Serpins (short for serine protease inhibitor) are a group of structurally related proteins, many of which inhibit peptidases (enzymes that degrade protein, old name: proteases). Although initially simply considered a class of protease inhibitors (proteins that block the action of peptidases), it was discovered later that it has members that do not inhibit any enzymes, but serve as storage proteins (ovalbumin, in egg white), carriage proteins (thyroxine-binding globulin, steroid-binding globulin) and hormone precursors (angiotensinogen). The term serpin is used for these members as well, despite their noninhibitory function. A representation of the 3D structure of myoglobin, showing coloured alpha helices. ... Peptidases (proteases [pronounced pro-tea-aces] and proteolytic enzymes are also commonly used) are enzymes which break peptide bonds of proteins. ... A representation of the 3D structure of myoglobin, showing coloured alpha helices. ... In biology and biochemistry, protease inhibitors are molecules that inhibit the function of peptidases (old name: protease, hence the term protease inhibitor). ... The egg white is a clear liquid (also called albumen or ovalbumin) contained within a birds egg. ... Albumen redirects here. ... Thyroxine-binding globulin (TBG) or transthyretin is the major binding protein of thyroid hormones in the bloodstream. ... A hormone (from Greek horman - to set in motion) is a chemical messenger from one cell (or group of cells) to another. ... Angiotensinogen, angiotensin I and angiotensin II are peptides involved in maintenance of blood volume and pressure. ...

Form and function

Serine proteases are defined by the presence of a serine residue in their active domain (e.g. thrombin). Most inhibitory serpins inhibit this group of enzymes. Some serpins, particularly the squamous cell carcinoma antigen 1 (SCCA1), have been shown to inhibit cysteine proteases using the same mechanism as other serpins use to inhibit serine proteases. Cysteine proteases differ from serine proteases in that they are defined by the presence of a cysteine residue, rather than a serine residue, in their active domain. Nonetheless, the enymatic chemistry is similar, which is one possible reason why serpins can inhibit them. Serpins are part of the larger group of protease inhibitors. In biochemistry, serine proteases or serine endopeptidases (newer name) are a class of peptidases (enzymes that cleave peptide bonds in proteins) that are characterised by the presence of a serine residue in the active center of the enzyme. ... Serine is one of the 20 natural amino acids. ... Thrombin (activated Factor II) is a coagulation protein that has many effects in the coagulation cascade. ... Ribbon diagram of the enzyme TIM. TIM is catalytically perfect, meaning its conversion rate is limited, or nearly limited to its substrate diffusion rate. ... Proteases are enzymes that degrade polypeptides. ... Cysteine is a naturally occurring hydrophobic amino acid which has a thiol group and is found in most proteins, though only in small quantities. ... In biology and biochemistry, protease inhibitors are molecules that inhibit the function of peptidases (old name: protease, hence the term protease inhibitor). ...

Although the function of serpins varies widely, they share a number of structural details: all have three beta sheets and eight or nine alpha helixes in a typical configuration. Serpins also possess an exposed region, called the reactive centre (or site) loop that determines which proteases are targeted for inhibition. Many mutations have been described that lead to serpin dysfunction and diseases ("serpinopathies") such as emphysema, thrombosis and dementia. Diagram of Β-Pleated sheet and bond structure of protein The β sheet (also β-pleated sheet) is a commonly occurring form of regular secondary structure in proteins, first proposed by Linus Pauling and Robert Corey in 1951. ... A diagram of the alpha helix structure of amino acids In proteins, the α helix is a major structural motif in secondary structure. ... In biology, mutations are changes to the genetic material (usually DNA or RNA). ...

Specificity

Most serpins are specific for a particular protease (usually a serine protease), but in the laboratory many can show inhibition of several other proteases as well. Additionally, pathological forms can occasionally inhibit the wrong serine protease. The physiological target of a serpin will be dictated not only by the ability to inhibit a given protease, but in what place and at what time that protease is found. For example antitrypsin is able to inhibit trypsin (a digestive enzyme), but its primary physiological target is elastase (in the lungs). This is something that scientists must take into account when they identify a new serpin-enzyme interaction in the laboratory.

Evolution

Serpins were initially believed to be restricted to eukaryote organisms, but have since been found in a number of bacteria and archaea (Irving et al). It remains unclear whether these prokaryote genes are the descendants of an ancestral prokaryotic serpin or whether they are the product of lateral gene transfer (genetic transfer between organsisms not by evolutionary descent). Kingdoms Animalia - Animals Fungi Plantae - Plants Protista A eukaryote (IPA: ), also spelled eucaryote, is an organism with a complex cell or cells, in which the genetic material is organized into membrane-bound nucleus/nuclei. ... Subgroups Actinobacteria Aquificae Bacteroidetes/Chlorobi Chlamydiae/Verrucomicrobia Chloroflexi Chrysiogenetes Cyanobacteria Deferribacteres Deinococcus-Thermus Dictyoglomi Fibrobacteres/Acidobacteria Firmicutes Fusobacteria Gemmatimonadetes Nitrospirae Planctomycetes Proteobacteria Spirochaetes Thermodesulfobacteria Thermomicrobia Thermotogae Bacteria (singular: bacterium) are a major group of living organisms. ... Phyla / Classes Phylum Crenarchaeota Phylum Euryarchaeota     Halobacteria     Methanobacteria     Methanococci     Methanopyri     Archaeoglobi     Thermoplasmata     Thermococci Phylum Korarchaeota Phylum Nanoarchaeota The Archaea (; from Greek αρχαία, old ones; singular Archaeum, Archaean, or Archaeon), also called Archaebacteria (), are a major division of living organisms. ...

Members

Proteins in the serpin class:

• Alpha 1-antitrypsin (probably the best-characterised serpin);
• Alpha 1-antichymotrypsin;
• Alpha 2-antiplasmin (inhibitor of fibrinolysis);
• Antithrombin (inhibitor of coagulation, specifically factor X, factor IX and thrombin);
• Complement 1-inhibitor;
• Neuroserpin (recently discovered, mutated in some familial forms of dementia);
• Plasminogen activator inhibitor-1 and 2 (fibrinolysis);
• Protein Z-related protease inhibitor (ZPI, inactivates factor Xa and factor XIa)

Alpha 1-antitrypsin or α1-antitrypsin (A1AT) is a serine protease inhibitor (serpin). ... Alpha 2-antiplasmin (or α2-antiplasmin or plasmin inhibitor) is a serine protease inhibitor (serpin) responsible for inactivating plasmin, an important enzyme that participates in fibrinolysis and degradation of various other proteins. ... Fibrinolysis is the process where a fibrin clot, the product of coagulation, is broken down. ... Image:Antithrombin. ... The coagulation of blood is a complex process during which blood forms solid clots. ... Factor X, also known by the eponym Stuart-Prower factor or as thrombokinase, is an enzyme ( EC 3. ... Factor IX (or Christmas factor or Christmas-Eve factor) is one of the serine proteases (EC 3. ... Thrombin (activated Factor II) is a coagulation protein that has many effects in the coagulation cascade. ... C1-inhibitor (C1inh) is a serine protease inhibitor (serpin) protein, the main function of which is inhibition of the complement system. ... Plasminogen activator inhibitor-1 is the principal inhibitor of tissue plasminogen activator (tPA) and urokinase (uPA), the activators of plasminogen and hence fibrinolysis (the physiological breakdown of blood clots). ... Fibrinolysis is the process where a fibrin clot, the product of coagulation, is broken down. ... Protein Z-dependent protease inhibitor is a protein circulating in the blood which inhibits factors Xa and XIa of the coagulation cascade. ... Factor X, also known by the eponym Stuart-Prower factor or as thrombokinase, is an enzyme ( EC 3. ... Factor XI or plasma thromboplastin antecent is one of the enzymes ( EC 3. ...

Classification

In 2001, a consensus (Silverman et al) was published in which the circa 500 serpins were classified in sixteen clades (based on structural similarity), with the remaining ten as orphans. Gettins (2002) cites evidence that related human serpins may have arisen due to recent gene duplication, as many form discrete clusters on particular chromosomes. 2001: A Space Odyssey. ... A clade is a term belonging to the discipline of cladistics. ... Schematic of a region of a chromosome before and after a duplication event Gene duplication occurs when an error in DNA replication leads to the duplication of a region of DNA containing a (generally functional) gene. ... Figure 1: Chromosome. ...

References

• Silverman GA, Bird PI, Carrell RW, Church FC, Coughlin PB, Gettins PG, Irving JA, Lomas DA, Luke CJ, Moyer RW, Pemberton PA, Remold-O'Donnell E, Salvesen GS, Travis J, Whisstock JC. The serpins are an expanding superfamily of structurally similar but functionally diverse proteins. Evolution, mechanism of inhibition, novel functions, and a revised nomenclature. J Biol Chem 2001;276:33293-6. PMID 11435447.
• Gettins PGW. Serpin structure, mechanism and function. Chem Rev 2002;102:4751-803. DOI 10.1021/cr010170+.
• Irving JA, Steenbakkers PJ, Lesk AM, Op den Camp HJ, Pike RN, Whisstock JC. Serpins in prokaryotes. Mol Biol Evol. 2002 Nov;19(11):1881-90. PMID: 12411597.
• Irving JA, Pike RN, Lesk AM, Whisstock. Phylogeny of the Serpin Superfamily: Implications of Patterns of Amino Acid Conservation for Structure and Function. Genome Res. 2006; 10; 1845-64.

External links

• PDB molecule of the month: Serine protease inhibitor