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Serine proteases (or serine endopeptidases) are enzymes that cleave peptide bonds in proteins. Serine serves as the nucleophilic amino acid at the (enzyme's) active site. They are found ubiquitously in both eukaryotes and prokaryotes. Serine proteases fall into two broad categories based on their structure: chymotrypsin-like (trypsin-like) or subtilisin-like. Classification The MEROPS protease classification system counts 16 superfamilies (as of 2013) each containing many families. Each superfamily uses the catalytic triad or dyad in a different protein fold and so represent convergent evolution of the catalytic mechanism. The majority belong to the S1 family of the PA clan (superfamily) of proteases. For superfamilies, P: superfamily, containing a mixture of nucleophile class families, S: purely serine proteases. superfamily. Within each superfamily, families are designated by their catalytic nucleophile, (S: serine proteases). Substrate specificity Serine proteases are characterised by a distinctive structure, consisting of two beta-barrel domains that converge at the catalytic active site. These enzymes can be further categorised based on their substrate specificity as either trypsin-like, chymotrypsin-like or elastase-like. Trypsin-like Trypsin-like proteases cleave peptide bonds following a positively charged amino acid (lysine or arginine). This specificity is driven by the residue which lies at the base of the enzyme's S1 pocket (generally a negatively charged aspartic acid or glutamic acid). Chymotrypsin-like The S1 pocket of chymotrypsin-like enzymes is more hydrophobic than in trypsin-like proteases. This results in a specificity for medium to large sized hydrophobic residues, such as tyrosine, phenylalanine and tryptophan. Thrombin-like These include thrombin, tissue activating plasminogen and plasmin. They have been found to have roles in coagulation and digestion as well as in the pathophysiology of neurodegenerative disorders such as Alzheimer's and Parkinson's induced dementia. Many highly-toxic thrombin-like serine protease isoforms are found in snake venoms. Elastase-like Elastase-like proteases have a much smaller S1 cleft than either trypsin- or chymotrypsin-like proteases. Consequently, residues such as alanine, glycine and valine tend to be preferred. Subtilisin-like Subtilisin is a serine protease in prokaryotes. Subtilisin is evolutionarily unrelated to the chymotrypsin-clan, but shares the same catalytic mechanism utilising a catalytic triad, to create a nucleophilic serine. This is the classic example used to illustrate convergent evolution, since the same mechanism evolved twice independently during evolution. Catalytic mechanism The main player in the catalytic mechanism in the serine proteases is the catalytic triad. The triad is located in the active site of the enzyme, where catalysis occurs, and is preserved in all superfamilies of serine protease enzymes. The triad is a coordinated structure consisting of three amino acids: His 57, Ser 195 (hence the name "serine protease") and Asp 102. These three key amino acids each play an essential role in the cleaving ability of the proteases. While the amino acid members of the triad are located far from one another on the sequence of the protein, due to folding, they will be very close to one another in the heart of the enzyme. The particular geometry of the triad members are highly characteristic to their specific function: it was shown that the position of just four points of the triad characterize the function of the containing enzyme.In the event of catalysis, an ordered mechanism occurs in which several intermediates are generated. The catalysis of the peptide cleavage can be seen as a ping-pong catalysis, in which a substrate binds (in this case, the polypeptide being cleaved), a product is released (the N-terminus "half" of the peptide), another substrate binds (in this case, water), and another product is released (the C-terminus "half" of the peptide). Each amino acid in the triad performs a specific task in this process: The serine has an -OH group that is able to act as a nucleophile, attacking the carbonyl carbon of the scissile peptide bond of the substrate. A pair of electrons on the histidine nitrogen has the ability to accept the hydrogen from the serine -OH group, thus coordinating the attack of the peptide bond. The carboxyl group on the aspartic acid in turn hydrogen bonds with the histidine, making the nitrogen atom mentioned above much more electronegative.The whole reaction can be summarized as follows: The polypeptide substrate binds to the surface of the serine protease enzyme such that the scissile bond is inserted into the active site of the enzyme, with the carbonyl carbon of this bond positioned near the nucleophilic serine. The serine -OH attacks the carbonyl carbon, and the nitrogen of the histidine accepts the hydrogen from the -OH of the [serine] and a pair of electrons from the double bond of the carbonyl oxygen moves to the oxygen. As a result, a tetrahedral intermediate is generated. The bond joining the nitrogen and the carbon in the peptide bond is now broken. The covalent electrons creating this bond move to attack the hydrogen of the histidine, breaking the connection. The electrons that previously moved from the carbonyl oxygen double bond move back from the negative oxygen to recreate the bond, generating an acyl-enzyme intermediate. Now, water comes into the reaction. Water replaces the N-terminus of the cleaved peptide, and attacks the carbonyl carbon. Once again, the electrons from the double bond move to the oxygen making it negative, as the bond between the oxygen of the water and the carbon is formed. This is coordinated by the nitrogen of the histidine, which accepts a proton from the water. Overall, this generates another tetrahedral intermediate. In a final reaction, the bond formed in the first step between the serine and the carbonyl carbon moves to attack the hydrogen that the histidine just acquired. The now electron-deficient carbonyl carbon re-forms the double bond with the oxygen. As a result, the C-terminus of the peptide is now ejected.Additional stabilizing effects It was discovered that additional amino acids of the protease, Gly 193 and Ser 195, are involved in creating what is called an oxyanion hole. Both Gly 193 and Ser 195 can donate backbone hydrogens for hydrogen bonding. When the tetrahedral intermediate of step 1 and step 3 are generated, the negative oxygen ion, having accepted the electrons from the carbonyl double bond, fits perfectly into the oxyanion hole. In effect, serine proteases preferentially bind the transition state and the overall structure is favored, lowering the activation energy of the reaction. This "preferential binding" is responsible for much of the catalytic efficiency of the enzyme. Regulation of serine protease activity Host organisms must ensure that the activity of serine proteases is ade.... Discover the Brenda Jernigan popular books. Find the top 100 most popular Brenda Jernigan books.

Best Seller Brenda Jernigan Books of 2024

  • Seduction synopsis, comments

    Seduction

    Brenda Jernigan

    Finalist Bookseller’s Best Award Brooke Hammond leaves England determined to make a success of the Louisiana plantation she inherited. Only one obstacle stands in her waya devilish...

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    The Wicked Lady

    Brenda Jernigan

    THE THIEF When Trevor Claremont was blindsided by a pickpocket on the docks beside his clipper ship, he tracked down the culpritonly to face a feisty, emeraldeyed beauty who stirre...

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    Until September

    Brenda Jernigan

    SHE MUST LIVE FOR TODAY . . . The finest doctors in Manhattan have told Claire Holladay she’d be lucky to live until September.  Determined to savor every moment, the beautifu...

  • The Choice synopsis, comments

    The Choice

    Brenda Jernigan

    TOP 100 Amazon Breakthrough Novel Award Brenna Fox knows she will always love Taylor Rothschild, but she doesn’t want to be a black stain on Taylor’s promising career after a scan...

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    Christmas in Camelot

    Brenda Jernigan

    The Greatest Gifts . . . Are Always Unexpected ... Lady Noelle has no intention of marrying just to save her family’s castle. She feels nothing for Sir Gavin, the man who will beco...

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    September Storm

    Brenda Jernigan

    It’s the wrong time … the wrong place . . . to fall in love. When Danielle Kapur, an advertising rep in San Antonio, decides to fly to Sea Horse Island, North Carolina, she figures...

  • WHISPERS ON THE WIND synopsis, comments

    WHISPERS ON THE WIND

    Brenda Jernigan

    BLOOD ON HER HANDS No one really understands Mary Costner, except her beloved goldmining partner, one of the only men in Colorado’s Gregory Gulch who knows she is a woman and who ...

  • Dance on the Wind synopsis, comments

    Dance on the Wind

    Brenda Jernigan

    A bargain made in haste.  Desperate but determined, lovely Brandy answers an advertisement for a mail order bride, hoping to build a new life out West for herself and the five...

  • The Misfits synopsis, comments

    The Misfits

    Brenda Jernigan

    They were misfits that no one wanted. Watch how they come together to become a family against all odds. If you love Julie Garwood’s “For the Roses”, I think you will enjoy The Misf...

  • Diamond in the Rough synopsis, comments

    Diamond in the Rough

    Brenda Jernigan

    When Kathy Taylor receives word that she has been left a million dollars by her late aunt, she doesn’t believe a word of it.  Nothing good ever happens to her.  Reluctant...

  • Love Only Once synopsis, comments

    Love Only Once

    Brenda Jernigan

    BITTER BETRAYAL Elizabeth Trent knew she was meant to marry Jonathan Hird, the dashing soldier who had miraculously returned from war, wounded but alive.  And though his kisse...

  • Stormy Passion synopsis, comments

    Stormy Passion

    Brenda Jernigan

    When is the right time to fall in Love? In a winter storm or a fierce hurricane, passion can strike at any time.  Will it be love at first glance or a lost love you cannot for...