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Chapter 3: Sugars and Fats: Are We What We Eat?
Life scientists yearn to understand the natural world. They persist in trying to unravel the mysteries of biology because these mysteries are inherently intriguing. But more pressingly, scientists want to learn how biological systems work so that they can control them. Such control yields benefits to health and to the human enterprise in countless ways. Harnessing biology's magic underlies the extraordinary promise of biotechnology.
To a great degree, the old saying is true: We are what we eat. Our diets—everything from broccoli to butter to bread (a mix of proteins, fats, and sugars)—contain the biochemical ingredients for life. Ultimately, sugars (called carbohydrates) and fats (called lipids) are your body's chief sources of fuel.
But wait—tempting culinary concoctions like velvety caramel or cookie—dough ice cream aren't exactly what scientists are talking about when they refer to sugars or fats. The proteins, fats, and sugars you eat actually contain varying mixtures of all three of these types of molecules, plus water. Your digestive system teases apart a towering swirl of frozen yogurt, for instance, into its constituent "biopolymer" parts (proteins, lipids, and carbohydrates). These biopolymers are further digested into even smaller pieces: proteins into amino acids; carbohydrates into smaller sugars called simple sugars (like glucose); and fats into two breakdown products, called glycerol and fatty acids. Your body then transforms most of these breakdown products into just a few common biochemical intermediates. These are the simple molecules fueling the metabolic engines that produce the energy you need to eat and breathe.
Form and Function
Sugars and fats are also key structural components in cells. It is true that fat has gained a certain notoriety, signifying the consequence of too many French fries that end up in extra pounds. But fats are essential ingredients that are constantly being produced, recycled, and incorporated into crucial fixtures such as the cell's lining and protective barrier, the plasma membrane. Fat and a fat-derived substance called cholesterol constitute important structural components of the plasma membrane—a greasy envelope of lipids and sugars with proteins threaded through—that encases and protects the DNA and myriad signaling and structural proteins nestled inside. Yet the plasma membrane is not just a simple barricade; rather, the construction of this interactive sheath is a true feat of cellular engineering, orchestrated by the orderly arrangement of ball-and-stick molecules called glycolipids (lipid chains adorned with sugars) and phospholipids (lipids marked with charged cellular tags called phosphate groups). When aligned, these fat-containing molecular creations resemble a double array of matchsticks lined up perfectly end-to-end. The components can line up so flawlessly due to the simple chemical rule that oil and water don't mix. A double-thickness plasma membrane more or less automatically forms when the matchstick end (the lipid part) of each glycolipid or phospholipid gravitates toward oil (other, similar lipid matchstick ends) and the matchstick head (the sugar or phosphate part) drifts naturally toward the watery environment typical of the areas inside and between cells. Varying amounts of cholesterol, also a matchstick-shaped molecule, account for the fluidity, or flexibility, of any given plasma membrane. "Sticks" of cholesterol slide in between phospholipids and glycolipids and influence interactions between them—making the entire membrane more liquid or solid, depending on the exact location and amount of the cholesterol molecules present.
Long chains of water-insoluble lipids are constructed from building blocks called fatty acids, which are also stowed away as a source of fuel in fat cells. The chemical bonds linking fatty acid units together in glycolipids and phospholipids determine how rigid or floppy the lipid chains will turn out to be. This, in turn, affects the shape of the cell structures they form.
In many cases, lipids are much more than passive molecular bystanders—they serve as active participants in cell function. Besides influencing the physical state—the fluidity, shape, and structure—of the membranes of all types of cells, lipids perform other important cellular tasks, such as carrying messages. Sugar and phosphate chemical tags target glycolipids and phospholipids for a journey throughout the cell interior, where they participate in the relay of cell signals—including those that tell a cell to grow and divide, or not.
How Much Sweeter It Is
By far, the majority of molecules people taste as sweet are carbohydrates. Besides table sugar (sucrose), many other sweet molecules do exist. Surely everyone is familiar, for instance, with the pink or blue artificial sweetener packets joining sugar as staples on restaurant and coffee shop tabletops. Sweet 'N Low® and Equal®, which contain the chemicals saccharin and aspartame, respectively, are roughly 200 times as sweet as table sugar. Saccharin, believe it or not, is a chemical derived from petroleum. Aspartame is a tiny molecule constructed from two of the body's natural amino acids, phenylalanine and aspartate. But drawbacks such as aftertaste and lack of heat stability have prompted food scientists to pursue alternative sugar substitutes. Among these is a protein, called brazzein, extracted from a fruit native to Africa. To date, scientists have discovered only seven proteins—not sugars—that our tongues perceive as sweet. Of these, brazzein is the smallest and among the sweetest—more than a thousand times sweeter than sucrose. Food industry researchers are hot on brazzein's trail, as the protein seems to leave no unpleasant aftertaste and can withstand unusually high temperatures. The molecule is amazingly stable to heat: It retains its sweetness even after being "cooked" for 2 hours at temperatures greater than 200 degrees Fahrenheit. In a surprising twist, scientists who recently unscrambled the three-dimensional structure of the brazzein molecule say it resembles plant proteins involved in defense against microbial pathogens and some arthropod toxins, such as those secreted by scorpions.
Fats That Protect Bacteria Can Harm People
The outer surfaces of the cells of some types of bacteria, such as E. coli or Salmonella, are coated with fat. This lipid-rich shield, a component common to all bacteria of one particular class called gram-negative bacteria, serves a barrier function and prevents the escape of important microbial enzymes. An integral part of this bacterial barrier is a lipid-and-sugar-containing substance called lipopolysaccharide (LPS). A key constituent of LPS is a molecule called lipid A, which scientists also call endotoxin. This molecule can be very toxic to humans who encounter it. During severe infections, large amounts of lipid A shed by gramnegative bacteria trigger the body's immune system to overreact, commanding an army of immune cells to mount an attack. The resulting overproduction of immune chemicals can damage blood vessels and lead to a deadly condition called septic shock, in which blood pressure plunges to dangerously low levels and key organs such as the heart and kidney quickly become starved of oxygen from the blood. For obvious reasons, lipid A is an important target for chemists interested in developing antibiotic drugs.
Scientists have already determined that depriving bacteria of lipid A—either by taking away the cells' ability to make it or by wiping it out with a drug—kills the bacteria that produce it. Biochemist Christian Raetz of Duke University in Durham, North Carolina, has extensively studied the pathways that bacteria use to make lipid A. In the process, Raetz and his colleagues have identified certain compounds that stifle the production of lipid A, some of which may lead to the discovery of new antibiotic drugs. Ironically enough, Raetz has found some precursors to the synthesis of lipid A, as well as some lipid A look-alike molecules, that block the lipid A-provoked inflammation that leads to septic shock. One of these compounds is currently undergoing testing in Phase II clinical trials, the stage in the testing of potential new drugs in which researchers determine if the compound is effective. (To progress to Phase II clinical testing, researchers have to first prove, in Phase I trials, that the compound is safe for use in people.)
Sugar-Coated Proteins
Sugars attached to proteins (glycoproteins) are another key ingredient of cell membranes. Just as the sugar portions of glycolipids are oriented toward the watery cell exterior, so too are the sugar components of glycoproteins. Jutting out from the cell, these sugary "decorations" serve an identifying role, sort of like cellular address labels. Signaling molecules coursing through body fluids encounter specific patterns of sugars, which either grant them entry or refuse access. In this way, glycoproteins play a gatekeeper role in human cells. By virtue of marking cell surfaces, glycoproteins also help organs and tissues form, by directing "like" cells to meld together properly. Sugar coatings also help roving cells move along blood vessels and other cellular surfaces inside the body, providing traction via their ability to latch on to cell surface receptors.
Sweet Therapy
In medical research studies, the "sugar pill" is usually the so-called placebo: a "dummy" pill that scientists administer to half of a test group of patients to evaluate how well the real pill works. In an interesting twist, biochemist Hudson Freeze of the Burnham Institute in La Jolla, California, and his colleagues are using sugar pills themselves to combat a rare, inherited childhood disease. Given the many crucial roles sugars play in the body, it is not surprising that when the body doesn't manufacture sugars properly, dire consequences follow. Usually, diseases caused by a body-wide lack of certain carbohydrate-containing proteins damage the central nervous system (often, the brain) and result in severe mental retardation, but other very serious symptoms, such as bleeding problems caused by defective blood proteins, are also a hallmark of some carbohydrate deficiencies. Upon analyzing the cells of a child with CDG (a group of diseases collectively called Congenital Disorders of Glycosylation), Freeze, who for years had studied sugar metabolism in a primitive organism called a slime mold, quickly noted a conspicuous shortage of one sugar in particular, called mannose. He worked out a plan to try supplementing the child's diet with the missing sugar. As a result of receiving this inexpensive treatment, the child—who, it turns out, lacks the enzyme that converts another sugar, glucose, into mannose—has been able to resume a normal life. Since then, approximately 20 children have had similar success with this treatment.
Chemical Biology in Action: Sticky Situations
A class of immune system cells called white blood cells are a case in point. Studding the exterior of these cells are protein molecules called L-selectins. These sugar-grabbing proteins help white blood cells perform their tasks, such as to travel to the site of an impending infection to fend off microorganisms. The body's process of recruiting immune cells to combat injury or infection, however, has its own shortcomings—in the act of responding to such crises, immune cells spill their toxic contents and inevitably damage normal cells in the process. The result can be inflammation and pain.
Developing means to quash inflammation is therefore an important goal, and indeed is the target of an ongoing, multibillion-dollar pharmaceutical effort. Chemist Laura Kiessling of the University of Wisconsin-Madison had a hunch that forcing L-selectin molecules on immune cells to cluster together might send a signal to the cells' clean-up crews to clip the molecules from the cell surface. By doing so, the cells would lose critical docking sites that normally render the cells capable of sticking to each other—a key step in setting off an inflammatory response. Her hunch was correct: A few members of a new class of synthetic sugar molecules called neoglycopolymers can perform this trick, causing L-selectin molecules on meandering cells first to cluster and then to fall off cell surfaces. Neoglycopolymers are simple to make and halt inflammatory processes in a distinctly different way than do existing anti-inflammatory drugs, such as aspirin or ibuprofen. While these medicines block signaling molecules inside the cell, neoglycopolymers prevent cells from touching each other in the first place. Kiessling's research is yielding valuable insights into cellular processes that hinge upon cell migration—not only inflammation, but also the spread of cancer throughout the body, and perhaps even the way in which bacteria infect humans.
In addition to blocking the sticky interactions that draw cell surfaces together, scientists are also interested in changing cellular landscapes altogether. To that end, Carolyn Bertozzi of the University of California, Berkeley, has gotten into the business of "remodeling" cell surfaces. Like Kiessling, Bertozzi is a chemist interested in intercepting biological maneuvers that underlie human disease processes such as infection, inflammation, and the unchecked spread of cancer cells. Bertozzi set about her goal by figuring out a way to trick a cell's own metabolic machinery into redecorating its surface with unnatural molecules—such as ones on cancer cells that might be especially attractive to cell-killing agents, or ones on heart cells that might be attractive to artificial materials like pacemakers and other medical implants. The method Bertozzi dreamed up is beautifully simple in design. Her experiments have shown that she can feed cells a novel synthetic sugar that is just a little bit different from a natural cell surface sugar and get the cell to build a chain of such sugars and send it to the surface for display. Bertozzi can coax different cell types to ingest and display varying amounts of the unnatural sugars, providing the cell with brand-new surface features. In many instances the cells don't even seem to notice!
A Complicated Recipe
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help chemists prevent unwanted chemical reactions.Many drugs currently in the development pipeline are proteins. Genetic engineering has enabled scientists to make proteins from DNA in just a few easy steps. But the going hasn't been so easy with sugars. Chemists have long struggled with the problem of being able to tailor-make sugar molecules in the laboratory, and finally some scientists are nearing the light at the end of the tunnel. An ability to make all types of sugars on demand will undoubtedly tap the innumerable resources these molecules harbor-as drugs, as cellular "handles" for drugs to hang onto, and as basic research tools to probe hidden facets of cells. In practical terms, the ability to make sugars and sugar-derived molecules in the lab will allow chemists to spend less time agonizing over how to make the sugars and more time on studying the many roles these complicated molecules play in the body.
One especially exciting avenue is the potential for scientists to make from scratch the various sugars that reside on the surfaces of bacteria and viruses. The ability to mimic such sugars will grant scientists the capacity to design new vaccines to control these disease-causing microorganisms.
Why is making proteins so easy and making sugars so hard? The answer lies in the fundamental structure of each (see drawing/illustration). Proteins are chains of amino acids that can only fit together one way: head-to-tail, sort of like beads on a string. On the other hand, oligosaccharides—long, and often branched, chains of sugars—can fit together in many different ways, and chemists have a tough time forcing the construction one way instead of another.
Just two of the building blocks of an oligosaccharide chain can chemically snap together in dozens of ways. Another constraint is the fact that chemists often want to make branched structures, as opposed to linear "beads on a string." Traditionally, chemists attach chemical masks (protecting groups) to prevent the simple-sugar building blocks from forming unwanted linkages. This way, by blocking every potential attachment site but one—the wanted one—a chemist can ensure that only that particular link will be made. Afterward, the protecting groups can be removed, leaving only the sugar. This process of carefully separating chemical mixtures and applying and removing protecting groups can be very time-consuming.
A Supporting Role
Throughout your body, sugars help communicate messages by serving as molecular routing slips like the ones that direct pieces of mail to their correct destination. Sugars also play important structural roles within and between cells. Sugars form the scaffolding for the alphabet of life, DNA. The two threadlike strands of DNA "zip" together by virtue of a biochemical concept called complementarity. The four letters of the DNA alphabet— the bases A, T, G, and C—spell out the sequence of your genes, sort of like words. Because of each base's shape, Gs stick only to Cs and As attach only to Ts. The double helix of DNA, therefore, is a consequence of these base-specific chemical attractions. Bolstering the bases in place is a scaffolding of sugars that is "glued" together via molecules called phosphates. In plants, bacteria, fungi, and some arthropods, the supportive structural role played by carbohydrates is dramatic: Sugars literally hold the cell together by helping to form and maintain a tough cell wall.
One-Pot Synthesis
Chi-Huey Wong of the Scripps Research Institute in La Jolla, California, devised an inventive strategy to make some types of sugars in his lab—in a fraction of the time required by most other approaches. Wong's recipe for making oligosaccharides takes little time because it can all be done in one pot. The ingredients for one-pot oligosaccharide synthesis (as he calls it) are individual sugar building blocks with masking groups attached, plus a computer. At present, the process isn't simple—a considerable amount of groundwork is required to get his computer to guide the assembly of sugar pieces in a pre-defined order. Just as cooking a meal requires the chef to cut up all the vegetable and meat ingredients before cooking, before Wong added components to the "pot," he had to prepare all his chemical ingredients. To do so, he first conducted a series of chemical reactions and assigned a computer to monitor these reactions, rank how fast each occurred, and keep track of all those reaction rates. Wong then instructed the computer to choose individual chain-building linkages by virtue of how fast, or reactive, they were. At the moment, he has only a limited set of building blocks and reactions to start with, but Wong predicts that entering even more structures and reactivities into his computer will ultimately allow for the process to be completely automated by robots.
Wong's strategy is but one of many aimed at synthesizing sugars on demand. Other chemists are using a variety of techniques—virtually all of which rely upon the use of protecting groups. (The ones that don't rely on the use of protecting groups use enzymes, which are uniquely capable of selecting one, and only one, particular attachment site.) Some chemists, such as Daniel Kahne of Harvard University are perfecting a technique to build sugar chains atop a solid support. The rationale for such an approach is that sugars exhibit unique shapes and properties when stuck to a surface compared to floating around in a solution. Studying some of those unique properties has obvious relevance to how sugars behave in real cells in real bodies, where they mostly exist on surfaces. Another plus to making, and studying, sugars on a solid surface is that the method is efficient and easily permits the use of combinatorial chemistry techniques that can randomly generate huge collections of surface-bound sugar arrays that are potentially useful as drug targets.
Question Box: Putting Things In Order
Ram Sasisekharan, a biochemist at the Massachusetts Institute of Technology, constantly finds himself caught up in sticky situations. In fact, it's his choice to do so. As a scientist who ponders the scores of roles sugars act out in physiological systems, he spends much of his time devising ways to figure out how long, complicated tangles of carbohydrates are hooked together. Sasisekharan uses a brew of chemistry, physics, and math to determine the letter-by-letter sequence of sugary molecular chains called polysaccharides. Historically, Sasisekharan says, biologists have tried to "get rid of sugars" in the samples of proteins and DNA they analyze, because "they got in the way and were a nuisance." This is hardly the truth, he says, extolling the virtue inherent in studying sugar molecules—in his words, "the most informationdense molecules Mother Nature makes." According to Sasisekharan, sugars are orders of magnitude more complex than proteins or nucleic acids, which is a likely reason they've been the molecule scientists left behind. With a recent explosion of research on sugars and the important things they do in the body, that's unlikely to be the case for long. The Chemistry of Health asked Sasisekharan to fill in some of the exciting details.
I see math as a form of communication cutting up a problem into smaller, more manageable pieces so you can put them all back together in a logical way and solve the problem.
CH: What are some of the things sugars do that make them so interesting to study?
Sasisekharan: Sugars are like clothes cells wear. Which sugar coat a cell wears—for example a wool coat or a T-shirt—affects how that cell perceives and responds to its environment. The sequence of a sugar chain can influence the job a cell performs. I hope the day will come that we can tell cells what to wear—so that by having cells wear the right clothes at the right time, we can influence what cells do!
CH: You've recently discovered a way to decipher the sequence of long chains of sugars—how do you do it?
Sasisekharan: The sequencing method we developed really hinges on two key principles: mathematical coding and atomic-scale measurements of the weights of sugars. First, we start with cellular material that contains not only sugars, but also proteins and lots of other stuff. We're starting with a sugar chain called a glycosaminoglycan (GAG, for short). We know that there are 32 subtly different sugar building blocks to make this particular kind of sugar. In order to be able to distinguish the building blocks—and all their chemical markings—from one another, each has to be uniquely coded by a computer.
Next, we chop up the sugar several different ways, with enzymes and chemicals, producing a huge number of overlapping pieces. Then we weigh the tiny pieces with atomic-level accuracy, using a powerful technology called mass spectrometry. Finally, we feed all this information to a computer, and using the mathematical code we developed, the computer helps us figure out the solution. A lot like a jigsaw puzzle, there's only one way this puzzle can be properly assembled. We had a real "wow" moment when we saw that our computer program could generate a database of all the input material and just pop out the answer!
CH: Using math seems very important to the type of research you do—is that true?
Sasisekharan: Yes. Math is everywhere—it's just another system of logic we use to solve problems. Everybody thinks about problems in some logical way—like how to get from the kitchen to the garage. I see math as a form of communication cutting up a problem into smaller, more manageable pieces so you can put them all back together in a logical way and solve the problem.
CH: How do you see advances in carbohydrate chemistry advancing human health?
Sasisekharan: I think the greatest gains will be in diagnosis, in getting a handle on correlating disease states. The ability to study sugars in detail will enable scientists to be able to find all the possible cellular landscapes, and possibly what alters them. Said simply—why do cells wear different sugar coats at different times? Pinpointing exactly which sugars appear on the surface of cells is going to play an important role in how we understand development—the very fundamental principles of how cells position themselves to form tissues and organs.
CH: Why do you find studying science exciting?
Sasisekharan: Besides basic survival, I think a fundamental human instinct is curiosity. Innovation and invention have been instrumental for the survival of humankind... like Isaac Asimov said, "No way but onwards."
Got It?
Why is it difficult for chemists to make carbohydrates from scratch?
Cholesterol has an essential function in every cell in your body—what is it?
Describe two roles carbohydrates play in your body.
Can you think of some possible ways that carbohydrate chemistry research might lead to improvements in treating disease?