Protein C inhibitor (PCI, SERPINA5) is a serine protease inhibitor (

serpin Serpins are a Protein superfamily, superfamily of proteins with similar structures that were first identified for their Protease inhibitor (biology), protease inhibition activity and are found in all kingdom (biology), kingdoms of life. The acr ...

) that limits the activity of

protein C Protein C, also known as autoprothrombin IIA and blood coagulation factor XIX, is a zymogen, that is, an inactive enzyme. The activated form plays an important role in regulating anticoagulation, inflammation, and apoptosis, cell death and ...

(an

anticoagulant Anticoagulants, commonly known as blood thinners, are chemical substances that prevent or reduce coagulation of blood, prolonging the clotting time. Some of them occur naturally in blood-eating animals such as leeches and mosquitoes, where the ...

). An

N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...

fragment of PCI is a possible serum biomarker for

prostate cancer Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that sur ...

. Protein C inhibitor is activated by

heparin Heparin, also known as unfractionated heparin (UFH), is a medication and naturally occurring glycosaminoglycan. Since heparins depend on the activity of antithrombin, they are considered anticoagulants. Specifically it is also used in the treatm ...

against thrombin. Protein C inhibitor (PCI) is serine protease inhibitor of serpin type that is found in most tissues and fluids, including blood plasma, seminal plasma and urine of human. It is a 52kD glycoprotein and belongs to serine protease inhibitor ( Serpin) super family of protein. In the beginning protein C Inhibitor (PCI) was identified as an inhibitor of activated protein C (APC), it is currently clear that this inhibitor has an expansive specificity, inhibiting several blood coagulation enzymes counting

thrombin Thrombin (, ''fibrinogenase'', ''thrombase'', ''thrombofort'', ''topical'', ''thrombin-C'', ''tropostasin'', ''activated blood-coagulation factor II'', ''blood-coagulation factor IIa'', ''factor IIa'', ''E thrombin'', ''beta-thrombin'', ''gamma- ...

and

factor Xa Factor X, also known by the eponym Stuart–Prower factor, is an enzyme () of the coagulation cascade. It is a serine endopeptidase (protease group S1, PA clan). Factor X is synthesized in the liver and requires vitamin K for its synthesis. Fac ...

Isolation

In the beginning, protein C inhibitor(PCI) was originally identified in human plasma by Griffin and Marlar and first isolation was performed by Suzuki et al. Protein C inhibitor (PCI) can be isolated from human plasma using an ordinary

chromatographic In chemical analysis, chromatography is a laboratory technique for the separation of a mixture into its components. The mixture is dissolved in a fluid solvent (gas or liquid) called the ''mobile phase'', which carries it through a system (a ...

procedure consisting of barium citrate adsorption,

polyethylene glycol Polyethylene glycol (PEG; ) is a polyether compound derived from petroleum with many applications, from industrial manufacturing to medicine. PEG is also known as polyethylene oxide (PEO) or polyoxyethylene (POE), depending on its molecular we ...

fractionation, DEAE-Sepharose CL-6B treatment, ammonium sulfate fractionation, dextran sulfate-agarose chromatography, gel filtration on ACA-44, and DEAE-Sephacel chromatography.

Structure

The structure (primary structure) of protein C inhibitor was deduced from its cDNA

nucleotide sequence A nucleic acid sequence is a succession of bases signified by a series of a set of five different letters that indicate the order of nucleotides forming alleles within a DNA (using GACT) or RNA (GACU) molecule. By convention, sequences are usu ...

. The human Protein C inhibitor have 19

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

signal peptide.

Gene organization

The study of genomic DNA by restriction mapping, polymerase chain reaction analysis and DNA sequencing showed the gene being 11.5 kilobases in length, consisting of five

exons An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...

separated by four

introns An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e. a region inside a gene."The notion of the cistron .e., gene. ...

. The genetic code of protein C inhibitor is similar to

alpha 1-antitrypsin Alpha-1 antitrypsin or α1-antitrypsin (A1AT, α1AT, A1A, or AAT) is a protein belonging to the serpin superfamily. It is encoded in humans by the ''SERPINA1'' gene. A protease inhibitor, it is also known as alpha1–proteinase inhibitor (A1PI) ...

and

alpha 1-antichymotrypsin Alpha 1-antichymotrypsin (symbol α1AC, A1AC, or a1ACT) is an alpha globulin glycoprotein that is a member of the serpin superfamily. In humans, it is encoded by the ''SERPINA3'' gene. Function Alpha 1-antichymotrypsin inhibits the activity o ...

Metabolism

The in vivo

half time In several team sports, matches are played in two halves. Half-time (also written halftime or half time) is the name given to the interval between the two halves of the match. Typically, after half-time, teams swap ends of the field of play in or ...

degradation Degradation may refer to: Science * Degradation (geology), lowering of a fluvial surface by erosion * Degradation (telecommunications), of an electronic signal * Biodegradation of organic substances by living organisms * Environmental degradatio ...

of protein C inhibitor in plasma is found to be 23 hours, whereas the half time degradation of protein C inhibitor and protein C complex is 20 minutes.

Binding with heparin

Protein C inhibitors have ability to inhibit protein C,

and other enzymes that are stimulated by heparin. The heparin binding site of protein C inhibitor is from 264-283 region. Heparin enhances the rate of inhibition leading to the

conformational change In biochemistry, a conformational change is a change in the shape of a macromolecule, often induced by environmental factors. A macromolecule is usually flexible and dynamic. Its shape can change in response to changes in its environment or oth ...

in the structure of Protein C and other proteases. The binding site of heparin is different for protein C inhibitor and other proteases Heparin regulates the protein C inhibitor (PCI) activity and furthermore its specificity in those system where there is presence of two or more target proteases.

Clinical significance

As an antimicrobial agent

Protein C inhibitor interacts with lipid membrane subsequently leading to permeabilization of bacterial pathogen exerting the antimicrobial activity. Protein C inhibitor a potent antimicrobial agent that have ability to destroy the bacterial cell wall, causing death of the bacteria.

Reproduction

Protein C inhibitor significantly reduces

fertilization Fertilisation or fertilization (see spelling differences), also known as generative fertilisation, syngamy and impregnation, is the fusion of gametes to give rise to a new individual organism or offspring and initiate its development. Proce ...

by inhibiting both the binding and penetration of zona free

hamster Hamsters are rodents (order Rodentia) belonging to the subfamily Cricetinae, which contains 19 species classified in seven genera.Fox, Sue. 2006. ''Hamsters''. T.F.H. Publications Inc. They have become established as popular small pets. The b ...

oocytes by human sperm. This effect of PCI is dose dependent as 0.04MicroM PCI inhibited 50% binding and penetration ability.

Inhibition of tumor growth

PCI communicated by malignant cells smothers tumor invasion by hindering urokinase-sort

plasminogen activator Plasminogen activators are serine proteases that catalyze the activation of plasmin via proteolytic cleavage of its zymogen form plasminogen. Plasmin is an important factor in fibrinolysis, the breakdown of fibrin polymers formed during blood clotti ...

, and restrains tumor development and

metastasis Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...

which is independent of its protease inhibitory activity.

Deficiency

Deficiency of protein C inhibitor in the human body may cause male infertility. Protein C inhibitor has a role in reproduction as it has ability to inhibit the

sperm Sperm is the male reproductive cell, or gamete, in anisogamous forms of sexual reproduction (forms in which there is a larger, female reproductive cell and a smaller, male one). Animals produce motile sperm with a tail known as a flagellum, whi ...

protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...

acrosin Acrosin is a digestive enzyme that acts as a protease. In humans, acrosin is encoded by the ''ACR'' gene. Acrosin is released from the acrosome of spermatozoa as a consequence of the acrosome reaction. It aids in the penetration of the Zona Pellu ...

. Large amounts of protein C inhibitor circulate in the male reproductive organ as a plasma protein. Either deficiency or the presence of inactive protein C inhibitor can lead to male caused infertility.

Interactions

Protein C inhibitor has often been shown to

interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...

with

prostate specific antigen Prostate-specific antigen (PSA), also known as gamma-seminoprotein or kallikrein-3 (KLK3), P-30 antigen, is a glycoprotein enzyme encoded in humans by the ''KLK3'' gene. PSA is a member of the kallikrein-related peptidase family and is secreted b ...

and

PLAU Urokinase, also known as urokinase-type plasminogen activator (uPA), is a serine protease present in humans and other animals. The human urokinase protein was discovered, but not named, by McFarlane and Pilling in 1947. Urokinase was originally i ...

References

External links

* The

MEROPS MEROPS is an online database for peptidases (also known as proteases, proteinases and proteolytic enzymes) and their inhibitors. The classification scheme for peptidases was published by Rawlings & Barrett in 1993, and that for protein inhibitor ...

online database for peptidases and their inhibitors
I04.004
* {{DEFAULTSORT:Protein C Inhibitor Serine protease inhibitors