SCIENCE & TECHNOLOGY LIFE
AND
DEATH
UNDERSTANDING BLOOD TYPES Subtle differences in the carbohydrates on red blood cells determine blood type AMANDA YARNELL, C&EN WASHINGTON
F
OR JESICA SANTILLAN,
the eight-carbon sugar JV-acetylgalactosamine made the difference between life and death. In early February the 17-year-old transplant patient at Duke University Medical Center received a new heart and lung. But this potentially lifesaving gift proved fatal when, as a result of a blood-type mismatch, her body rejected the donated organs. Human blood types are determined by subde differences in the sugars displayed on the surface of red blood cells. The type-A organs that Santillan received were decorated with polysaccharides tipped with Nacetylgalactosamine—but the same polysaccharide on the red blood cells in her own type-O blood lacked this terminal sugar. "Remarkably small differences in the chemical structures of these polysaccharides can lead to potentially fatal consequences," says chemistry professor Monica M. Palcic of the University of Alberta. In fact, the difference between type-Aand type-B blood is even smaller: The terminal sugars on type-A and type-B polysaccharides differ in structure by only a single substituent, an acetamido group instead of a hydroxyl group. Practically speaking, knowing which sugars your red blood cells show off is crucial for successful transplants and transfusions —a mismatch triggers an immune response that can lead to hypotension, shock, liver failure, and even death. But the true biological function of these sugars remains a mystery
SETOR FIGU COURTESY OF STEPHEN EVANS/ UNIVERSITY OF OTTAWA
ATYPICAL The structure of GTB with uridine diphosphate in the active site shows how this enzyme makes the sugar that defines type-B blood. It also suggests how GTA, which differs by only a few amino acids (orange), makes the type-A sugar. (Oxygen, red; carbon, gray; nitrogen, blue; manganese, purple.) The ABO blood group (the group that encompasses types A, B, AB, and O) is one of dozens of human blood groups found on the surface of red blood cells. Besides ABO, only one of these—the Rh blood group—is important in medicine. Named for the rhesus monkeys from which it was first isolated, Rh protein dots the surface of red blood cells in about three-quarters of the human population. The plus or minus sign that follows your ABO blood type indicates whether you have it or not. Although the frequency of each blood
type varies in populations throughout the world, most of us have type-0+ or typeA+ blood. Type A B - is the rarest group. THE BLOOD TYPES A, B, and O were first identified more than a century ago by an Austrian physician named Karl Landsteiner. Less than a decade later, Landsteiner's blood-typing methods—which relied on mixing two blood samples and seeing whether they clumped togetherhad revolutionized blood transfusions, making them safer and vastly more popular. He received the 1930 Nobel Prize in Medicine or Physiology for his groundbreaking work. But it wasn't until the late1950s that scientists identified the sugary source of Landsteiner's blood types. Biochemists Winifred M . Watkins and Walter T. J. Morgan of the Lister Institute of Preventative Medicine in London were the first to show that type-O people like Santillan display a polysaccharide known as the H antigen on their red blood cells. The H antigen is tethered to red blood cells via integral membrane proteins or membrane-associated lipids. Type-A individuals also display the H antigen, but it's tipped with the sugar a-N-acetylgalactosamine. In type-B individuals, the H antigen is tipped with a subdy different sugar, a-galactose. Those who are type AB make both A and B antigens. Scientists now know a great deal about the intricate enzymatic mechanisms that give rise to these antigens. The A antigen is made by an enzyme called N-acetylgalactosaminyl transferase (GTA), which attaches ^acetylgalactosamine to the H antigen, and the B antigen is created by another enzyme, galactosyltransferase (GTB), which adds galactose to the H antigen. In both enzymes, the appropriate sugar is delivered by the nucleotide cofactor uridine diphosphate (UDP). Individuals with type-AB blood have both GTA and GTB enzymes; those with type-O blood have neither. The GTA and GTB transferases, while mechanistically distinct, have nearly identical amino acid sequences. The two enzymes' 354-amino-acid sequences differ at only four residues, making them among the
Remarkably small differences in the chemical structures of these polysaccharides can lead to potentially fatal consequences/' 42
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most homologous natural glycosyltrans- ical problems (other than the fact that they be created when the immune system is can receive blood or organs only from oth- challenged by the foreign antigens present ferases that use different donor sugars. In fact, the ability of these two enzymes ers with the same rare disorder). "We sim- in meat as well as in various bacteria and to distinguish between A and B donor sug- ply have no idea whether blood groups other pathogens. These antibodies' biological purpose alars is determined almost entirely by a sin- have a true biological function," Palcic says. Nor do scientists understand why blood so remains a mystery Glycobiologist Ajit gle amino acid residue, according to crysP. Varki of the University of Caltallographer Stephen V Evans ifornia, San Diego, and others of the University of Ottawa. In HO M HO X)H have suggested that the variety collaboration with Palcic, Evans ofhuman blood types may serve and graduate student Sonia I. HO JMr HO mf HO m to slow the spread of viral disPatenaude recently reported Xease [Glycobiology, 9,747 (1999)]. ray crystal structures of the catVirus particles produced in alytic domains ofboth GTAand ^ ^ 0 H type-A human hosts display A GTB with UDP in their active ..I OH HO antigens on their surfaces. Such sites [Nat. Struct. Biol. 9, 685 viruses would have no trouble in(2002)}. HO^OH fecting other type-A hosts, but TYPECAST The terminal The protein-substrate conthey might be recognized as forsugar on a certain kind of tacts observed in the two eign and destroyed by hosts with polysaccharide attached to structures are identical with other blood types. Consequentred blood cells determines one exception: An active-site ly the diversification of human I OH blood type. In type-A methionine residue interacts blood types could have been the individuals, the last sugar is with UDP-galactose in GTB, result of evolutionary pressure to ^-acetylgalactosamine but the leucine found in the corprevent the rapid spread of viral (blue), and in type-B individuals, it's galactose (red). responding position in GTA diseases. The last sugar is missing in type-0 people (bottom). does not make a similar contact. But this possible evolutionary The smaller leucine residue in the bottom of GTAs active site gives plasma contains antibodies against foreign benefit can wreak havoc in modern medithe enzyme a larger cleft for binding its blood-group antigens. The human immune cine. Giving a type-O recipient like Santilbulkier substrate. This lowering of the ac- system doesn't make antibodies to antigens lan the red blood cells from a type-A donor tive site's "floor" reveals ahistidine that hy- found on its own red blood cells. Curious- causes the A antibodies in the recipient's drogen-bonds to the amine group of N- ly it does make antibodies to blood-group type-O blood to bind to and cross-link the antigens from blood ofother types. So type- donor's A sugars, leading to aggregation of acetylgalactosamine, GTAs donor sugar. But although the molecular details of Ablood contains antibodies that recognize the donor's red blood cells—the clumping these polysaccharides' structures and B sugars, type-B blood contains antibodies first observed by Landsteiner. This clumpbiosyntheses are now clear, the reason they against Asugars, type-O blood contains an- ing can result in life-threatening blockages exist in the first place is still a mystery In tibodies against both A and B sugars, and of the recipient's bloodvessels. As the case fact, people with a rare genetic condition type-AB blood contains neither antibody ofSantillan tragically illustrates, sometimes The origin of these antibodies is puz- a single sugar molecule is all that stands bethat prevents them from generating H, A, or B antigens don't seem to have any med- zling. Some have suggested that they might tween life and death. •
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