentioning

confidence: 99%

Dietary restriction of amino acids for Cancer therapy

Kang

2020

Nutr Metab (Lond)

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Biosyntheses of proteins, nucleotides and fatty acids, are essential for the malignant proliferation and survival of cancer cells. Cumulating research findings show that amino acid restrictions are potential strategies for cancer interventions. Meanwhile, dietary strategies are popular among cancer patients. However, there is still lacking solid rationale to clarify what is the best strategy, why and how it is. Here, integrated analyses and comprehensive summaries for the abundances, signalling and functions of amino acids in proteomes, metabolism, immunity and food compositions, suggest that, intermittent dietary lysine restriction with normal maize as an intermittent staple food for days or weeks, might have the value and potential for cancer prevention or therapy. Moreover, dietary supplements were also discussed for cancer cachexia including dietary immunomodulatory.

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Section: Glycine Restriction and Supplementmentioning

confidence: 99%

Dietary restriction of amino acids for Cancer therapy

Kang

2020

Nutr Metab (Lond)

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“…An additional ramification of the current results may be in the area of cancer biology, where there has been interest in the potential use of GLO-1 inhibitors to target metabolic vulnerabilities of cancer cells. 51,59 The apparent cardiotoxic effects of SBB-GSH-CpE ( Fig. 6) suggest that caution may be required in the use of such drugs to ensure they do not elicit cardiac toxicity.…”

Section: Discussionmentioning

confidence: 99%

“…While such a finding might cast focus on oxidative stress as a phenotypic driver in Alkbh7 -/- , recent discoveries have implicated the GLO-1/GLO-2 system in epigenetic signaling. Specifically, the product of GLO-1, S-lactoylglutathione (SLG), has been shown to mediate the lactylation of lysine residues ( Gaffney et al, 2020 ), including in histones ( Zhang et al, 2019 ), which may represent a link between metabolism and gene regulation. As such, it is possible that SLG levels may be elevated in Alkbh7 -/- , which could drive epigenetic changes that underlie the phenotypes of the knockout.…”

Section: Discussionmentioning

confidence: 99%

“…As such, it is interesting to speculate whether the mechanisms of ischemic tolerance seen in the male Alkbh7 -/- heart, stemming from GLO-1 upregulation, may also apply to the diabetic heart. An additional ramification of the current results may be in the area of cancer biology, where there has been interest in the potential use of GLO-1 inhibitors to target metabolic vulnerabilities of cancer cells ( Gaffney et al, 2020 ; Rabbani et al, 2018 ). The apparent cardiotoxic effects of SBB-GSH-CpE ( Figure 6 ) suggest that caution may be required in the use of such drugs to ensure they do not elicit cardiac toxicity.…”

Section: Discussionmentioning

confidence: 99%

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ALKBH7 mediates necrosis via rewiring of glyoxal metabolism

Kulkarni

Nadtochiy

Kennedy

et al. 2020

eLife

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Alkb homolog 7 (ALKBH7) is a mitochondrial α-ketoglutarate dioxygenase required for DNA alkylation induced necrosis, but its function and substrates remain unclear. Herein we show ALKBH7 regulates dialdehyde metabolism, which impacts the cardiac response to ischemia-reperfusion (IR) injury. Using a multi-omics approach, we find no evidence ALKBH7 functions as a prolyl-hydroxylase, but we do find Alkbh7-/- mice have elevated glyoxalase I (GLO-1), a dialdehyde detoxifying enzyme. Metabolic pathways related to the glycolytic by-product methylglyoxal (MGO) are rewired in Alkbh7-/- mice, along with elevated levels of MGO protein adducts. Despite greater glycative stress, hearts from Alkbh7-/- mice are protected against IR injury, in a manner blocked by GLO-1 inhibition. Integrating these observations, we propose ALKBH7 regulates glyoxal metabolism, and that protection against necrosis and cardiac IR injury bought on by ALKBH7 deficiency originates from the signaling response to elevated MGO stress.

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“…The investigators identified a non-enzymatic acyl transfer of lactate from LGSH to protein Lys residues of glycolytic enzymes. This "LactoylLys" modification of metabolic proteins characterizes a previously unexplored feedback mechanism for regulation of central metabolism [114]. These studies highlight the interplay between endogenously formed electrophilic metabolites and metabolic regulation of the NRF2-KEAP1 signaling in the EpRE/ARE.…”

Section: Lipid Electrophilesmentioning

confidence: 92%

Electrophile Modulation of Inflammation: A Two-Hit Approach

O’Brien

Wendell

2020

Metabolites

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Electrophilic small molecules have gained significant attention over the last decade in the field of covalent drug discovery. Long recognized as mediators of the inflammatory process, recent evidence suggests that electrophiles may modulate the immune response through the regulation of metabolic networks. These molecules function as pleiotropic signaling mediators capable of reversibly reacting with nucleophilic biomolecules, most notably at reactive cysteines. More specifically, electrophiles target critical cysteines in redox regulatory proteins to activate protective pathways such as the nuclear factor erythroid 2-related factor 2-Kelch-like ECH-associated protein 1 (Nrf2-Keap1) antioxidant signaling pathway while also inhibiting Nuclear Factor κB (NF-κB). During inflammatory states, reactive species broadly alter cell signaling through the oxidation of lipids, amino acids, and nucleic acids, effectively propagating the inflammatory sequence. Subsequent changes in metabolic signaling inform immune cell maturation and effector function. Therapeutic strategies targeting inflammatory pathologies leverage electrophilic drug compounds, in part, because of their documented effect on the redox balance of the cell. With mounting evidence demonstrating the link between redox signaling and metabolism, electrophiles represent ideal therapeutic candidates for the treatment of inflammatory conditions. Through their pleiotropic signaling activity, electrophiles may be used strategically to both directly and indirectly target immune cell metabolism.

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Non-enzymatic Lysine Lactoylation of Glycolytic Enzymes

Cited by 154 publications

References 28 publications

Dietary restriction of amino acids for Cancer therapy

Dietary restriction of amino acids for Cancer therapy

ALKBH7 mediates necrosis via rewiring of glyoxal metabolism

Electrophile Modulation of Inflammation: A Two-Hit Approach

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