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Skin Color and Albinism

• Wild Type Phenotypes are produced by the proper operation of Biochemical Pathways
• Biochemical reactions are catalyzed by proteins called enzymes
• Albinism
• Mutant Phenotypes are produced by the malfunction of variant proteins as a result of defective SHAPE.

Tay Sachs Disease

Marfans Syndrome

Fibrillin and Marfan's Syndrome - an example of a structural protein

b-Globin and Sickle Cell Anemia - an example of a transport protein

Online Mendelian Inheritance in Man (OMIM): The Bible of Genetic Diseases

Skin Color and Albinism

As every student of Organic Chemistry knows, a chemical is synthesized in a number of steps - each step is a separate chemical reaction.  Biological organisms must also synthesize thousands of chemicals (sugars, fatty acids, amino acids, steroid hormones, vitamins etc.).  The sequence of steps by which each of these chemicals is synthesized is referred to as a biochemical pathway.  The chemical reaction at each step is catalyzed by an enzyme !!

An example of a biochemical pathway is the biosynthesis of melanin, a pigment found in the skin, hair, scales and feathers of almost all animals.  In this pathway:
 

Click on the image to see it full-size!	Phenylalanine is hydroxylated at the para position by the enzyme  phenylalanine hydroxylase to form tyrosine. a second hydroxyl is added to tyrosine at a meta position by the enzyme tyrosine hydroxylase to form DOPA. DOPA is used as a precursor to a series of other chemical reactions (one of the earliest reactions is catalyzed by the enzyme tyrosinase) which ultimately produce melanin. NOTE:  You should be able to diagram and explain this pathway without using your notes!
Click on the image to see it full-size!	Phenylalanine hydroxylase catalyzes the hydroxylation of its substrate (phenylalanine), because the active site has a shape which is complementary to that of the amino acid. When phenylalanine enters the active site a hydroxyl group is transferred to it from the enzyme. Tyrosine hydroxylase catalyzes the hydroxylation of its substrate (tyrosine), because the active site has a shape which is complementary to that of the amino acid. When tyrosine enters the active site a hydroxyl group is transferred to it from the enzyme. Since both enzymes catalyze the same type of reaction - a hydroxylation - why do we need two enzymes, and what is the difference between them?
Click on the image to see it full-size!	Melanic humans (the wild type phenotype) have special skin cells called melanocytes which synthesize melanin. This dark pigment produces the coloration of skin, hair and the iris of the eyes. In some people this produces very dark skin color or hair color, but even in people with light skin and blond hair there is some melanin production no matter how inefficient their biochemistry. When skin is exposed to the damaging effects of uv irradiation from the sun, the melanocytes "up regulate"  melanin biosynthesis. This makes the skin darker (tanning) and has a protective effect. The protection is imperfect however and long term exposure leads to skin damage and premature ageing. and even a cancer of the melanocytes known as malignant melanoma. In its early stages, melanoma appears as a very dark mole with irregular edges and coloring. However other colors may occur. If the malignancies are removed in the earliest stages, the cure rate is approximately 95%. If it progresses, it is invariably fatal.
Click on the image to see it full-size!	A  phenotype common to many animals is albinism.  The albino phenotype results from an inability to synthesize melanin.  Hence there is no pigment in the skin or hair. The eyes appear pink because there is no pigment in the iris of the eye, so light is reflected from the capillary beds of the retina and passes back out of the eye. This phenotype results because: defective tyrosine hydroxylasedoes not catalyze the chemical reaction which hydroxylates tyrosine to synthesize Dihydroxyphenylalanine (DOPA). NOTE: Albinism could also result if one of the other biochemical reactions"down the line" from DOPA did not take place, but this is not common.
Click on the image to see it full-size!	Why would tyrosine hydroxylase in albinos fail to catalyze the hydroxylation of tyrosine?  BECAUSE .... the SHAPE of the active site is changed! The changed shape is no longer complementary to tyrosine ........ which means that tyrosine cannot fit into it .......... which means the hydroxylation reaction is not catalyzed!

Tay Sachs Disease

Tay-SachsDisease.This is one of a family of genetic diseases known as lysosomal storage diseases.  The lysosomes are the "waste disposal sites" of the cell, whose function is to degrade damaged and worn-out molecules. To perform this function, they are filled with a wide variety of digestive enzymes to chemically degrade damaged and worn out molecules. In particular lipopolysaccharides (LPS) are continually recycled by the neurons of the Central Nervous System (CNS). Old LPS are transported to the lysosomes in each neuron where they are processed through a degradation pathway with a series of reactions catalyzed by a number of different enzymes. Tay Sachs Disease occurs when one of these enzymes fails to catalyze a particular reaction in the biochemical pathway of degradation. As a result the lysosomes become stuffed, and the neurons begin to die. The result is progressive mental and physical deterioration and death by the age of 4. NOTE:  You should be able to diagram and explain this biochemical pathway from your notes, or you should be able to explain it from memory if any part of it is presented to you.

Marfans Syndrome
 

Marfans Syndrome. This genetic disease results from a mutation in the gene for a structural protein.  Ligaments must be elastic in order to function correctly. If they are too stiff, they result in developmental abnormalities such as excessive bone length.  Damage to the ligaments of the joints, foot and eye are pronounced. Weakened connective tissue in the aortic artery results in aneurysyms which are fatal if uncorrected. The protein which is defective in Marfans Syndrome is fibrillin.

Online Mendelian Inheritance in Man (OMIM): The Bible of Genetic Diseases

OMIM is a catalog of human genes and genetic disorders authored and edited by Dr. Victor A. McKusick and his colleagues at Johns Hopkins and elsewhere, and developed for the World Wide Web by NCBI, the National Center for Biotechnology Information. The database contains textual information and references.  It also contains copious links to MEDLINE and sequence records in the Entrez system, and links to additional related resources at NCBI and elsewhere. This is the "gold standard" reference for human genetic diseases!

       NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by
       genetics researchers, and by advanced students in science and medicine. While the OMIM database is open to the
       public, users seeking information about a personal medical or genetic condition are urged to consult with a qualified
       physician for diagnosis and for answers to personal questions.

Reference Books online at NCBI .

This source has approximately 20 advanced textbooks online covering Genetics, Cell Biology, Molecular Biology, Immunnology, Developmental Biology and other subjects. Even better, a search engine is available which searches all the references at one time! For example a single search for "fibrillin" would show hits in all 20 references ....... the books do not have to be queried individually. This is an invaluable resource!

To access these references, go to:   www.ncbi.nlm.nih.gov   Then click on the tab at the top of the page which says "Books".