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Adriamycin inhibits glycolysis through downregulation of key enzymes in Saccharomyces cerevisiae.

ABSTRACT: Adriamycin is a widely used drug for the treatment of various types of cancers, but its clinical application is limited because of irreversible dilated cardiomyopathy. The incidence of cardiomyopathy is a consequence of disrupted energy production, which could be related to the defects in glycogen, lipid and mucopolysaccharide metabolism. We explored the effect of Adriamycin on enzymes involved in glycolysis and apoptotic genes through molecular docking. We used Saccharomyces cerevisiae as model organism and studied the effect of Adriamycin on selected enzymes involved in glycolysis. The docking studies revealed that Adriamycin interacts with phosphofructokinase and enolase in an efficient manner. In phosphofructokinase, Adriamycin binds at the active site and with enolase the drug interacts at the cofactor-binding site (Mg²⁺) which might impair the activity of the enzyme. Gene expression studies revealed that Adriamycin causes the dysregulation of glycolysis through dysregulation of hexokinase, phosphoglycerate mutase, enolase and downregulation of pyruvate kinase. The drug shows a biphasic effect on the expression of genes enolase and pyruvate kinase. The impairment in glycolysis might reduce the ATP synthesis, and the cells might be deprived of energy. The condition is further worsened by elevated ROS levels triggering the cell to undergo apoptosis evidenced by downregulation of SOD and upregulation of BAX and caspase. In conclusion, our study reveals that Adriamycin impairs glycolysis and cause cell to undergo apoptosis due to oxidative stress in yeast cells.

SUBMITTER: Mohan UP

PROVIDER: S-EPMC7778664 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Thioredoxins are small proteins that regulate the cellular redox state, prevent oxidative damage, and play an active role in cell repair. Oxidative stress has proven to be of much relevance in biotechnological processes when the metabolism of Saccharomyces cerevisiae is mainly respiratory. During wine yeast starter production, active dry yeast cytosolic thioredoxin Trx2p is a key player in protecting metabolic enzymes from being oxidized by carbonylation. Less is known about the role of redox control during grape juice fermentation. A mutant strain that lacked both cytosolic thioredoxins, Trx1p and Trx2p, was tested for grape juice fermentation. Its growth and sugar consumption were greatly impaired, which indicates the system's relevance under fermentative conditions. A proteomic analysis indicated that deletion of the genes TRX1 and TRX2 caused a reduction in the ribosomal proteins and factors involved in translation elongation in addition to enzymes for glycolysis and amino acid biosynthesis. A metabolomic analysis of the trx1Δ trx2Δ mutant showed an increase in most proteogenic amino acids, phospholipids, and sphingolipids and higher fatty acid desaturase Ole1p content. Low glycolytic activity was behind the reduced growth and fermentative capacity of the thioredoxin deletion strain. All three hexokinases were downregulated in the mutant strain, but total hexokinase activity remained, probably due to posttranslational regulation. Pyruvate kinase Cdc19p presented an early level of aggregation in the trx1Δ trx2Δ mutant, which may contribute to a diminished hexose metabolism and trigger regulatory mechanisms that could influence the level of glycolytic enzymes.IMPORTANCE Oxidative stress is a common hazardous condition that cells have to face in their lifetime. Oxidative damage may diminish cell vitality and viability by reducing metabolism and eventually leading to aging and ultimate death. Wine yeast Saccharomyces cerevisiae also faces oxidative attack during its biotechnological uses. One of the main yeast antioxidant systems involves two small proteins called thioredoxins. When these two proteins are removed, wine yeast shows diminished growth, protein synthesis, and sugar metabolism under wine-making conditions, and amino acid and lipid metabolism are also affected. Altogether, our results indicate that proper redox regulation is a key factor for metabolic adaptations during grape juice fermentation.

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Adriamycin inhibits glycolysis through downregulation of key enzymes in Saccharomyces cerevisiae.

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