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Much of what we know about the processes that regulate the body’s metabolism and the enzymes that carry out metabolic reactions in individual cells comes from studies of metabolic disorders. By examining defective metabolic states and comparing them to healthy states, we’ve learned a great deal about how the healthy system works. In this section, we highlight a few of these disorders. Finally, we discuss how scientists can use their knowledge of metabolism to engineer systems that benefit human health—and the health of the planet.
Each reaction in a metabolic pathway feeds the next reaction in the pathway. A defective enzyme can interrupt the sequence, with striking medical consequences.
Metabolic Warning - In response to an increasing awareness and understanding of metabolic disorders, manufacturers are making more information about the ingredients in their products available on product labels. Many refreshments are sweetened with aspartame, which contains phenylalanine, an amino acid that should not be consumed by individuals with phenylketonuria.
Metabolic Disorders
Defects in the mechanisms that regulate metabolic activities in cells and in organs can lead to disease. Some of these conditions are extremely rare: maple sugar urine disease, which hampers the body’s ability to break down certain amino acids, affects 1 baby in 180,000. Others are all too common: obesity has reached epidemic proportions, afflicting, by some estimates, one-third of all adults.
Many metabolic disorders are caused by mutations that disrupt the activity of a single enzyme. Defects in a single enzyme can block or severely impair the activity of an entire metabolic pathway, preventing the production of molecules that are needed by the cell (a key amino acid, for example) or causing a buildup of molecules that are unwanted, even toxic. It’s often this toxic buildup that causes the damage associated with a disease.
For example, babies born with phenylketonuria (FEN-uhl-kee-toe-nyoor-ee-uh), or PKU, lack an enzyme needed to break down the amino acid phenylalanine. Elevated concentrations of phenylalanine can lead to brain damage and seizures. Today, newborns are screened for phenylketonuria at birth. People with this disorder have to severely limit their consumption of foods high in protein, because most proteins contain phenylalanine. Eggs, cheese, milk, and meats are off the menu. Even diet sodas are restricted: the aspartame used as an artificial sweetener contains phenylalanine.
A number of other metabolic disorders are also treated with diet. Interestingly, many of these disorders are associated with a characteristic odor in sweat, urine, or other bodily products. Babies with maple syrup urine disease smell like burnt sugar or caramel. And people with trimethylaminuria, who lack an enzyme that breaks down the compound trimethylamine, smell strongly of rotten fish.
But some metabolic diseases have no treatment. In Tay-Sachs disease, a defect in an enzyme that breaks down certain lipids causes those lipids to accumulate in the brain and spinal cord, severely damaging nerve cells. Babies born with this disease often die before they reach school age. Although there is no treatment for Tay-Sachs, prospective parents can be screened to determine whether they carry the mutation that could lead to Tay-Sachs before they start a family.
Metabolic Engineering
Metabolic road maps like the one shown in the previous section give us an overview of all the reaction pathways that are available to a given cell or organism. What they don't reveal is which of those pathways are actually active—and when. Do some reactions occur all the time? Or are some preferred in times of plenty, when food is readily available, while others operate only when food is scarce or at times of stress? Do certain conditions favor particular metabolic products? Do the pathways ever get backed up? And if they do, are bottlenecks a function of too much traffic or of some form of regulation?
The answers to questions like these help us understand the flow of traffic along metabolic pathways. They also offer a unique opportunity for metabolic engineering, the manipulation of metabolic pathways to optimize their production of a desired substance. By targeting key enzymes, biologists can develop or improve drugs to treat specific disorders. They can also reroute reactions around bottlenecks, eliminate inhibitors, push pathways toward specific products, or add enzymes that will promote the production of new molecules or drugs. For example, researchers have used metabolic engineering to boost plants' retention of iodine—a nutrient essential for human health. Similar strategies are being used to coax plants into producing the omega-3 fatty acids normally made by fish.
The benefits of metabolic engineering extend beyond providing us with a plentiful source of nutritional supplements. Researchers have also used metabolic engineering to get bacteria to produce indigo, the dye that makes blue jeans blue. Originally extracted from plants, indigo is currently made from coal or oil. Engineered bacteria have the potential to produce a more environmentally friendly blue dye that doesn’t depend on fossil fuels. Researchers are also working with microbes to produce biofuels that may someday offer cheaper and safer alternatives to gasoline and diesel. It may well be that an understanding of how energy flows through the web of metabolic reactions in living systems will benefit not only human health, but the health of the entire planet.
Versatile Plant - Many metabolic pathways are common to all organisms, with occasional species-specific reactions branching from the main routes. A small adjustment to the lipid synthesis pathway in this Camelina sativa plant allows it to produce the nutritionally valuable omega-3 fatty acids normally produced by fish but not by plants.
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