User:Sazfar21/sandbox

Draft of Article Work

Adjusted Mechanism Section:

This reduction in the effective concentration of the ES complex decreases the maximum enzyme activity (V_max), as it takes longer for the substrate or product to leave the active site. The reduction in K_m - the substrate concentration at which the enzyme can operate at half of its maximal velocity, often used to approximate an enzyme's affinity for a substrate - can be explained by the fact that having the inhibitor bound to the ES complex reduces the effective concentration of pure ES complex. Much of it is converted to ESI complex, which is considered a separate complex altogether. Le Chatelier's principle opposes this decrease in ES concentration and attempts to make up for this loss, so more free enzyme is converted to the ES form. An increase in ES generally indicates that the enzyme has a high degree of affinity for its substrate. K_m generally decreases as affinity for a substrate increases, though it is not a perfect predictor of affinity since it accounts for other factors as well; regardless, this increase in affinity will correspond to a decrease in K_m.

Images to Add to Mechanism Portion and Introduction Section: Mechanism of uncompetitive inhibition and Michaelis Menten Plot (Current version only has Lineweaver-Burke)

Michaelis-Menten plot of uncompetitive inhibition. Note the decrease in Km and Vmax

General mechanism of uncompetitive inhibition

Implications in Biological Systems

The unique traits of uncompetitive inhibition lead to a variety of implications for the inhibition's effects within biological and biochemical systems. Uncompetitive inhibition is present within biological systems in a number of ways. In fact, it becomes clear that often the traits of inhibition specific to uncompetitive inhibitors, such as their tendency to act at their best at high concentrations of substrate, are essential to some important bodily functions operating properly.

Involvement in Cancer Mechanisms

Uncompetitive mechanisms are involved with certain types of cancer. Human alkaline phosphatases such as CGAP have been found to be over-expressed in certain types of cancers, and those phosphotases often operate via uncompetitive inhibition. It has also been found that a number of the genes that code for human alkaline phosphatases (TSAPs) are inhibited uncompetitively by amino acids such as Leucine and Phenylalanine. Studies of the involved amino acid residues have been undertaken in attempts to regulate alkaline phosphatase activity and learn more about its relevance to cancer.

Additionally, uncompetitive inhibitors work alongside TP53 to help repress the activity of cancer cells and prevent tumorigenesis in certain forms of the illness, as it inhibits G6PD (glucose-6-phosphate dehydrogenase, an enzyme primarily involved in certain metabolic pathways). One of the side roles G6PD is responsible for is helping to regulate is the control of reactive oxygen levels, as reactive oxygen species must be kept at appropriate levels to allow cells to survive. When G6PD's substrate concentration is high, uncompetitive inhibition of the enzyme becomes far more effective. As substrate concentration increases, the amount of ES complex increases as well, and with more ES complex to bind, uncompetitive inhibitors become far more active. Essentially, this inhibition works such that the higher the concentration of substrate is in the system initially, the harder it is to reach the maximum velocity of the reaction. At low initial substrate concentrations, increasing the concentration of substrate is sometimes enough to entirely or even fully restore the enzyme's function, but as soon as initial concentration increases past a certain point, reaching the maximal enzyme velocity is all but impossible. It should be noted that this extreme sensitivity to substrate concentration implicates uncompetitive inhibition rather than mixed inhibition, which displays similar traits but is often less sensitive to substrate concentration due to some inhibitor binding to free enzymes regardless of the substrate's presence. As such, the extreme strength of uncompetitive inhibitors at high substrate concentrations and the overall sensitivity to substrate amount indicates that only uncompetitive inhibition can make this type of process possible.

Presence in Cell Membranes

Although this form of inhibition is present in various diseases within biological systems, it does not necessarily only relate to pathologies. It can be involved in typical bodily functions. For example, active sites capable of uncompetitive inhibition appear to be present in membranes, as removing lipids from cell membranes and making active sites more accessible through conformational changes has been shown to invoke elements resembling the effects of uncompetitive inhibition (i.e. both K_M and V_Max decrease). In mitochondrial membrane lipids specifically, removing lipids decreases the alpha-helix content in mitochondria and leads to changes in ATPase resembling uncompetitive inhibition.

This presence of uncompetitive enzymes in membranes has also been supported in a number of other studies. A type of protein called an Arf protein involved in regulating membrane activity was being studied, and it was found that an inhibitor called BFA trapped one of Arf's intermediates via uncompetitive inhibition. This made it clear that this type if inhibition exists within various types of cells and organelles as opposed to just in pathological cells. In fact, BFA was found to relate to the activity of the Golgi apparatus its role in movement across the cell membrane.

Presence in the Cerebellar Granule Layer

Uncompetitive inhibition can play roles in various other parts of the body as well. It is part of the mechanism by which NMDA (N-methyl-D-aspartate) glutamate receptors are inhibited in the brain, for example. Specifically, this type of inhibition impacts the granule cells that make up a layer of the cerebellum. These cells have the aforementioned NMDA receptors, and the activity of said receptors typically increases as ethanol is consumed, leading to withdrawal symptoms if said ethanol is removed. Various uncompetitive blockers act as antagonists at the receptors and modify the process, with one example being an inhibitor called memantine. In fact, in similar cases (involving over-expression of NMDA, though not necessarily via ethanol), it has been shown that uncompetitive inhibition helps in nullifying the over-expression due to its particular properties. Since uncompetitive inhibitors block high concentrations of substrates very efficiently, their traits alongside the innate characteristics of the receptors themselves lead to very effective blocking of NMDA channels when they are excessively open due to massive amounts of NMDA agonists.

Image for Bio section:

NMDA Inhibitor Memantine

Specify which uncompetitive inhibitor maybe? Draw a small arc shape blocking it, note in the caption that this type of binding only occurs when it's overly expressed in the open form (i.e. substrate bound, binding ES complex)

NMDA Receptor modeled in a state of uncompetitive inhibition. Substrate is bound and the active site is subsequently blocked by the inhibitor, represented by the large red arc.

Sources

5 Articles/Sources:

• Biochemistry Free for All Textbook
  • Explains reduced Km and Vmax
  • Could help expand Mechanism section by actually explaining why they decrease and not just saying they do
• Lithium and the phosphoinositide cycle: an example of uncompetitive inhibition and its pharmacological consequences.
  • Discusses restoration, which isn't really mentioned in the current page
  • Discusses some general biological implications
• Biophysical studies on agents affecting the state of membrane lipids: biochemical and pharmacological implications.
  • A few specific implications discussing membranes are brought up
  • Delipidation, perturbing submitochondrial particles, etc.
• Biology of human alkaline phosphatases with special reference to cancer.
  • Discussion of how uncompetitive inhibition can be useful in current studies; potential extra section? or maybe just add into biological/biochemical implications.
  • Potential tie in to cancer research?
• Detection of a novel, primate-specific 'kill switch' tumor suppression mechanism that may fundamentally control cancer risk in humans: an unexpected twist in the basic biology of TP53.
  • Direct link of uncompetitive inhibition to cancer as a "kill switch"
  • Discusses a few basic mechanisms and how they relate to disease, ideal for biochemical significance tie in

Article Selections/Evaluations

Uncomp. Inhibitor- Neutrally written. Generally has a good number of citations to back up accurate claims. Notably lacks information in the mechanism category, and only has a few sentences before jumping into mathematical equations. Consider revising the mechanism section.

Hydro. Collapse- Neutrally written, and discusses folding and its thermodynamics in a way which is relevant and has well-supported claims. Most notably lacking section to improve is likely the bit about biological importance. It's barely touched upon, and even at a glance without doing research I can think of a few things to talk about like amphipathic molecules.

Globular Proteins- fairly neutral and has a decent amount of info, but extremely lacking in examples of proteins, has very little elaboration in roles of the proteins, and does not seem to discuss significance of globular vs. other types of proteins (at a glance). What it has is well written and properly backed up, but it barely has anything. Also has very few references.

Proton pump- has lots of neutral and relevant info but with very few citations, so it is hard to say how accurate lots of it is. There do not seem to be any examples discussed particularly well in depth either, which could be good for the article (though the function section does seem to attempt this, it feels rather underdeveloped).

Being bold is important on Wikipedia.

Article Evaluation: Cyborg Anthropology

General Notes:

• Intro notes it is a new field, not expecting too much information
• Only one important name is discussed, Amber Case (other than an author or two). Potential weakness in that the article lists other important figures but simply links back to their articles without giving any information on them.

Evaluation Questions

• Most sections seem relevant, though lots of comparison to other fields such as digital anthropology is used likely since there isn't much material just for the cyborg anthropology.
• All material is relatively new. The references are virtually all within 25 years of current date (1995) and the earliest date even noted offhand in the article was around 1960.
• A little more work could be done in the intro. There was very little done to introduce the general concept of cyborg anthropology (two sentences) before jumping into history and specifics.

Tone

• The article remains neutral by neglecting to comment on whether the implications of this new field is positive or negative, at most denoting it as "novel". It becomes pretty clear that the editors working on this were interested in the subject but wrote without bias.
• Although much of the article is written regarding the developments within the field and their implications, a few lines are given from opponents of the field (such as members who think robots could never hope to develop a culture, which is a concept specific to humans), so most viewpoints are at least considered. Again though, much of the article is neutral so it is hard to explicitly discuss which positive and negative views are even present.

Sources

• I tried three of the citation links. Two worked perfectly, one led to a page that said "Page not found" which leads me to believe the article may need some updating.
• Most facts are directly cited; the article has a pretty nice number of sources especially given its own relatively small size. Most authors appear to be independent researchers of the field and very few are associated with untrustworthy sources like small news outlets and the like which are likely to be biased, so much of the information cited is likely used properly.

Talk

• There is a rather large list of amendments to the document. A user also provided a reference in his own section with a note than anyone wishing for more info could wait until he had time to share. Another user did some reorganizing, and another removed some info and said it included original research.
• WikiProject Anthropology. It is rated as Start Class and High Importance.
• Not much seems different than in class. It takes a generally objective point of view. The author uses appropriate sources and avoids opinions, and when outside opinions come into play both viewpoints are presented. It works quite well.

Optional Activity

• Added a slight suggestion to the talk page as part of the evaluation.
  

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