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Aspirin inhibits glucose‑6‑phosphate dehydrogenase activity in HCT 116 cells through acetylation: Identification of aspirin-acetylated sites.

Ai G, Dachineni R, Kumar DR, Alfonso LF, Marimuthu S, Bhat GJ - Mol Med Rep (2016)

Bottom Line: The expression of G6PD is elevated in several types of tumor, including colon, breast and lung cancer, and has been implicated in cancer cell growth.Our previous study demonstrated that exposure of HCT 116 human colorectal cancer cells to aspirin caused acetylation of G6PD, and this was associated with a decrease in its enzyme activity.One of the important amino acid targets of aspirin included lysine 235 (K235, in isoform a) and this corresponds to K205 in isoform b, which has previously been identified as being important for catalysis.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, South Dakota State University College of Pharmacy, Avera Health and Sciences Center, Brookings, SD 57007, USA.

ABSTRACT
Glucose-6-phosphate dehydrogenase (G6PD) catalyzes the first reaction in the pentose phosphate pathway, and generates ribose sugars, which are required for nucleic acid synthesis, and nicotinamide adenine dinucleotide phosphate (NADPH), which is important for neutralization of oxidative stress. The expression of G6PD is elevated in several types of tumor, including colon, breast and lung cancer, and has been implicated in cancer cell growth. Our previous study demonstrated that exposure of HCT 116 human colorectal cancer cells to aspirin caused acetylation of G6PD, and this was associated with a decrease in its enzyme activity. In the present study, this observation was expanded to HT‑29 colorectal cancer cells, in order to compare aspirin‑mediated acetylation of G6PD and its activity between HCT 116 and HT‑29 cells. In addition, the present study aimed to determine the acetylation targets of aspirin on recombinant G6PD to provide an insight into the mechanisms of inhibition. The results demonstrated that the extent of G6PD acetylation was significantly higher in HCT 116 cells compared with in HT‑29 cells; accordingly, a greater reduction in G6PD enzyme activity was observed in the HCT 116 cells. Mass spectrometry analysis of aspirin‑acetylated G6PD (isoform a) revealed that aspirin acetylated a total of 14 lysine residues, which were dispersed throughout the length of the G6PD protein. One of the important amino acid targets of aspirin included lysine 235 (K235, in isoform a) and this corresponds to K205 in isoform b, which has previously been identified as being important for catalysis. Acetylation of G6PD at several sites, including K235 (K205 in isoform b), may mediate inhibition of G6PD activity, which may contribute to the ability of aspirin to exert anticancer effects through decreased synthesis of ribose sugars and NADPH.

No MeSH data available.


Related in: MedlinePlus

3-Dimension space-filling model of recombinant glucose-6-phosphate dehydrogenase (G6PD; NP_000393), is shown. The location of aspirin-acetylated lysine residues are highlighted in blue (K77, K112, K119, K201, K235, K390, K396, K416, K438, K459, K462, K527, K538, K544).
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f4-mmr-14-02-1726: 3-Dimension space-filling model of recombinant glucose-6-phosphate dehydrogenase (G6PD; NP_000393), is shown. The location of aspirin-acetylated lysine residues are highlighted in blue (K77, K112, K119, K201, K235, K390, K396, K416, K438, K459, K462, K527, K538, K544).

Mentions: Molecular modeling of recombinant G6PD (NCBI accession no: NP_000393) demonstrated that the majority of the aspirin-acetylated lysine residues are surface-exposed/solvent accessible (Fig. 4). The ability of aspirin to acetylate G6PD in vitro suggests that it is a non-enzymatic chemical reaction, consistent with its ability to acetylate numerous other proteins in-vitro (23).


Aspirin inhibits glucose‑6‑phosphate dehydrogenase activity in HCT 116 cells through acetylation: Identification of aspirin-acetylated sites.

Ai G, Dachineni R, Kumar DR, Alfonso LF, Marimuthu S, Bhat GJ - Mol Med Rep (2016)

3-Dimension space-filling model of recombinant glucose-6-phosphate dehydrogenase (G6PD; NP_000393), is shown. The location of aspirin-acetylated lysine residues are highlighted in blue (K77, K112, K119, K201, K235, K390, K396, K416, K438, K459, K462, K527, K538, K544).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4940102&req=5

f4-mmr-14-02-1726: 3-Dimension space-filling model of recombinant glucose-6-phosphate dehydrogenase (G6PD; NP_000393), is shown. The location of aspirin-acetylated lysine residues are highlighted in blue (K77, K112, K119, K201, K235, K390, K396, K416, K438, K459, K462, K527, K538, K544).
Mentions: Molecular modeling of recombinant G6PD (NCBI accession no: NP_000393) demonstrated that the majority of the aspirin-acetylated lysine residues are surface-exposed/solvent accessible (Fig. 4). The ability of aspirin to acetylate G6PD in vitro suggests that it is a non-enzymatic chemical reaction, consistent with its ability to acetylate numerous other proteins in-vitro (23).

Bottom Line: The expression of G6PD is elevated in several types of tumor, including colon, breast and lung cancer, and has been implicated in cancer cell growth.Our previous study demonstrated that exposure of HCT 116 human colorectal cancer cells to aspirin caused acetylation of G6PD, and this was associated with a decrease in its enzyme activity.One of the important amino acid targets of aspirin included lysine 235 (K235, in isoform a) and this corresponds to K205 in isoform b, which has previously been identified as being important for catalysis.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, South Dakota State University College of Pharmacy, Avera Health and Sciences Center, Brookings, SD 57007, USA.

ABSTRACT
Glucose-6-phosphate dehydrogenase (G6PD) catalyzes the first reaction in the pentose phosphate pathway, and generates ribose sugars, which are required for nucleic acid synthesis, and nicotinamide adenine dinucleotide phosphate (NADPH), which is important for neutralization of oxidative stress. The expression of G6PD is elevated in several types of tumor, including colon, breast and lung cancer, and has been implicated in cancer cell growth. Our previous study demonstrated that exposure of HCT 116 human colorectal cancer cells to aspirin caused acetylation of G6PD, and this was associated with a decrease in its enzyme activity. In the present study, this observation was expanded to HT‑29 colorectal cancer cells, in order to compare aspirin‑mediated acetylation of G6PD and its activity between HCT 116 and HT‑29 cells. In addition, the present study aimed to determine the acetylation targets of aspirin on recombinant G6PD to provide an insight into the mechanisms of inhibition. The results demonstrated that the extent of G6PD acetylation was significantly higher in HCT 116 cells compared with in HT‑29 cells; accordingly, a greater reduction in G6PD enzyme activity was observed in the HCT 116 cells. Mass spectrometry analysis of aspirin‑acetylated G6PD (isoform a) revealed that aspirin acetylated a total of 14 lysine residues, which were dispersed throughout the length of the G6PD protein. One of the important amino acid targets of aspirin included lysine 235 (K235, in isoform a) and this corresponds to K205 in isoform b, which has previously been identified as being important for catalysis. Acetylation of G6PD at several sites, including K235 (K205 in isoform b), may mediate inhibition of G6PD activity, which may contribute to the ability of aspirin to exert anticancer effects through decreased synthesis of ribose sugars and NADPH.

No MeSH data available.


Related in: MedlinePlus