Michael Farrell
Prof. Macosko
27 February 2007
The Alternative Pathway and the Molecular Machines Used in It
The human body uses a very complex system called the Immune System in order to heal and protect itself from injuries and infections. One of the components of this intricate system is called the Complement System. The Complement System is a “biochemical cascade… that helps clear pathogens from an organism, and promote healing” (“The Complement System”). The Complement System is composed of three different pathways, each of which has its own function. The pathway which this paper focuses on is named the Alternative Pathway. The Alternative Pathway is also a biochemical cascade, which is “a series of chemical reactions in which the products of one reaction are consumed in the next reaction” (“Biochemical Cascade”), whose purpose is to find pathogens in the body and protect the body from possible harm using molecular machines.
The Alternative Pathway can be broken down into four distinct steps, each one as important as the previous step. The first step “begins with the activation of C3 and requires Factors B and D and Mg++ cation, all present in normal serum” (“Immunology- Chapter 2: Complement”). C3 is a protein produced in the liver, and Factors B and D are proteins which are also found in the body and are essential to the Alternative Pathway. Serum is just another name for blood and it where all these molecules are found. In this serum, hydrolysis of C3 is occurring and the C3i complex is formed. C3i is simply the name for the hydrolyzed form of C3. After C3i is formed, Factor B then binds to it, which makes the substance susceptible to cleavage by Factor D. Not surprisingly, Factor D then cleaves Factor B into Bb. This cleavage forms a new complex named C3iBb. C3iBb acts then acts as a convertase for C3. A convertase is “an enzyme that catalyzes the conversion of a substance to its active state” (“Convertase”). This C3iBb complex will then cleave C3 from the surrounding serum into C3a and C3b. This newly formed C3b will also bind the Factor B protein and become susceptible to cleavage by Factor D, similar to the process C3iB went through. Now, C3bB will be cleaved by Factor D resulting in the C3bBb complex. C3bBb is also a C3 convertase, like C3iBb, and cleave the surrounding C3 into even more C3a and C3b. It is important to note that in this first step, unlike the other two pathways of the Complement System, the Alternative Pathway is “triggered by C3 hydrolysis directly on the surface of the pathogen, it does not rely on pathogen-binding proteins like the other pathways” (“The Complement System”).
During the first step of the Alternative Pathway, the C3 that is being produced binds to the surface of a pathogen in the blood. If there is no pathogen present, the C3b will be deactivated and will end the biochemical cascade. As the C3 binds to the pathogen it interacts with the Decay Accelerating Factor (DAF). The DAF can perform a number of tasks but they all result in the same outcome: stopping the production and formation of additional C3b in the blood. One way it could do this is by “blocking the association of Factor B with C3b thereby preventing the formation of additional C3 convertase” (“Immunology- Chapter 2: Complement”). Another possible function of the DAF is to “accelerate the dissociation of Bb from C3b in C3 convertase that has already formed, thereby stopping the production of additional C3b” (“Immunology- Chapter 2: Complement”). An additional way the amount of C3b is controlled is by the “enzymatic degradation of C3b by Factor I” (“Immunology- Chapter 2: Complement”), which is facilitated by complement receptor 1 (CR1). Not every cell has CR1, but it also helps in controlling the levels of C3b inside a cell. It may not seem important to control the levels of C3b, since it provides a good service to the immune system, but studies have shown that people with surpluses of C3b are actually more prone to contract certain infections (“Immunology- Chapter 2: Complement”). This process of controlling the amount of C3b comprises the second step of the Alternative Pathway.
The third step continues the biochemical cascade with more reactions. Now that the C3b has stopped being produced, the previously mentioned C3bBb comes to the forefront of the cascade. It has been “‘hooked’ onto the surface of the pathogen, (and) will then act like a ‘chainsaw’, catalyzing the hydrolysis of C3… which positively effects the number of C3bBb hooked onto a pathogen” (“The Complement System”). The C3bBb complex is a very unstable substance, but when it binds to the pathogen, or “activator surface” (“Immunology- Chapter 2: Complement”), it stabilizes. C3bBb is also stabilized by the protein Factor P, or properdin, binding to it. Some of the pathogens that it can bind to are bacterial, yeast or plant polysaccharides, fungi, bacteria and viruses. Once it stabilizes, it is able to create more C3b by cleaving C3. This stabilization of the C3bBb complex is the third step of the Alternative Pathway.
At this point in the process, there is an abundance of C3b and C3bBb just outside of the pathogen. These two combine to form the C3bBbC3b complex, also known as C5. This generation of C5 is where the Alternative Pathway ends. From here, C5 will cleave into C5a and C5b and C5b will help form the Membrane Attack Complex (MAC). The MAC punches a hole into the membrane of the pathogen and initiates cell lysis. In addition the MAC, the Alternative Pathway can also lead to mast cell degranulation, another form of protecting the human body from disease and infection.
The Alternative Pathway is the most basic of the three pathways of the Complement System and scientists believe that the other pathways may have derived from it (“Immunology- Chapter 2: Complement”). The Alternative Pathway is more of a general defense mechanism against disease and infections, as compared to the other two pathways which target specific pathogens. Although it is primitive, many molecular machines are still involved. All of the enzymes that cleave proteins in the pathway are considered molecular machines. This list includes Factor D, C3iBb and C3bBb. These machines could theoretically be used to cleave other substances in practical life and be useful to humans in other fields besides immunology.
Other than the protein C3, the structures of the complexes named above are unknown and a distant goal of scientists currently. This is a main reason why not much is known about the possibilities of these molecular machines and how they could help humans in the future.
When looking at the Alternative Pathway, it is important to understand the dynamic of the biochemical cascade. Without a previous reaction, the next cannot be completed. So even though it may seem like C3 doesn’t need to be cleaved twice during the pathway, it needs to because of the order of the cascade. It is important to keep this in mind when trying to understand the process of the Alternative Pathway.
The Alternative Pathway is a main aspect of the body’s defense against pathogens and molecular machines play a vital role in its application. These microscopic wonders protect people from disease by triggering certain chemical responses, without which diseases and infections would run rampant in our bodies.
Works Cited
“The Alternative Complement Pathway.” Microbiology @
Immunity. 2004. 26 February 2007.
http://www-micro.msb.le.ac.uk/MBChB/Merralls/Alternative.html
“Biochemical Cascade.” Wikipedia. 29 January 2006. 26 February 2007.
http://en.wikipedia.org/wiki/Biochemical_cascade
“Blood Plasma.” Wikipedia. 24 February 2007. 26 February 2007.
http://en.wikipedia.org/wiki/Blood_plasma
“The Complement System.” Wikipedia. 25 February 2007. 26 February 2007.
http://en.wikipedia.org/wiki/Complement_system
“Convertase.” The American Heritage Stedman's Medical Dictionary. 2nd ed. 2004.
“Immunology- Chapter 2: Complement.” Microbiology and Immunology On-Line.
11 September 2006.
http://pathmicro.med.sc.edu/ghaffar/complement.htm
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