MadSci Network: Biochemistry

Re: Why are enzymes so big?

Date: Wed Oct 24 16:47:47 2001
Posted By: Michael Onken, MadSci Admin
Area of science: Biochemistry
ID: 1003710917.Bc

Before launching into "Enzymology 101", I feel it necessary to give a reference that covers the basics of proteins and how they work. Fortunately, the good folks at the National Center for Biotechnology Information have made available Molecular Biology of the Cell online; so, if you want more information, or examples, or a refresher, consult Chapter 5: Protein Functions. Now, on to the question:

Only a small section of the enzyme is the active site - so why does the rest of the enzyme exist?

Although the reasons differ from enzyme to enzyme - not all of the reasons below apply to all enzymes, and some enzymes may have reasons of their own that are not covered here - there are four major considerations when looking at the relation of an enzymes active site to the rest of the protein.

  1. Conformation This, I think, is the main reason that you are seeking in your question. While active sites can be fairly small, they almost always require an exact, three-dimensional shape to function properly. The problem comes in getting the active site to both acquire and keep its shape in the context of the cell. Proteins are able to spontaneously fold into specific configurations based on the interactions between the amino acids in the protein chain and their surroundings; for example, the "backbone" will try to form helices or sheets, while some "hydrophobic" amino acids will move toward the center of the protein to avoid contact with the surrounding water, and other "hydrophilic" amino acids will move to the outside of the protein. For many active sites - like the heme-binding site in hemoglobin - the amino acids that compose the site are so widely spaced that bringing them close together requires a lot of very specific folding and turning driven by the characteristics of the many amino acids not involved in the active site. In other words, for the active site to have the correct spatial orientation, the entire enzyme must assume and keep a tightly controlled shape.

  2. Regulation For many enzymes, it is important for the cell to control the rate of reaction and the amount of active enzyme. In most cases, the amount of enzyme is controlled genetically by turning the gene that produces the enzyme on and off; however, a more important means of control lies in the cell's ability to control the proteins directly. The two main mechanisms for controlling the activities of enzymes are inhibition and modification. Inhibition involves the binding of anything, from small molecules to large proteins, to the enzyme such that its rate of reaction is reduced. Many inhibitors are non-competitive, meaning that they inhibit the enzyme with affecting the active site, and many enzymes contain regulatory sites that specifically bind inhibitors allowing the cell to quickly affect activity. Beyond inhibition, many enzymes require binding by other proteins to become active, and so protein-binding domains often account for a large portion of the enzyme's structure.

    Modification refers to the addition of small molecules to the protein, such as phosphates, acetyl groups, and ubiquitin Most of these modifications do not occur in the active site, and either activate or inactivate the enzyme in other ways. In short, for the cell to control an enzyme's activity, the enzyme has to have built-in regulatory regions as well as an active site.

  3. Targetting One of the key aspects of an enzymes' activity is where in the cell that enzyme is active - lysosomal proteases would wreak havoc if they were active in the cytosol, and transcription factors are ineffective if they cannot access the chromosomes in the nucleus. With all of the different compartments within the cell, it is essential that each enzyme be transported and kept in its relevant place. Almost all of this trafficking and targetting is accomplished through protein recognition tags composed of stretches of amino acids that are contained within the sequence of the enzyme. There are nuclear localization signals, mitochondrial targetting sequences, and a host of secretory markers, each of which ensure the correct compartmentalization of each enzyme's activity. The more specific the localization, the more non-active site sequences have to be appended to the protein.

  4. Conservation From an evolutionary standpoint, the structure, function, and amino acid sequence of an enzyme are the results of the mutations and modifications hundreds of millions of years of adaptation. However, in many cases, the best way to build an active site is not always the first way it was built. It is often the case, that a better, more compact form of an enzyme can do the job as well or better than the native enzyme found in many higher eukaryotes. The problem is that to go from the original, clunky form of the enzyme to the more streamlined form usually requires several intermediate steps that greatly reduce the enzymes activity before the conversion to the new form is complete. As a result, these intermediates are almost always selected against if the enzyme's activity is necessary for survival. So, many of the essential, "house-keeping" enzymes found in animals are structurally primitive because of evolutionary pressure to maintain the activity, while the homologous enzymes in bacteria are highly efficient and streamlined - bacteria mutate and divide faster, and can allow for several generations of minor deficits. From a biochemical perspective, modern eukaryotes are quite primitive compared to modern bacteria.

    Conservation also plays a role in the formation of new enzymes from older proteins. Many of the enzymes present in human cells are the results of past genetic duplications that generated two identical proteins that have since diverged to perform two different functions. While the functions have changed, many of the older structural components are often maintained for reasons similar to those mentioned above, such that much of a particular protein's structure may be more a reminder of its evolutionary origins than an essential domain to its present function.

While it is easy in today's world of designer pharmaceuticals and genetically modified enzymes to think of the non-active site domains of an enzyme to be superfluous, it is important to look at the entire enzyme and its importance in the context of the evolving organism to how little of it is actually wasted.

Molecular Biology of the Cell, 3rd Ed. (1994), Bruce Alberts, Dennis Bray, Julian Lewis, Martin Raff, Keith Roberts, and James D. Watson, Garland Publishing .

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