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Exploring Enzyme Function Through Human Genetic Disease

Elizabeth Paine, PhD
Product Developer
Carolina Biological Supply Company

EnzymeThe importance of enzymes is an abstract concept for many students. Make the subject relevant and alive by highlighting the connection between enzymes and human genetic disease.

As newborns, most of your students were screened for phenylketonuria and galactosemia, genetic diseases caused by the loss or malfunction of a single enzyme. Had the tests indicated either of those conditions, the infants would have been placed on special diets to minimize the effects.


Phenylketonuria (PKU) is an autosomal recessive disease that occurs at a frequency of 1 in 15,000 births in the U.S. The incidence of the disease varies widely between populations—from 1 in 4,000 births in Turkey to a low of 1 in 200,000 births in Thailand. Some of the symptoms are mental impairment, seizures, rashes, and light skin, hair, and eyes.

The classical form of PKU occurs when there is a mutation in both copies of the gene coding for the phenylalanine hydroxylase enzyme (PAH). The PAH enzyme adds a hydroxyl group to the aromatic side chain of phenylalanine to form tyrosine, one of the essential amino acids. This reaction is also a critical step in the breakdown of phenylalanine. Although phenylalanine is an essential amino acid, at high levels it becomes toxic. (Because of PAH's role in the synthesis of tyrosine, people with PKU may also have a deficiency of tyrosine.) PAH activity requires the cofactor tetrahydrobiopterin (BH4); other forms of PKU occur if this cofactor is absent or nonfunctioning.

In developed countries most newborns are tested for PKU. Those who test positive for low PAH activity are put on a diet low in phenylalanine. Maintaining such a diet goes a long way toward preventing development of symptoms. For infants, phenylalanine-free formula is available. Foods that are high in protein must be avoided, including not only the expected meat, fish, eggs, cheeses, nuts, and seeds, but also standard bread. Even low-protein foods, including some vegetables, must be eaten only in very small amounts. It is easy to understand how such a diet can be difficult to adhere to. Because of this difficulty, a focus on diet alone does not appear to prevent all negative effects of the disease. Thus, further research is being done to determine methods to handle PKU more effectively.


People with galactosemia are unable to break down galactose. Galactosemia (not to be confused with lactose intolerance, in which people are missing the enzyme for digesting lactose) is an autosomal recessive disease that can result from the loss of a single enzyme and occurs in approximately 1 in 30,000 to 1 in 60,000 births. (In some populations, the incidence is outside this range.)

Classic galactosemia results from the loss of galactose-1-phosphate uridyl transferase (GALT). GALT plays a critical role in the LeLoir pathway, by which the common sugar galactose is converted into its energetically useful form, glucose-1-phosphate. Specifically, GALT converts galactose-1-phosphate and uridine diphosphate-glucose into glucose-1-phosphate and uridine diphosphate-galactose. Because our bodies metabolize lactose (found in both cow and human milk) into its subunits, glucose and galactose, individuals with galactosemia should avoid ingesting lactose. Other forms of galactosemia occur if the other enzymes in the galactosidase catabolism pathway are hindered or missing, but people missing GALT display the most severe and common form.

In classic galactosemia, galactose-1 phosphate and possibly its metabolites build up in body tissues. This may result in intellectual impairment and other neurological problems, speech difficulties, an enlarged and/or cirrhotic liver, kidney failure, cataracts, ovarian failure, and decreased bone density. In infants, if galactosemia goes untreated, the symptoms include (but are not limited to) feeding difficulties, bleeding, bacteria in the blood (sepsis), liver damage, failure to thrive, cataracts, and shock.

Individuals diagnosed with galactosemia, especially infants and young children, need to avoid consuming galactose and lactose. Infants must be taken off both human and cow's milk and given a special formula that lacks the 2 sugars. As a child grows older, foods containing lactose (e.g., dairy foods) should not be eaten, and food containing galactose (even many fruits and vegetables) should also be avoided. How strict this avoidance needs to be later in life is unclear. As with PKU, diet, especially early in life, is important in preventing or slowing development of the symptoms. Some researchers believe that some symptoms persist even under a strict dietary regimen because the human body produces some galactose on its own; however, other mechanisms may be involved. Further research is being done to understand the disease so that it may be better controlled.

These 2 diseases provide a vivid example of how critical enzymes are to life; the loss of 1 enzyme can lead to severe consequences for an entire, complex organism. You may wish to have your students do additional research to find other diseases or disorders linked to the loss of specific enzyme activity. They might also conduct research on the genetics behind PKU and galactosemia as a way to reinforce their understanding of the connection between genotype, proteins, and phenotype.

References and resources

At the time this article was written, PubMed and NCBI Bookshelf, both sites maintained by the National Center for Biotechnology Information (NCBI), have reliable information on both PKU and galactosemia. The DNA Learning Center (www.dnalc.org) also maintains a Web site with clear information on multiple genetic diseases, including PKU.

Cleary, M.A. 2010. "Phenylketonuria". Paediatrics and Child Health. 21(2): 61–4.

Hendriksz, C.J., Walter, J.H. 2004. "Update on phenylketonuria." Current Paediatrics 14: 400–6.

Blau, N., van Spronsen, F.J., Levy, H.L. 2010. "Phenylketonuria." Lancet 376: 1417–27.

Hufton, S.E., Jennings, I.G., Cotton, R.G.H. 1995. "Structure and function of the aromatic acid hydroxylases." Biochemical Journal 311: 353–66.

Bosch, A.M. 2006. "Classical galactosaemia revisited." Journal of Inherited Metabolic Disease 29: 516–25.

Fridovich-Keil, J.L. 2006. "Galactosaemia: the good, the bad, and the unknown." Journal of Cellular Physiology 209: 701–5.

Holden, H.M., Rayment, I., Thoden, J.B. 2003. "Structure and function of enzymes of the Leloir pathway for galactose metabolism." The Journal of Biological Chemistry 278: 43885–8.

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