Pepsin: Difference between revisions

Theodor Schwann discovered [[Pepsin]] in 1836. He named the enzyme pepsis from the Greek word peptein which means to digest. Pepsin was the first animal enzyme to be discovered, and, in 1929, it became one of the first enzymes to be crystallized, by John H. Northrop.  

==Protein Function==

==Overall Structure==

Pepsin is bilobal, and composed of two nearly equal N and C domains related by an intra dyad <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" />. Each of these domains consists predominantly of β-sheets <ref name="flexible" />. In fact, 44% of the structures residues are within a β-sheet. There are six small right-handed α-helical segments, the longest being hc which spans from residues 225-236. All the a-helices except h'c are partially exposed and have some amphiphilic characteristics especially hc. Hc has a solvated surface and a buried side <ref name="Xray" />. The two most prominent strands of mixed β-sheets in both domains are 1N and 1C sheets. These sheets are related by an intra-lobe topological 2-fold symmetry. The most important β-sheet consists of six anti-parallel β-strands. “Two further β-sheets, 2N and 2C are each related by an intra-lobe 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 overall peptide folds and active site 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" />. The interface between sheets 1N and 1C forms the catalytic center consisting of the two nearly co-planar carboxyl groups of aspartate residues <scene name='Sandbox_179/Asp/1'>32 and 215</scene>, that are held in close proximity by a network of hydrogen bonds, and are shielded from solvents by a β-hairpin loop. Both catalytic residues can be protonated, although only one carboxyl group can be negatively charged at any one time <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 stabilization 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, there is a total of 43. The protein is phosphorylated at Ser68 and has three disulphide bridges. Furthermore, pepsin contains several salt-bridges. One salt-bridge connecting the molecules at the 206 to 210 positions enclose the pepsins only type II turn. Type I turns are the most prevalent in pepsin <ref name="Xray" />. Lastly, are typically three basic residues in pepsin, Arg308, His53, and Lys320.   

==What are the Structures Implications?==

Image 1. The hydrogen bonds between Asp138 and Arg316[[Image:Hydrogen bond.png|450 px ]]

=References=

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