Chemical genetics and its application to moonlighting in glycolytic enzymes

Jung, Da Woon; Kim, Woong‐Hee; Williams, Darren R.

doi:10.1042/bst20140201

Cited by 21 publications

(16 citation statements)

References 44 publications

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“…Other glycolytic enzymes such as phosphofructokinase 1, aldolase and triose phosphate isomerase, phosphoglycerate mutase, and pyruvate kinase have all been reported to take part in several cellular functions that have a direct relation to tumorigenesis. Hence, it is entirely plausible that individually or collectively, the glycolytic enzymes and in particular GAPDH may constitute integral parts of the MDR phenotype by acting in a non-canonical fashion ( 37 ).…”

Section: Introductionmentioning

confidence: 99%

Metabolic Reprogramming During Multidrug Resistance in Leukemias

et al. 2018

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Cancer outcome has improved since introduction of target therapy. However, treatment success is still impaired by the same drug resistance mechanism of classical chemotherapy, known as multidrug resistance (MDR) phenotype. This phenotype promotes resistance to drugs with different structures and mechanism of action. Recent reports have shown that resistance acquisition is coupled to metabolic reprogramming. High-gene expression, increase of active transport, and conservation of redox status are one of the few examples that increase energy and substrate demands. It is not clear if the role of this metabolic shift in the MDR phenotype is related to its maintenance or to its induction. Apart from the nature of this relation, the metabolism may represent a new target to avoid or to block the mechanism that has been impairing treatment success. In this mini-review, we discuss the relation between metabolism and MDR resistance focusing on the multiple non-metabolic functions that enzymes of the glycolytic pathway are known to display, with emphasis with the diverse activities of glyceraldehyde-3-phosphate dehydrogenase.

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Section: Introductionmentioning

confidence: 99%

Metabolic Reprogramming During Multidrug Resistance in Leukemias

et al. 2018

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“…The above considerations led to the hypothesis of targeting ENO1 to simultaneously disturb cancer cells in multiple ways. An interesting report by Jung et al described a different cell permeable glycolysis inhibitor (AP-III-a4) able to bind the outer active site of ENO1 hence dubbed “ENOblock” [ 114 , 115 ]. However, it was reported that ENOblock is not able to inhibit ENO1 activity in vitro [ 116 ].…”

Section: Eno1 As Metabolic Target In Cancer Treatmentmentioning

confidence: 99%

Next Generation Immunotherapy for Pancreatic Cancer: DNA Vaccination is Seeking New Combo Partners

Cappello

Curcio

Mandili

et al. 2018

Cancers

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Pancreatic Ductal Adenocarcinoma (PDA) is an almost incurable radio- and chemo-resistant tumor, and its microenvironment is characterized by a strong desmoplastic reaction associated with a significant infiltration of T regulatory lymphocytes and myeloid-derived suppressor cells (Tregs, MDSC). Investigating immunological targets has identified a number of metabolic and cytoskeletal related molecules, which are typically recognized by circulating antibodies. Among these molecules we have investigated alpha-enolase (ENO1), a glycolytic enzyme that also acts a plasminogen receptor. ENO1 is also recognized by T cells in PDA patients, so we developed a DNA vaccine that targets ENO1. This efficiently induces many immunological processes (antibody formation and complement-dependent cytotoxicity (CDC)-mediated tumor killing, infiltration of effector T cells, reduction of infiltration of myeloid and Treg suppressor cells), which significantly increase the survival of genetically engineered mice that spontaneously develop pancreatic cancer. Although promising, the ENO1 DNA vaccine does not completely eradicate the tumor, which, after an initial growth inhibition, returns to proliferate again, especially when Tregs and MDSC ensue in the tumor mass. This led us to develop possible strategies for combinatorial treatments aimed to broaden and sustain the antitumor immune response elicited by DNA vaccination. Based on the data we have obtained in recent years, this review will discuss the biological bases of possible combinatorial treatments (chemotherapy, PI3K inhibitors, tumor-associated macrophages, ENO1 inhibitors) that could be effective in amplifying the response induced by the immune vaccination in PDA.

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“…Therefore, even for extensively characterized proteins, deciphering protein functions is highly enigmatic when precisely delineating how they perform their roles in a specific cellular context ( Henderson and Martin, 2014 ). Numerous enzymes of the glycolytic pathway reflect such dynamic behavior in which the prevailing view of the individual glycolytic enzymes as proteins with well-designated catalytic functions and structural properties has been revised ( Jeffery, 2009 ; Jung et al, 2014b ; Menard et al, 2014 ). Multiple glycolytic enzymes have been more recently classified as proteins with non-canonical roles ( Dai et al, 2008 ; Jung et al, 2014a ; Rawat et al, 2012 ; Subramanian and Miller, 2000 ).…”

Section: Introductionmentioning

confidence: 99%

Novel myristoylation of the sperm-specific hexokinase 1 isoform regulates its atypical localization

2015

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The hexokinase 1 variant in mammalian spermatozoa (HK1S) has a unique N-terminus and this isoform atypically localizes to the plasma membrane. However, the mechanism of this process currently remains ambiguous. In this report, we show that fatty acylation underlies the specific sorting of HK1S. Employing chimeric reporter constructs, we first established that compartmentalization of HK1S does not function exclusively in sperm cells and that this feature is swappable to somatic HEK293 cells. Although the N-terminus lacks the classical consensus signature for myristoylation and the sequence-based predictions fail to predict myristoylation of HK1S, complementary experimental approaches confirmed that HK1S is myristoylated. Using live-cell confocal microscopy, we show that the mutation of a single amino acid, the myristoyl recipient Gly2, impedes the prominent feature of plasma membrane association and relocates the enzyme to the cytosol but not the nucleus. Additionally, substitutions of the putatively palmitoylated Cys5 is also reflected in a similar loss of compartmentalization of the protein. Taken together, our findings conclusively demonstrate that the N-terminal ‘MGQICQ’ motif in the unique GCS domain of HK1S acquires hydrophobicity by dual lipidic modifications, N-myristoylation and palmitoylation, to serve the requirements for membranous associations and thus its compartmentalization.

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Chemical genetics and its application to moonlighting in glycolytic enzymes

Cited by 21 publications

References 44 publications

Metabolic Reprogramming During Multidrug Resistance in Leukemias

Metabolic Reprogramming During Multidrug Resistance in Leukemias

Next Generation Immunotherapy for Pancreatic Cancer: DNA Vaccination is Seeking New Combo Partners

Novel myristoylation of the sperm-specific hexokinase 1 isoform regulates its atypical localization

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