In a new study, MIT biological engineers have found that defects in enzymes that control purines can severely alter a cell’s DNA sequences, which may explain why people who carry certain genetic variants of purine metabolic enzymes have a higher risk for some types of cancer.
Many critical cell functions depend on a class of molecules called purines, which form half of the building blocks of DNA and RNA, and are a major component of the chemicals that store a cell’s energy. Cells keep tight control over their purine supply, and any disruption of that pool can have serious consequences.
“A cell needs to control the concentrations very carefully so that it has just the right amount of building blocks when it’s synthesizing DNA. If the cell has an imbalance in the concentrations of those nucleotides, it’s going to make a mistake,” says Peter Dedon, a professor of biological engineering at MIT and senior author of the study.
In addition to forming the backbone of DNA and RNA, purines are also a major component of ATP, the cell’s energy currency; other molecules that manage a cell’s energy flow; and small chemical cofactors required for the activity of thousands of cell enzymes.
Dozens of enzymes are involved in purine metabolism, and it has long been known that malfunction of those enzymes can have adverse effects.
Abnormal purine metabolism can also lead to side effects for people taking a class of drugs called thiopurines. In some people, these drugs, often used to treat leukemia, lymphoma, Crohn’s disease, rheumatoid arthritis and organ-transplant rejection, can be metabolized into toxic compounds. Genetic testing can reveal which patients should avoid thiopurine drugs.
In the new study, Mr Dedon and his colleagues disrupted about half a dozen purine metabolism enzymes in E. coli and yeast. After altering the enzymes, the researchers measured how much xanthine and hypoxanthine was integrated into the cells’ DNA and RNA, using a highly sensitive mass spectrometry technique.
The researchers found that the malfunctioning enzymes could produce dramatic increases - up to 1,000-fold - in the amounts of hypoxanthine incorporated into DNA and RNA in place of adenine. However, they saw very little change in the amount of xanthine inserted in place of guanine.
Have your say and discuss with your peers on the InfoGrok community.