PhenylalaninePathway

BIOCHEMISTRY OF GENETIC DISEASES

ALBINISM

Albinos are found in virtually every species in which they have been looked for, and they are found in every human ethnic group throughout the world. Albino deer have been sighted by hunters many times (and are much more visible and easy to shoot). The common laboratory white rat is an albino. There are even similar cases in plants, although white plants die very soon after germination because they cannot photosynthesize.

TOP LEFT: Albino Squirrel. Note the pink eyes. From Brooker, R.J. "Genetics", Addison Wesley Longman, 1999, p 623.

TOP RIGHT: Albino Wildebeest. Note that this individual is very young. Because of their lack of protective coloration, albinos in most species do not survive long. From Brooker, R.J. "Genetics", Addison Wesley Longman, 1999, p 623.

MIDDLE LEFT: Albino Sea Turtle. http://ankur.netfx.net/pics.html

MIDDLE RIGHT: A Hopi girl with albinism. From Weaver R.F. and Hedrick, P.W.; "Genetics", WC Brown., 1997, p 36.

BOTTOM LEFT: Human family in which albinism is inherited. From Brooker, R.J. "Genetics", Addison Wesley Longman, 1999, p 623.

BOTTOM RIGHT: Albino Burmese Python. http://www.amberle.com/ats/

The set of six pictures above shows the phenotype of Albinism. Albinos do not produce the pigment melanin. This is generally a dark pigment, but there are different forms with different colors. Melanin is deposited in the skin, hair and irises of the eyes. It accounts for:

hair color. Hair color in humans may vary from very light, through darker colors of blond, to brown and black. The color depends upon the amount of melanin and the type of melanin which is deposited in the cells of the hair shafts (red hair is produced by another pigment altogether). Albinos produce no melanin, so their hair is white.

skin color. Skin color in humans, like hair, varies from very light to very dark. The reasons are the same. No matter how light an individual's skin pigmentation may be, everyone produces some melanin. Tanning results when skin cells produce additional melanin in response to damage from the cancer causing wavelengths of ultraviolet light. Albinos produce no melanin, so their skin is white.

eye color. Contrary to popular opinion eye color is not inherited as a simple mendelian trait where "B is for brown eyes" and "b is for blue eyes". This is immediately obvious because not everyone has the same shade of brown, or the same shade of blue - in fact people with green, hazel or gray eye color don't have either. Eye color is determined by genes but there are many genes involved, and the inheritance is very complex. Eye color is depends on both the amount of melanin deposited in the iris of the eye, and where in the iris it is deposited. Blue eyes have no melanin in the anterior part of the iris, but a small amount in the posterior layers. Brown eyes have melanin deposited in the anterior layer of the iris as well, and there is more of it. The structure of the iris also influences the color of the iris because of the way light passes through it. Albinos produce no melanin, so their irises are colorless. Albinos appear to have pink eyes because light which enters the eye is reflected out again by the pink tissues at the back of the eye, and passes through the unpigmented iris.

What makes an individual an Albino?

As explained above, the typical phenotype results from a lack of melanin in hair, skin and iris. But why are the cells of these tissues incapable of producing melanin? Clearly, in order to understand the answer to this question we must first understand why the cells of most individuals do produce melanin!

As with so many other genetic diseases the explanation lies in biochemistry. Most of the biological chemicals upon which life depends (sugars, amino acids, DNA bases, lipids etc) must be chemically synthesized by cells. The series of chemical reactions used by cells to synthesize biological chemicals (called a biosynthetic pathway) are exactly the same reactions used by organic chemists in a laboratory. The only difference is that cells use enzymes to catalyze these reactions rather than heat, heavy metals or pH adjustments.

Albinism results from defects in the the biosynthetic pathway leading from the amino acid phenylalanine. Before you go farther view the chemical structure of phenylalanine and the 3-dimensional shape of phenylalanine ******** link to RasMol ******

The phenyalanine pathway is involved in 3 important genetic diseases or conditions of humans:

Albinism
Phenyl ketonuria
Alkaptonuria

Each of these genetic diseases results from a defective protein - one of the enzymes which catalyzes a critical step in the biochemical pathway of phenylalanine. You will remember from Principles of Biology I and Cell Biology that enzymes function because a substrate fits into their active site. This means that the substrate must fit into the active site - if it cannot fit, then the enzyme cannot facilitate the reaction. In these 3 genetic diseases, the SHAPE of the enzyme is defective. Because of the defective shape, the substrate cannot fit into the active site and the reaction is not catalyzed.

The biochemical defect in Albinism .

In normal humans the amino acid phenylalanine is hydroxylated at the para position of the phenyl group. This chemical reaction is catalyzed by the enzyme phenylalanine hydroxylase. The product is another common amino acid, called tyrosine. As illustrated above, the ability of the enzyme to catalyze this reaction depends upon complementary fit between the active site and the substrate.

Tyrosine is then hydroxylated a second time to produce 3,4-dihydroxyphenylalanine (DOPA). The enzyme which catalyzes this second hydroxylation is tyrosine hydroxylase. DOPA is the precursor in a sequence of many chemical reactions which ultimately produce the brown pigment melanin (the biochemical pathway has been simplified, and appears to indicate that melanins is produced directly from DOPA; this is not so). The first reaction in this series of reactions is catalyzed by an enzyme called tyrosinase.

Albinism results when either of two enzymes - tyrosine hydroxylase or tyrosinase - is defective! They are defective in having the wrong SHAPE, so that their substrates cannot fit into the active site.

If the shape of the active site of tyrosine hydroxylase is defective, then the substrate tyrosine cannot fit in, the product DOPA is not synthesized. Without DOPA, melanin cannot be synthesized.

If the shape of the active site of tyrosinase is defective then the substrate DOPA cannot fit in and the product cannot be synthesized. Without the second intermediate, melanin cannot be synthesized.

The figure used to illustrate Albinism was modified from Strickberger, M.W., "Genetics 2nd ed.", Macmillan, 1976, p 601.

The biochemical defect in Phenylketonuria (PKU).

In normal humans the amino acid phenylalanine is hydroxylated at the para position of the phenyl group. The product is another common amino acid, called tyrosine. This chemical reaction is catalyzed by the enzyme phenylalanine hydroxylase. Because tyrosine is used in other ways (see albinism and alkaptonuria below), it does not ordinarily accumulate in the cells and bloodstream:

Phenylketonuria occurs when phenylalanine hydroxylase doesn't work. If the shape of phenylalanine hydroxylase is defective, then the substrate phenylalanine cannot fit in and the product tyrosine is not synthesized. Unlike tyrosine, there is no good way for cells to get rid of excess phenylalanine. Consequently, if phenylalanine is not converted to tyrosine, it does accumulate in cells and the levels in the bloodstream go up. When it reaches high levels phenylalanine is metabolized, but these products are toxic to developing cells in the brain and central nervous system. This results in extensive damage to the brain - and mental retardation!

Another characteristic of children afflicted with PKU is their very light hair, blue eyes and fair skin. The reason for this is related to the reason for Albinism. With lower than normal levels of tyrosine, the cells of these individuals produce less DOPA and ultimately, less melanin! They are not albinos because the tyrosine hydroxylase and tyrosinase in these individuals is not defective. Some tyrosine is available in the diet and this can be used to make some melanin.

Treatment for PKU is relatively straightforward. In the U.S., all babies are tested for PKU at birth. These babies are placed on special diets low in phenylalanine until they are about 5 years old. Since the human brain is fully developed by the age of 3, the toxic products of unusual phenylalanine metabolism do not have any damaging effects past this age. However a female with PKU will have to return to the low phenylalanine diet if she becomes pregnant; otherwise the toxic metabolites will damage the immature CNS of her fetus.

About 1 in 11,000 live births are diagnosed with PKU which means that approximately 1 in 100 adults is a carrier for PKU. Of the 5500 students at Clarion, the odds are that 55 of them are carriers of the defective allele for defective phenylalanine hydroxylase which produces PKU.

The figure used to illustrate PKU was modified from Strickberger, M.W., "Genetics 2nd ed.", Macmillan, 1976, p 601.

The biochemical defect in Alkaptonuria.

In normal humans not all tyrosine is hydroxylated to dihydroxyphenylalanine (DOPA) in the pathway to melanin biosynthesis as discussed above. SOME of the tyrosine is converted to another dihydroxy- compound homogentisic acid (HA). In this part of the phenylalanine pathway, 3 things happen to tyrosine:

it is decarboxylated and deaminated (the carboxyl group and amino group are removed).
the a carbon which then remains is oxidized to an acidic carboxyl group.
the phenyl ring is hydroxylated - it now is substituted with 2 hydroxyl groups.

The resulting product is HA, a benzene ring with an acetic acid substituent. This makes it an 8 carbon compound (6 carbons in the phenyl group, plus 2 carbons in the acetyl group). HA is further metabolized by homogentisic acid oxidase, which oxidizes the phenyl ring, opening it up and producing an 8 carbon linear chain terminated by carboxyl groups - this is maleyl acetoacetic acid. Maleyl acetoacetic acid is readily broken down to other water-soluble acids which are readily soluble and excreted in the urine.

Alkaptonuria results when homogentisic acid oxidase does not work. This results in an accumulation of homogentisic acid to high levels. HA, like most phenolic compounds, spontaneously oxidizes to various dark colored products. These are deposited in the soft tissues of the body, especially cartilage. Hence people with alkaptonuria have very dark noses and ears. Some pigment is also deposited in the cartilage of the joints turning them black and causing arthritis in later life.

Many of the oxidized products are also excreted in the urine, so the urine is black. This forms the basis for a very simple diagnosis of the disease in newborns. Babies born with alkaptonuria (about 1 in 20,000 live births) have black diapers! Other than arthritis and esthetically unpleasing noses and ears, this genetic condition is relatively benign. Many alkaptonuriacs reproduce and survive to old age.

The figure used to illustrate Alkaptonuria was modified from Strickberger, M.W., "Genetics 2nd ed.", Macmillan, 1976, p 601.

After you have studied each of the 3 individual pathways view the entire pathway.

After you have studied each of the 3 individual pathways view the summary table.

After you have viewed the entire pathway, work on the SELF TEST QUESTIONS.

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