Sandbox 38

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<Structure load='9PAP' size='400' frame='true' align='right' caption='Structure of Papain' scene='Sandbox_36/Papain_main/4'/>
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<scene name='Sandbox_38/Adenylate_kinase_overall/1'>Adenylate kinase</scene> is an enzyme that catalyzes the reaction ATP + AMP = 2ADP. It consists of two identical subunits, A (shown in blue) and B (shown in green). For simplicity's sake, only the A chain will be shown in subsequent green links.
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=='''Papain'''==
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==Basic structural elements==
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<Structure load='1AKE' size='500' frame='true' align='right' caption='Adenylate Kinase' scene='Insert optional scene name here' />
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Like many proteins, the <scene name='Sandbox_38/Adenylate_kinase_2o_structure/12'>secondary structure</scene> of adenylate kinase consists of two elements: alpha-helices, which are shown in light green, and beta-sheets, which are shown in dark green. Some of these are parallel, while others are anti-parallel. (Non-repetitive structural elements are shown in light blue/gray.) In addition to the regular hydrogen bonding that results in the secondary structure of the protein, additional <scene name='Sandbox_38/Adenylate_kinase_2o_structure/15'>hydrogen bonding</scene> is present in the backbone of adenylate kinase (shown in yellow), which also contributes to the overall stability/folding of the molecule.
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An additional, significant factor in the structural stability/folding of the molecule is the polarity of the amino acid residues. The <scene name='Sandbox_38/Adenylate_kinase_2o_structure/18'>hydrophobic</scene> (nonpolar) residues are shown in gray, while the <scene name='Sandbox_38/Adenylate_kinase_2o_structure/17'>hydrophilic</scene> (polar/charged) residues are shown in red.
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==Reactive structural elements==
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As mentioned above, adenylate kinase catalyzes the reaction ATP + AMP = 2ADP. The <scene name='Sandbox_38/Adenylate_kinase_2o_structure/19'>catalytic residues</scene> that interact with the substrate to accomplish this are shown in purple. The amino acids that comprise these residues are Arg, Asp, and Lys.
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However, the enzyme does not only interact with the ATP and AMP--it also interacts with <scene name='Sandbox_38/Adenylate_kinase_2o_structure/20'>Bis(adenosine)-5'-Pentaphosphate</scene> (shown in red), a non-hydrolysable substrate with structural similarity to the enzyme's actual substrate. The <scene name='Sandbox_38/Adenylate_kinase_2o_structure/29'>contact residues</scene>, i.e. the residues that are in contact with the ligand, can be seen (cationic residues are shown in blue, whereas anionic residues are shown in bright red). Similar to the catalytic residues, which have positively-charged side chains, most of the side chains that interact with the ligand are also charged, although oxygen (primarily from Thr side chains) interacts with it as well. Furthermore, the carbonyl and nitrogen parts of the amino acid backbone also interact with the ligand.
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NOTE: The highlighted contact residues are actually those that are within 4 angstroms of the ligand, and all of them may not actually be in contact with it (although most of them are).
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== Introduction ==
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==Water Accessibility==
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Papain (EC 3.4.22.2) is a cysteine protease derived from the papaya plant. This protein consists of 212 amino acids that contribute to a single polypeptide chain with a molecular weight of 23.4 kD. Like other proteins, Papain contains a <scene name='Sandbox_38/C-n_terminus/1'>3' Carbon and a 5' Nitrogen terminus</scene>. The red end of the protein indicates the 3' Carbon end, while the blue end indicates the 5' Nitrogen terminal. The varying colors in between are merely used to show the progression between the two terminals. The <scene name='Sandbox_38/Ss/2'>secondary structure</scene> of this molecule consists of 25% alpha helices, seen as pink "rockets", and 21% beta sheets, seen as orange "planks" . Since papain is a protease, it is able to hydrolyze the peptide bonds of leucine and glycine, however it ideally cleaves residues that are followed by a large hydrophobic residue. Traditionally, Papain has be used as a commercial meat tenderizer. This enzyme also has some medicinal uses, as it has be been used in wound debridement, and is occasionally administered as a dietary supplement. This enzyme is able to aid in digestive problems, as it is able to break down food so it is easier to digest.
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Of course, this enzyme is not reacting with its substrate or ligand in a vacuum, but rather in solvent, such as water. However, the molecule has a specific <scene name='Sandbox_38/Adenylate_kinase_2o_structure/24'>solvent accessibility</scene> (water is shown in blue, the enzyme shown in white, and the ligand is shown in red). Because of the protein's folding, the solvent can't interact with every part of it; usually the outside is covered in solvent molecules, while the inside has less interaction with the solvent. It should be noted, however, that even some of the <scene name='Sandbox_38/Adenylate_kinase_2o_structure/27'>internal residues</scene> are in contact with the solvent.
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== History: ==
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Papain was discovered during the colonial period in Congo, as the native inhabitants discovered that wrapping their elephant meat in papaya leaves helped to tenderize the meat. While they did not know the direct cause, this was when the proteolytic enzyme was first discovered. Papain was originally ''explored '' in 1973 by G.C. Roy, however the active binding site of this enzyme was first discovered by Drenth et al., through the crystallographic analysis of the enzymes structure.
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== Function: ==
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[[Image:Papainmech6.jpg|200px|left|thumb| mechanism of papain <ref>[http://chemistry.umeche.maine.edu/CHY431/Peptidase10.html] University of Maine</ref>.]]The <scene name='Sandbox_38/Active_site/3'>active site</scene> of this hydrolytic enzyme is able to break peptide bonds through the help of a catalytic triad, consisting of Cys-25, His-159, and Arg-175. The Cys-25 residue is deprotonated by His-159, while Asp-125 is able to stabilize the Histadine ring in order for this deprotonation to take place. The Cys-25 residue is then able to perform a nucleophilic attack on the carbonyl carbon of the peptide backbone, freeing the amino terminal of the peptide, and forming a covalent intermediate. Next, the enzyme is deacylated by water, and the carboxy-terminal portion of the peptide is released. A link for the specific mechanism of this process can be viewed on the left hand side of this page.
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== Composition of Papain: ==
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Papain consists primarily of carbon, nitrogen, sulfur, and oxygen. The <scene name='Sandbox_38/Composition_of_papain/1'>composition of the enzyme</scene> can be view, as carbon is labled gray, oxygen red, nitrogen blue, and sulfur yellow. There are three <scene name='Sandbox_38/Disulfide_bridges/1'>disulfide bridges</scene> that contribute to the structure of Papain. These bonds are indicated by their yellow color, as they link particular cysteine residues. Throughout this enzyme, there are specific charged residues, indicating the most polar portions of the molecule. These <scene name='Sandbox_38/Charge/3'>charged residues</scene> can be visualized, as the cationic residues are blue in color, while the anionic residues are red. Partially charged residues are simply lighter in color. It is interesting to note that nearly all of these charged residues are located on the outer portion of the molecule in order to interact with the surrounding environment.
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== Hydrophobicity and Hydrophilicity: ==
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These charged residues contribute to the overall <scene name='Sandbox_38/Polar_residues/1'>polar</scene>and <scene name='Sandbox_38/Non_polar_residues/1'>nonpolar</scene> regions of the protein. This results is particular hydrophobic (water hating) and hydrophilic (water loving) portions of the enzyme. These <scene name='Sandbox_38/Hydrophobic_and_polar_residues/2'>hydrophobic and hydrophilic regions</scene> are huge factors in determining the tertiary structure of the protein. As mentioned before, the charged, hydrophilic, portions of the enzyme are primarily located on the out portion of the molecule. The polar amino acids are indicated by a purple color, while the hydrophobic residues are gray.
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== Ligands of Papain ==
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Papain binds to an abundance of <scene name='Sandbox_38/Ligands/1'>ligands</scene>, as they are the molecules colored green. Since methanol was used as a solvent in the crystallization of Papain, many of these molecules surround the protein. These ligands interact with Papain through various <scene name='Sandbox_38/Ligand_hydrogen_bonds/1'>hydrogen bonds</scene>, which are distinctly colored blue. <scene name='Sandbox_38/Water_interactions/1'>Water molecules</scene> are also able to surround the molecule and form hydrogen bonds as well. A pseudosubstrate that is able to mimic the actual substrate and therefore inhibit Papain is called Leupeptin. The <scene name='Sandbox_38/Leupeptin-papain_complex/1'>leupeptin-papain complex</scene> (PDC ID: 1POP), clearly indicated by the blue Nitrogen of the substrate, indicates that the inhibitors carbonyl carbon is covalently bound to the Cys-25 sulfer atom of papain and is organized in a tetrahedral manner. The carbonyl oxygen atom of the inhibitor is not only able to face the oxyanion hole, it is also able to form hydrogen bond contacts with Gln-19 and Cys-25.
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References:
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*http://chemistry.umeche.maine.edu/CHY431/Peptidase10.html
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*http://www.pdb.org/pdb/explore/explore.do?structureId=1pop
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*http://www.pdb.org/pdb/explore/explore.do?structureId=9PAP
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*http://www.worthington-biochem.com/pap/default.html
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Current revision

Please do NOT make changes to this Sandbox. Sandboxes 30-60 are reserved for use by Biochemistry 410 & 412 at Messiah College taught by Dr. Hannah Tims during Fall 2012 and Spring 2013.

is an enzyme that catalyzes the reaction ATP + AMP = 2ADP. It consists of two identical subunits, A (shown in blue) and B (shown in green). For simplicity's sake, only the A chain will be shown in subsequent green links.

Basic structural elements

Adenylate Kinase

Drag the structure with the mouse to rotate

Like many proteins, the of adenylate kinase consists of two elements: alpha-helices, which are shown in light green, and beta-sheets, which are shown in dark green. Some of these are parallel, while others are anti-parallel. (Non-repetitive structural elements are shown in light blue/gray.) In addition to the regular hydrogen bonding that results in the secondary structure of the protein, additional is present in the backbone of adenylate kinase (shown in yellow), which also contributes to the overall stability/folding of the molecule. An additional, significant factor in the structural stability/folding of the molecule is the polarity of the amino acid residues. The (nonpolar) residues are shown in gray, while the (polar/charged) residues are shown in red.

Reactive structural elements

As mentioned above, adenylate kinase catalyzes the reaction ATP + AMP = 2ADP. The that interact with the substrate to accomplish this are shown in purple. The amino acids that comprise these residues are Arg, Asp, and Lys. However, the enzyme does not only interact with the ATP and AMP--it also interacts with (shown in red), a non-hydrolysable substrate with structural similarity to the enzyme's actual substrate. The , i.e. the residues that are in contact with the ligand, can be seen (cationic residues are shown in blue, whereas anionic residues are shown in bright red). Similar to the catalytic residues, which have positively-charged side chains, most of the side chains that interact with the ligand are also charged, although oxygen (primarily from Thr side chains) interacts with it as well. Furthermore, the carbonyl and nitrogen parts of the amino acid backbone also interact with the ligand. NOTE: The highlighted contact residues are actually those that are within 4 angstroms of the ligand, and all of them may not actually be in contact with it (although most of them are).

Water Accessibility

Of course, this enzyme is not reacting with its substrate or ligand in a vacuum, but rather in solvent, such as water. However, the molecule has a specific (water is shown in blue, the enzyme shown in white, and the ligand is shown in red). Because of the protein's folding, the solvent can't interact with every part of it; usually the outside is covered in solvent molecules, while the inside has less interaction with the solvent. It should be noted, however, that even some of the are in contact with the solvent.

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