Enzymatic properties of the N- and C-terminal halves of human hexokinase II

Ahn, Keun Jae; Kim, Jongsun; Yun, Mijin; Park, Jeon Han; Lee, Jong Doo

doi:10.5483/bmbrep.2009.42.6.350

Cited by 31 publications

(26 citation statements)

References 26 publications

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“…In considering the mechanism by which phosphorylation of HK-II at Thr-473 leads to an increase in mitochondrial HK-II binding, we determined whether dissociation of HK-II induced by G-6P was affected by phosphorylation. We found that mitochondrial binding of WT HK-II is inhibited in the range of 0.1–3 m m , which is in agreement with G-6P concentration increases of ∼0.17 to ∼1.3 m m in perfused working heart (52) and with the reported IC 50 of G-6P versus HK-II (53, 54). Our finding that the T473D mutant is more resistant to G-6P-dependent dissociation than the WT or the non-phosphorylatable mutant (T473A, Fig 6, A and B ) strongly suggests that phosphorylation of Thr-473 decreases the sensitivity of HK-II to G-6P-induced mitochondrial dissociation and, thereby, increases mitochondrial HK-II.…”

Section: Discussionsupporting

confidence: 89%

Akt Phosphorylates HK-II at Thr-473 and Increases Mitochondrial HK-II Association to Protect Cardiomyocytes

Roberts

Tan-Sah

Smith

et al. 2013

Journal of Biological Chemistry

199

185

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Backgound: Hexokinase II binds to mitochondria and promotes cell survival.Results: Akt phosphorylates HK-II but not the threonine 473 mutant. The phosphomimetic T473D mutant decreases its dissociation from mitochondria induced by G-6P and increases cell viability against stress.Conclusion: Akt phosphorylates HK-II at Thr-473, resulting in increased mitochondrial HK-II and cell protection.Significance: The Akt-HK-II signaling nexus is important in cell survival.

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Section: Discussionsupporting

confidence: 89%

Akt Phosphorylates HK-II at Thr-473 and Increases Mitochondrial HK-II Association to Protect Cardiomyocytes

Roberts

Tan-Sah

Smith

et al. 2013

Journal of Biological Chemistry

199

185

View full text Add to dashboard Cite

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“…A promising strategy has been to use pHK, a peptide that corresponds to the VDAC‐binding N‐terminal 15 aa of HKII, to selectively dissociate HKII from mitochondria to inhibit activity of the enzyme (60) and trigger apoptosis (16). As pHK is poorly cell permeable (Figs.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, whereas elevated levels of mitochondria‐associated HKII are needed to maintain the high glycolytic rates that are necessary for energy production and biomolecule synthesis in rapidly dividing cancer cells, noncancerous cells rely on oxphos as their primary energy‐generating pathway (1, 3, 14, 15). Thus, dissociation of HKII from mitochondria, which inhibits the enzyme's activity (60), is far less detrimental to noncancerous cells compared with cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Hexokinase II–derived cell‐penetrating peptide targets mitochondria and triggers apoptosis in cancer cells

et al. 2017

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Overexpression of mitochondria-bound hexokinase II (HKII) in cancer cells plays an important role in their metabolic reprogramming and protects them against apoptosis, thereby facilitating their growth and proliferation. Here, we show that covalently coupling a peptide corresponding to the mitochondrial membrane–binding N-terminal 15 aa of HKII (pHK) to a short, penetration-accelerating sequence (PAS) enhances the cellular uptake, mitochondrial localization, and cytotoxicity of the peptide in HeLa cells. Further analysis revealed that pHK-PAS depolarized mitochondrial membrane potential, inhibited mitochondrial respiration and glycolysis, and depleted intracellular ATP levels. The effects of pHK-PAS were correlated with dissociation of endogenous full-length HKII from mitochondria and release of cytochrome c. Of significance, pHK-PAS treatment of noncancerous HEK293 cells resulted in substantially lower cytotoxicity. Thus, pHK-PAS effectively disrupted the mitochondria-HKII association in cancer cells, which led to mitochondrial dysfunction and, finally, apoptosis. Our results demonstrate the potential of the pHK-PAS cell-penetrating peptide as a novel therapeutic strategy in cancer.—Woldetsadik, A. D., Vogel, M. C., Rabeh, W. M., Magzoub, M. Hexokinase II–derived cell-penetrating peptide targets mitochondria and triggers apoptosis in cancer cells.

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“…A continuous supply of glucose to HK maintains this activity at a constant level and controls the flux through the mitochondrial electron transport chain, influencing mitochondrial ROS production [152]. HK binds through hydrophobic interaction to VDAC1, the prevalent pore protein in the outer mitochondrial membrane [24, 82, 143–146], thereby assuring and gaining a preferential access to ATP [82, 150, 153]. Translocation of HK2 from the cytosol to the mitochondria is regulated through phosphorylation of HK by Akt [141]; HK2 only binds VDAC after phosphorylation by Akt [151, 152].…”

Section: Effects Of Jasmonates On Mammalian Cancer Cellsmentioning

confidence: 99%

Methyl Jasmonate: Putative Mechanisms of Action on Cancer Cells Cycle, Metabolism, and Apoptosis

Cesari

Carvalho

Rodrigues

et al. 2014

International Journal of Cell Biology

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Methyl jasmonate (MJ), an oxylipid that induces defense-related mechanisms in plants, has been shown to be active against cancer cells both in vitro and in vivo, without affecting normal cells. Here we review most of the described MJ activities in an attempt to get an integrated view and better understanding of its multifaceted modes of action. MJ (1) arrests cell cycle, inhibiting cell growth and proliferation, (2) causes cell death through the intrinsic/extrinsic proapoptotic, p53-independent apoptotic, and nonapoptotic (necrosis) pathways, (3) detaches hexokinase from the voltage-dependent anion channel, dissociating glycolytic and mitochondrial functions, decreasing the mitochondrial membrane potential, favoring cytochrome c release and ATP depletion, activating pro-apoptotic, and inactivating antiapoptotic proteins, (4) induces reactive oxygen species mediated responses, (5) stimulates MAPK-stress signaling and redifferentiation in leukemia cells, (6) inhibits overexpressed proinflammatory enzymes in cancer cells such as aldo-keto reductase 1 and 5-lipoxygenase, and (7) inhibits cell migration and shows antiangiogenic and antimetastatic activities. Finally, MJ may act as a chemosensitizer to some chemotherapics helping to overcome drug resistant. The complete lack of toxicity to normal cells and the rapidity by which MJ causes damage to cancer cells turn MJ into a promising anticancer agent that can be used alone or in combination with other agents.

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Enzymatic properties of the N- and C-terminal halves of human hexokinase II

Cited by 31 publications

References 26 publications

Akt Phosphorylates HK-II at Thr-473 and Increases Mitochondrial HK-II Association to Protect Cardiomyocytes

Akt Phosphorylates HK-II at Thr-473 and Increases Mitochondrial HK-II Association to Protect Cardiomyocytes

Hexokinase II–derived cell‐penetrating peptide targets mitochondria and triggers apoptosis in cancer cells

Methyl Jasmonate: Putative Mechanisms of Action on Cancer Cells Cycle, Metabolism, and Apoptosis

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