Structural basis for allosteric regulation of pyruvate kinase M2 by phosphorylation and acetylation

Razzaghi, Mortezaali; Srivastava, Dhiraj; Dey, Mishtu

doi:10.1074/jbc.ra120.015800

Cited by 35 publications

(30 citation statements)

References 57 publications

(102 reference statements)

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“…In mature neurons, PKM1 is the dominant isoform and is enzymatically constitutively active, while in immature neurons, PKM2 is the dominant isoform, and its enzymatic activity is allosterically controlled ( Su et al, 2017 ; Nandi et al, 2020 ). The enzymatic activity of PKM2 depends on if PKM2 is a dimer or tetramer.…”

Section: Resultsmentioning

confidence: 99%

Metabolic Reprogramming in HIV-Associated Neurocognitive Disorders

Allen

Arjona

Santerre

et al. 2022

Front. Cell. Neurosci.

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A significant number of patients infected with HIV-1 suffer from HIV-associated neurocognitive disorders (HAND) such as spatial memory impairments and learning disabilities (SMI-LD). SMI-LD is also observed in patients using combination antiretroviral therapy (cART). Our lab has demonstrated that the HIV-1 protein, gp120, promotes SMI-LD by altering mitochondrial functions and energy production. We have investigated cellular processes upstream of the mitochondrial functions and discovered that gp120 causes metabolic reprogramming. Effectively, the addition of gp120 protein to neuronal cells disrupted the glycolysis pathway at the pyruvate level. Looking for the players involved, we found that gp120 promotes increased expression of polypyrimidine tract binding protein 1 (PTBP1), causing the splicing of pyruvate kinase M (PKM) into PKM1 and PKM2. We have also shown that these events lead to the accumulation of advanced glycation end products (AGEs) and prevent the cleavage of pro-brain-derived neurotrophic factor (pro-BDNF) protein into mature brain-derived neurotrophic factor (BDNF). The accumulation of proBDNF results in signaling that increases the expression of the inducible cAMP early repressor (ICER) protein which then occupies the cAMP response element (CRE)-binding sites within the BDNF promoters II and IV, thus altering normal synaptic plasticity. We reversed these events by adding Tepp-46, which stabilizes the tetrameric form of PKM2. Therefore, we concluded that gp120 reprograms cellular metabolism, causing changes linked to disrupted memory in HIV-infected patients and that preventing the disruption of the metabolism presents a potential cure against HAND progression.

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Section: Resultsmentioning

confidence: 99%

Metabolic Reprogramming in HIV-Associated Neurocognitive Disorders

Allen

Arjona

Santerre

et al. 2022

Front. Cell. Neurosci.

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“…Fructose 1,6‐bisphosphate (FBP) activates the association of PKM2 monomer to become tetrameric, leading to an increase in PKM2 activity (Ashizawa et al, 1991). However, FBP fails to activate PKM2 variants, K433E and S37E/K433E, suggesting that an acetyl‐lysine or a phosphoserine mimetic can undergo dimerization while PKM2 exists in a tetrameric state in presence of certain concentration FBP (Nandi et al, 2020).…”

Section: Overview Of Pkm2mentioning

confidence: 99%

Multiple functions of pyruvate kinase M2 in various cell types

Lee

Min

Kim

et al. 2021

Journal Cellular Physiology

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Glucose metabolism is a mechanism by which energy is produced in form of adenosine triphosphate (ATP) by mitochondria and precursor metabolites are supplied to enable the ultimate enrichment of mature metabolites in the cell. Recently, glycolytic enzymes have been shown to have unconventional but important functions. Among these enzymes, pyruvate kinase M2 (PKM2) plays several roles including having conventional metabolic enzyme activity, and also being a transcriptional regulator and a protein kinase. Compared with the closely related PKM1, PKM2 is highly expressed in cancer cells and embryos, whereas PKM1 is dominant in mature, differentiated cells. Posttranslational modifications such as phosphorylation and acetylation of PKM2 change its cellular functions. In particular, PKM2 can translocate to the nucleus, where it regulates the transcription of many target genes. It is notable that PKM2 also acts as a protein kinase to phosphorylate several substrate proteins. Besides cancer cells and embryonic cells, astrocytes also highly express PKM2, which is crucial for lactate production via expression of lactate dehydrogenase A (LDHA), while mature neurons predominantly express PKM1. The lactate produced in cancer cells promotes tumor progress and that in astrocytes can Yoon-Beom Lee and Jung Ki Min contributed equally to this study.

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“…Structure analyses of PKM2 showed that a phosphomimicking mutation at S37 alters key residues in the FBP-binding pocket and reduces metabolic activity of PKM2, underscoring the role of PKM2 S37 phosphorylation in switching its metabolic function to nonmetabolic functions [58].…”

Section: Enolasementioning

confidence: 96%