Sandbox 179: Difference between revisions

<table style="background-color:#ffffc0" cellpadding="8" width="95%" border="0"><tr><td>Please do NOT make changes to this Sandbox until after April 23, 2010. Sandboxes 151-200 are reserved until then for use by the Chemistry 307 class at UNBC taught by Prof. [[User:Andrea Gorrell|Andrea Gorrell]].</td></tr>

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{{STRUCTURE_5pep|  PDB=5pep  |  SCENE=Sandbox_179/Scenedefault/2}}

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Pepsin is one of three proteolytic, or protein degrading enzymes in the digestive system. It resides in the alimentary canal and is produced by mucosal cells. Pepsin degrades peptides, and is optimally active at low pHs <ref name="Xray">PMID: 2115088</ref>. Pepsin is an aspartic proteinase, more specifically a eukaryotic aspartic protease enzyme. Pepsin was among the first enzymes to be isolated in crystalline form <ref name="flexible">PMID: 2217165</ref>.  Aspartic proteinases are widespread in nature, and pepsin in particular has been known to be medically important <ref name="native">The prosegment catalyzed pepsin folding to a kinetically trapped native state. Biochemistry 49:365-371</ref>.   

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Pepsin is bilobal, composed of two nearly equal N and C domains related by an intra dyad <ref name="flexible" />. Each of these domains consists predominantly of β-sheets <ref name="flexible" />. 44% of the structures residues are within a β-sheet, although there are six small right-handed α-helical segments, the longest being hc which spans from residues 225-236. All of the a-helices except h`c are partially exposed and have some amphiphilic character especially hc, which has a solvated surface and a buried side <ref name="Xray" />. The two most prominent strands of mixed β-sheets are 1N and 1C, these sheets are related by an intra-lobe topological 2-fold symmetry. The most important β-sheet consists of six anti-parallel β-strands, this sheet is called sheet 3.  “Two further β-sheets, 2N and 2C are each related by an intra-lode topologically related β-hairpins folded below the 1N and 1C sheets, further a six-stranded sheet spans the two lobes and forms a structure resembling an arch upon which the other four strands reside <ref name="Xray" />.” The interface between sheets 1N and 1C forms the catalytic center consisting of the nearly co-planar carboxyl group of aspartate residues 32 and 215, which are held in close proximity by a network of hydrogen bonds, and which are shielded from solvents by a β-hairpin loop. Both catalytic residues may be protonated, although only one carboxyl group would be negatively charged at any one time <ref name="Xray" />. The overall peptide folds and active sites structures are homologous <ref name="flexible" />. Aspartic proteinases, including pepsin are distinguishable by the presence of two conserved aspartic acid residues in the active site <ref name="flexible" />. Each domain in pepsin contains one of two catalytically important aspartic acid residues <ref name="flexible" />. There are 326 residues in pepsin, forming two topologically similar lobes. Residues 1-175 form the N-terminal lobe, and residues 176-327 constitute the C-terminal lobe. A large portion of the residues are polar and buried <ref name="Xray" />. The side chains are involved in hydrogen-bond interactions with the main chain of the protein or other conserved side-chains of the enzyme <ref name="Xray" />.”  Hydrogen-bonds are what stabilize the fold of pepsin, this stabilizing is called the fireman`s grip. About 188 main-chain-main –chain hydrogen bonds exist. The enzyme also has a high proportion of serine and threonine residues, the total being 60. Of these, 32 are involved with side-chain hydrogen-bond interactions with other residues of the enzyme. There are 2425 non-hydrogen protein atoms and 371 water molecules <ref name="Xray" /> . Pepsin has a very low pI in the range of 2-3 pH units, which is due to the high proportion of carboxyl residues, 43. The protein is phosphorylated at Ser68 and has three disulphide bridges. Pepsin also contains several salt-bridges one of which from 206 to 210 encloses the pepsins only type II turn. Type I turns are the most prevalent in pepsin <ref name="Xray" />. There are typically three basic residues in pepsin, Arg308, His53, and Lys320.   

   

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