Photo by Tiffany Dawn Nicholson
Woman smoking
Smoking can prevent anemia in individuals with a rare hemoglobin mutation, according to research published in the Journal of Biological Chemistry.
The so-called Kirklareli mutation was found to be the cause of mild anemia in a young woman in Germany.
But a smoking habit protected the young woman’s father, who also carried the mutation, from developing anemia.
The Kirklareli mutation is one of more than 1000 discovered so far in adult human hemoglobin.
Most of these mutations appear to have no effect on people, but when medical problems occur, the disease is called a hemoglobinopathy and often named after the city or hospital where it was discovered. In this case, the family was living in Mannheim, Germany, but the father was born in the Turkish city of Kirklareli.
The Kirklareli mutation did not affect the iron content of the father’s blood, but it did appear to be the root cause of the young woman’s chronic anemia, according to researchers.
Further investigation revealed that absorbing carbon monoxide from cigarette smoke is therapeutic for individuals with this rare genetic disorder.
The Kirklareli mutation is in the alpha subunit of human hemoglobin (H58L) and causes it to rapidly auto-oxidize, which causes the protein to fall apart, lose heme, and precipitate. As a result, the protein loses its ability to carry oxygen. Eventually, red cells become deformed and are destroyed.
This mutation also gives the protein an 80,000-fold higher affinity for carbon monoxide than for oxygen. Carbon monoxide from a cigarette will be selectively taken up by the mutant hemoglobin and prevent it from oxidizing and denaturing.
This high affinity for carbon monoxide explained why the father showed no signs of anemia, the researchers said.
“He may never be an athlete because his blood can’t carry as much oxygen, but smoking has prevented him from being anemic,” said study author John Olson, PhD, of Rice University in Houston, Texas.
“And there’s a side benefit. People with this trait are more resistant to carbon monoxide poisoning.”
Dr Olson said he doesn’t know how or if doctors treated the young woman, but he suspects her iron-deficiency anemia was more an annoyance than a threat to her life and would not recommend she start smoking to relieve it.
“She shouldn’t smoke,” Dr Olson said. “But she could take antioxidants, such as a lot of vitamin C, which would help prevent oxidation of her mutant hemoglobin. Her anemia is not that severe. At the same time, she shouldn’t worry too much about secondhand smoke, which might have a positive effect.”
After ruling out common causes of anemia—such as blood loss, gastritis, or congenital defects—the woman’s doctors were curious enough about her ailment to call upon Emmanuel Bissé, MD, PhD, a researcher at Universitätsklinikum Freiburg in Freiburg, Germany, who discovered the Kirklareli mutation after sequencing the woman’s DNA.
Dr Bissé, in turn, recruited Dr Olson and his team to help determine why the histidine-to-leucine change caused anemia in the daughter but not the father.
Coincidentally, Ivan Birukou, a graduate student in Dr Olson’s lab, had already generated the Kirklareli mutation in human hemoglobin to study how the protein rapidly and selectively binds oxygen.
“Emmanuel wrote to me and said, ‘I know you’ve been making all these mutants in hemoglobin, and you’ve probably done the H58L mutation in [alpha] chains. Does this phenotype make sense?’” Dr Olson recalled.
“I said, ‘We can do a really neat study here, because we’ve already made the mutant hemoglobin in a recombinant system.’ We actually had a crystal structure [matching Kirklareli] that Ivan and [staff scientist] Jayashree Soman never published but had deposited in the Protein Data Bank. We had made this mutation to try to understand what the distal histidine was doing in alpha subunits.”
The researchers found in a 2010 study that replacing the histidine, which forms a strong hydrogen bond to oxygen, with leucine caused a dramatic decrease in oxygen affinity and an increase in carbon monoxide binding.
Dr Olson and Birukou realized back then that histidine played a key role in discriminating between oxygen and carbon monoxide in hemoglobin.
“When Emmanuel wrote to me about his discovery, I already ‘knew’ what was happening with respect to carbon monoxide binding,” Dr Olson said.
He said the normal hydrogen bond causes bound oxygen to stick more tightly to hemoglobin in the same way hydrogen bonds cause spilled soda to feel sticky.
“When you touch it, the sugar oxygens and hydrogens make hydrogen bonds with the polysaccharides on your finger,” Dr Olson said. “That stickiness helps hold onto oxygen. But leucine is more like an oil, like butane or hexane, and oxygen does not stick well inside hemoglobin. In contrast, bound carbon monoxide is more like methane or ethane and can’t form hydrogen bonds.”
Andres Benitez Cardenas, PhD, a researcher in Dr Olson’s lab, did the experiment in which he put carbon monoxide on the mutant alpha subunit of hemoglobin Kirklareli. The bound carbon monoxide slowed down oxidation of the protein and prevented loss of heme and precipitation.
“In effect, Andres did the ‘smoking experiment’ to show why the father’s hemoglobin didn’t denature and cause anemia,” Dr Olson said.
He noted that the effect caused by Kirklareli, though unusual, is not unique. Patients with hemoglobin Zurich also have an abnormal form of hemoglobin that more readily binds to carbon monoxide.
