Editing Active site (section)

==Examples of competitive and irreversible enzyme inhibitors==

===Competitive inhibitor: HIV protease inhibitor===
[[File:Indinavir, an HIV protease inhibitor.jpg|thumb|Indinavir, an HIV protease inhibitor.jpg|300px]]
[[Protease inhibitor (biology)|HIV protease inhibitors]] are used to treat patients having [[AIDS]] virus by preventing its [[DNA replication]]. [[HIV-1 protease|HIV protease]] is used by the virus to cleave Gag-Pol polyprotein into 3 smaller proteins that are responsible for virion assembly, package and maturation. This enzyme targets the specific [[phenylalanine]]-[[proline]] cleave site within the target protein.<ref name="Flexner">{{cite journal|vauthors=Flexner C|date=1998|title=HIV-protease inhibitors|journal=[[The New England Journal of Medicine]]|volume=338|issue=18|pages=1281–1292|doi=10.1056/NEJM199804303381808|pmid=9562584}}</ref> If HIV protease is switched off the virion particle will lose function and cannot infect patients. Since it is essential in viral replication and is absent in healthy human, it is an ideal target for [[drug development]].

HIV protease belongs to [[aspartic protease]] family and has a similar mechanism. Firstly the [[aspartate]] residue activates a water molecule and turns it into a [[nucleophile]]. Then it attacks the [[carbonyl group]] within the [[peptide bond]] (NH-CO) to form a tetrahedral intermediate. The nitrogen atom within the intermediate receives a proton, forming an [[amide|amide group]] and subsequent rearrangement leads to the breakdown of the bond between it and the intermediate and forms two products.<ref name="Ashraf">{{cite journal|vauthors=Ashraf B, Chi-Huey W|date=2003|title=HIV-1 protease: mechanism and drug discovery|journal=[[Organic & Biomolecular Chemistry]]|volume=1|issue=1|pages=5–14|doi=10.1039/B208248A|pmid=12929379}}</ref>

Inhibitors usually contain a nonhydrolyzable hydroxyethylene or hydroxyethylamine groups that mimic the tetrahedral intermediate. Since they share a similar structure and electrostatic arrangement to the [[transition state]] of substrates they can still fit into the active site but cannot be broken down, so hydrolysis cannot occur.

===Non-competitive inhibitor: Strychnine===
Strychnine is a [[neurotoxin]] that causes death by affecting nerves that control [[muscular contraction]] and cause respiration difficulty. The impulse is transmitted between the synapse through a [[neurotransmitter]] called [[acetylcholine]]. It is released into the [[synapse]] between nerve cells and binds to receptors in the postsynaptic cell. Then an [[action potential]] is generated and transmitted through the postsynaptic cell to start a new cycle.

[[Glycine]] can inhibit the activity of neurotransmitter receptors, thus a larger amount of acetylcholinesterase is required to trigger an action potential. This makes sure that the generation of nerve impulses is tightly controlled. However, this control is broken down when strychnine is added. It inhibits glycine receptors(a [[chloride channel]]) and a much lower level of neurotransmitter concentration can trigger an action potential. Nerves now constantly transmit signals and cause excessive muscular contraction, leading to [[asphyxia]]tion and death.<ref name="Gray">{{cite journal|vauthors=Gray W, Rick G|date=1993|title=Cytoprotection by inhibition of chloride channels: The mechanism of action of glycine and strychnine|journal=[[Life Sciences (journal)|Life Sciences]]|volume=53|issue=15|pages=1211–1215|doi=10.1016/0024-3205(93)90539-F|pmid=8412478}}</ref>

===Irreversible inhibitor: Diisopropyl fluorophosphate===

[[File:DIFP serine inactivation.svg|thumb|Irreversible inhibition of a serine protease by DIPF.|300px]]
[[Diisopropyl fluorophosphate]] (DIFP) is an irreversible inhibitor that blocks the action of [[serine protease]]. When it binds to the enzyme a [[nucleophilic substitution]] reaction occurs and releases one [[hydrogen fluoride]] molecule. The OH group in the active site acts as a nucleophile to attack the [[phosphorus]] in DIFP and form a tetrahedral intermediate and release a proton. Then the P-F bond is broken, one electron is transferred to the F atom and it leaves the intermediate as F<sup>−</sup> anion. It combines with a proton in solution to form one HF molecule. A covalent bond formed between the active site and DIFP, so the serine side chain is no longer available to the substrate.<ref name="JANSEN">{{cite journal|vauthors=Jansen EF, Nuttig F, Balls AK|date=1949|title=Mode of inhibition of chymotrypsin by diisopropyl fluorophosphate; introduction of phosphorus|journal=[[The Journal of Biological Chemistry]]|volume=179|issue=1|pages=201–204|doi=10.1016/S0021-9258(18)56828-9|pmid=18119235|doi-access=free}}</ref>