Editing Enzyme (section)

=== Substrate binding ===
Enzymes must bind their substrates before they can catalyse any chemical reaction. Enzymes are usually very specific as to what [[substrate (biochemistry)|substrates]] they bind and then the chemical reaction catalysed. [[Chemical specificity|Specificity]] is achieved by binding pockets with complementary shape, charge and [[hydrophilic]]/[[hydrophobic]] characteristics to the substrates. Enzymes can therefore distinguish between very similar substrate molecules to be [[chemoselectivity|chemoselective]], [[regioselectivity|regioselective]] and [[stereospecificity|stereospecific]].<ref>{{cite journal | vauthors = Jaeger KE, Eggert T | title = Enantioselective biocatalysis optimized by directed evolution | journal = Current Opinion in Biotechnology | volume = 15 | issue = 4 | pages = 305–313 | date = August 2004 | pmid = 15358000 | doi = 10.1016/j.copbio.2004.06.007 }}</ref>

Some of the enzymes showing the highest specificity and accuracy are involved in the copying and [[Gene expression|expression]] of the [[genome]]. Some of these enzymes have "[[Proofreading (biology)|proof-reading]]" mechanisms. Here, an enzyme such as [[DNA polymerase]] catalyzes a reaction in a first step and then checks that the product is correct in a second step.<ref>{{cite journal | vauthors = Shevelev IV, Hübscher U | title = The 3' 5' exonucleases | journal = Nature Reviews. Molecular Cell Biology | volume = 3 | issue = 5 | pages = 364–376 | date = May 2002 | pmid = 11988770 | doi = 10.1038/nrm804 | s2cid = 31605786 }}</ref> This two-step process results in average error rates of less than 1 error in 100 million reactions in high-fidelity mammalian polymerases.<ref name = "Stryer_2002"/>{{rp|5.3.1}} Similar proofreading mechanisms are also found in [[RNA polymerase]],<ref>{{cite journal | vauthors = Zenkin N, Yuzenkova Y, Severinov K | title = Transcript-assisted transcriptional proofreading | journal = Science | volume = 313 | issue = 5786 | pages = 518–520 | date = July 2006 | pmid = 16873663 | doi = 10.1126/science.1127422 | s2cid = 40772789 | bibcode = 2006Sci...313..518Z }}</ref> [[aminoacyl tRNA synthetase]]s<ref>{{cite journal | vauthors = Ibba M, Soll D | title = Aminoacyl-tRNA synthesis | journal = Annual Review of Biochemistry | volume = 69 | pages = 617–650 | year = 2000 | pmid = 10966471 | doi = 10.1146/annurev.biochem.69.1.617 }}</ref> and [[ribosome]]s.<ref>{{cite journal | vauthors = Rodnina MV, Wintermeyer W | title = Fidelity of aminoacyl-tRNA selection on the ribosome: kinetic and structural mechanisms | journal = Annual Review of Biochemistry | volume = 70 | pages = 415–435 | year = 2001 | pmid = 11395413 | doi = 10.1146/annurev.biochem.70.1.415 }}</ref>

Conversely, some enzymes display [[enzyme promiscuity]], having broad specificity and acting on a range of different physiologically relevant substrates. Many enzymes possess small side activities which arose fortuitously (i.e. [[Neutral evolution|neutrally]]), which may be the starting point for the evolutionary selection of a new function.<ref name=Tawfik10>{{cite journal | vauthors = Khersonsky O, Tawfik DS | title = Enzyme promiscuity: a mechanistic and evolutionary perspective | journal = Annual Review of Biochemistry | volume = 79 | pages = 471–505 | year = 2010 | pmid = 20235827 | doi = 10.1146/annurev-biochem-030409-143718 }}</ref><ref>{{cite journal | vauthors = O'Brien PJ, Herschlag D | title = Catalytic promiscuity and the evolution of new enzymatic activities | journal = Chemistry & Biology | volume = 6 | issue = 4 | pages = R91–R105 | date = April 1999 | pmid = 10099128 | doi = 10.1016/S1074-5521(99)80033-7 | doi-access = free }}</ref>

[[File:Hexokinase induced fit.svg|alt=Hexokinase displayed as an opaque surface with a pronounced open binding cleft next to unbound substrate (top) and the same enzyme with more closed cleft that surrounds the bound substrate (bottom)|thumb|400px|Enzyme changes shape by induced fit upon substrate binding to form enzyme-substrate complex. [[Hexokinase]] has a large induced fit motion that closes over the substrates [[adenosine triphosphate]] and [[xylose]]. Binding sites in blue, substrates in black and [[magnesium|Mg<sup>2+</sup>]] cofactor in yellow. ({{PDB|2E2N}}, {{PDB2|2E2Q}})]]

==== "Lock and key" model ====
To explain the observed specificity of enzymes, in 1894 [[Hermann Emil Fischer|Emil Fischer]] proposed that both the enzyme and the substrate possess specific complementary geometric shapes that fit exactly into one another.<ref>{{cite journal | vauthors = Fischer E | year = 1894 | title = Einfluss der Configuration auf die Wirkung der Enzyme | language = de | trans-title = Influence of configuration on the action of enzymes | journal=Berichte der Deutschen Chemischen Gesellschaft zu Berlin | volume = 27 | issue = 3 | pages = 2985–93 | url = http://gallica.bnf.fr/ark:/12148/bpt6k90736r/f364.chemindefer|doi=10.1002/cber.18940270364 }} From page 2992: ''"Um ein Bild zu gebrauchen, will ich sagen, dass Enzym und Glucosid wie Schloss und Schlüssel zu einander passen müssen, um eine chemische Wirkung auf einander ausüben zu können."'' (To use an image, I will say that an enzyme and a glucoside [i.e., glucose derivative] must fit like a lock and key, in order to be able to exert a chemical effect on each other.)</ref> This is often referred to as "the lock and key" model.<ref name="Stryer_2002" />{{rp|8.3.2}} This early model explains enzyme specificity, but fails to explain the stabilization of the transition state that enzymes achieve.<ref name="Cooper_2000">{{cite book | author = Cooper GM | title = The Cell: a Molecular Approach | date = 2000 | publisher = ASM Press | location = Washington (DC ) | isbn = 0-87893-106-6 | edition = 2nd | chapter = Chapter 2.2: The Central Role of Enzymes as Biological Catalysts | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK9921/ | url-access = registration | url = https://archive.org/details/cell00geof }}</ref>

==== Induced fit model ====
In 1958, [[Daniel E. Koshland, Jr.|Daniel Koshland]] suggested a modification to the lock and key model: since enzymes are rather flexible structures, the active site is continuously reshaped by interactions with the substrate as the substrate interacts with the enzyme.<ref>{{cite journal | vauthors = Koshland DE | title = Application of a Theory of Enzyme Specificity to Protein Synthesis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 44 | issue = 2 | pages = 98–104 | date = February 1958 | pmid = 16590179 | pmc = 335371 | doi = 10.1073/pnas.44.2.98 | doi-access = free | bibcode = 1958PNAS...44...98K }}</ref> As a result, the substrate does not simply bind to a rigid active site; the amino acid [[Side chain|side-chains]] that make up the active site are molded into the precise positions that enable the enzyme to perform its catalytic function. In some cases, such as [[glycosidases]], the substrate [[molecule]] also changes shape slightly as it enters the active site.<ref>{{cite journal | vauthors = Vasella A, Davies GJ, Böhm M | title = Glycosidase mechanisms | journal = Current Opinion in Chemical Biology | volume = 6 | issue = 5 | pages = 619–629 | date = October 2002 | pmid = 12413546 | doi = 10.1016/S1367-5931(02)00380-0 }}</ref> The active site continues to change until the substrate is completely bound, at which point the final shape and charge distribution is determined.<ref>{{cite book | vauthors = Boyer R | title = Concepts in Biochemistry | edition = 2nd | publisher = John Wiley & Sons, Inc. | location = New York, Chichester, Weinheim, Brisbane, Singapore, Toronto. | isbn = 0-470-00379-0 | pages=137–8 | chapter = Chapter 6: Enzymes I, Reactions, Kinetics, and Inhibition | year = 2002 | oclc = 51720783 }}</ref>
Induced fit may enhance the fidelity of molecular recognition in the presence of competition and noise via the [[conformational proofreading]] mechanism.<ref>{{cite journal | vauthors = Savir Y, Tlusty T | title = Conformational proofreading: the impact of conformational changes on the specificity of molecular recognition | journal = PLOS ONE | volume = 2 | issue = 5 | pages = e468 | date = May 2007 | pmid = 17520027 | pmc = 1868595 | doi = 10.1371/journal.pone.0000468 | veditors = Scalas E | doi-access = free | bibcode = 2007PLoSO...2..468S }}</ref>