Molecular association of glucose-6-phosphate isomerase and pyruvate kinase M2 with glyceraldehyde-3-phosphate dehydrogenase in cancer cells View Full Text


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Article Info

DATE

2016-02-24

AUTHORS

Mahua R. Das, Arup K. Bag, Shekhar Saha, Alok Ghosh, Sumit K. Dey, Provas Das, Chitra Mandal, Subhankar Ray, Saikat Chakrabarti, Manju Ray, Siddhartha S. Jana

ABSTRACT

BACKGROUND: For a long time cancer cells are known for increased uptake of glucose and its metabolization through glycolysis. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a key regulatory enzyme of this pathway and can produce ATP through oxidative level of phosphorylation. Previously, we reported that GAPDH purified from a variety of malignant tissues, but not from normal tissues, was strongly inactivated by a normal metabolite, methylglyoxal (MG). Molecular mechanism behind MG mediated GAPDH inhibition in cancer cells is not well understood. METHODS: GAPDH was purified from Ehrlich ascites carcinoma (EAC) cells based on its enzymatic activity. GAPDH associated proteins in EAC cells and 3-methylcholanthrene (3MC) induced mouse tumor tissue were detected by mass spectrometry analysis and immunoprecipitation (IP) experiment, respectively. Interacting domains of GAPDH and its associated proteins were assessed by in silico molecular docking analysis. Mechanism of MG mediated GAPDH inactivation in cancer cells was evaluated by measuring enzyme activity, Circular dichroism (CD) spectroscopy, IP and mass spectrometry analyses. RESULT: Here, we report that GAPDH is associated with glucose-6-phosphate isomerase (GPI) and pyruvate kinase M2 (PKM2) in Ehrlich ascites carcinoma (EAC) cells and also in 3-methylcholanthrene (3MC) induced mouse tumor tissue. Molecular docking analyses suggest C-terminal domain preference for the interaction between GAPDH and GPI. However, both C and N termini of PKM2 might be interacting with the C terminal domain of GAPDH. Expression of both PKM2 and GPI is increased in 3MC induced tumor compared with the normal tissue. In presence of 1 mM MG, association of GAPDH with PKM2 or GPI is not perturbed, but the enzymatic activity of GAPDH is reduced to 26.8 ± 5 % in 3MC induced tumor and 57.8 ± 2.3 % in EAC cells. Treatment of MG to purified GAPDH complex leads to glycation at R399 residue of PKM2 only, and changes the secondary structure of the protein complex. CONCLUSION: PKM2 may regulate the enzymatic activity of GAPDH. Increased enzymatic activity of GAPDH in tumor cells may be attributed to its association with PKM2 and GPI. Association of GAPDH with PKM2 and GPI could be a signature for cancer cells. Glycation at R399 of PKM2 and changes in the secondary structure of GAPDH complex could be one of the mechanisms by which GAPDH activity is inhibited in tumor cells by MG. More... »

PAGES

152

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/s12885-016-2172-x

DOI

http://dx.doi.org/10.1186/s12885-016-2172-x

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1008234053

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/26911935


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28 schema:description BACKGROUND: For a long time cancer cells are known for increased uptake of glucose and its metabolization through glycolysis. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a key regulatory enzyme of this pathway and can produce ATP through oxidative level of phosphorylation. Previously, we reported that GAPDH purified from a variety of malignant tissues, but not from normal tissues, was strongly inactivated by a normal metabolite, methylglyoxal (MG). Molecular mechanism behind MG mediated GAPDH inhibition in cancer cells is not well understood. METHODS: GAPDH was purified from Ehrlich ascites carcinoma (EAC) cells based on its enzymatic activity. GAPDH associated proteins in EAC cells and 3-methylcholanthrene (3MC) induced mouse tumor tissue were detected by mass spectrometry analysis and immunoprecipitation (IP) experiment, respectively. Interacting domains of GAPDH and its associated proteins were assessed by in silico molecular docking analysis. Mechanism of MG mediated GAPDH inactivation in cancer cells was evaluated by measuring enzyme activity, Circular dichroism (CD) spectroscopy, IP and mass spectrometry analyses. RESULT: Here, we report that GAPDH is associated with glucose-6-phosphate isomerase (GPI) and pyruvate kinase M2 (PKM2) in Ehrlich ascites carcinoma (EAC) cells and also in 3-methylcholanthrene (3MC) induced mouse tumor tissue. Molecular docking analyses suggest C-terminal domain preference for the interaction between GAPDH and GPI. However, both C and N termini of PKM2 might be interacting with the C terminal domain of GAPDH. Expression of both PKM2 and GPI is increased in 3MC induced tumor compared with the normal tissue. In presence of 1 mM MG, association of GAPDH with PKM2 or GPI is not perturbed, but the enzymatic activity of GAPDH is reduced to 26.8 ± 5 % in 3MC induced tumor and 57.8 ± 2.3 % in EAC cells. Treatment of MG to purified GAPDH complex leads to glycation at R399 residue of PKM2 only, and changes the secondary structure of the protein complex. CONCLUSION: PKM2 may regulate the enzymatic activity of GAPDH. Increased enzymatic activity of GAPDH in tumor cells may be attributed to its association with PKM2 and GPI. Association of GAPDH with PKM2 and GPI could be a signature for cancer cells. Glycation at R399 of PKM2 and changes in the secondary structure of GAPDH complex could be one of the mechanisms by which GAPDH activity is inhibited in tumor cells by MG.
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35 schema:keywords ATP
36 EAC cells
37 Ehrlich
38 GAPDH activity
39 GAPDH complex
40 GAPDH complex leads
41 GAPDH inactivation
42 GAPDH inhibition
43 IP
44 PKM2
45 R399
46 R399 of PKM2
47 R399 residue
48 Treatment of methylglyoxal
49 activity
50 analysis
51 association
52 association of GAPDH
53 cancer cells
54 carcinoma cells
55 cells
56 changes
57 circular dichroism spectroscopy
58 complex lead
59 complexes
60 dehydrogenase
61 dichroism spectroscopy
62 docking analysis
63 domain
64 domain preference
65 domains of GAPDH
66 enzymatic activity
67 enzyme
68 enzyme activity
69 experiments
70 expression
71 glucose
72 glucose-6-phosphate isomerase
73 glycation
74 glyceraldehyde-3-phosphate dehydrogenase
75 glycolysis
76 immunoprecipitation experiments
77 inactivation
78 inhibition
79 interaction
80 isomerase
81 key regulatory enzyme
82 kinase M2
83 lead
84 levels
85 long time cancer cells
86 m2
87 mM methylglyoxal
88 malignant tissues
89 mass spectrometry analysis
90 mechanism
91 mechanism of methylglyoxal
92 metabolites
93 metabolization
94 methylglyoxal
95 molecular association
96 molecular docking analysis
97 molecular mechanisms
98 mouse tumor tissues
99 normal metabolite
100 normal tissues
101 oxidative levels
102 pathway
103 phosphorylation
104 preferences
105 presence
106 protein
107 protein complexes
108 pyruvate kinase M2
109 regulatory enzyme
110 residues
111 secondary structure
112 signatures
113 silico molecular docking analysis
114 spectrometry analysis
115 spectroscopy
116 structure
117 terminal domain
118 terminal domain preference
119 termini of PKM2
120 terminus
121 time cancer cells
122 tissue
123 treatment
124 tumor cells
125 tumor tissue
126 tumors
127 uptake
128 uptake of glucose
129 variety
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