Kallikreins are a subgroup of

serine protease 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. Serin ...

enzymes An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as pro ...

capable of cleaving peptide bonds in proteins. In humans, plasma kallikrein (encoded by '' KLKB1 gene'') has no known paralogue, while tissue kallikrein-related peptidases (''KLKs'') encode a family of fifteen closely related serine proteases. These genes are localised to chromosome 19q13, forming the largest contiguous cluster of proteases within the human genome. Kallikreins are responsible for the coordination of various physiological functions including

blood pressure Blood pressure (BP) is the pressure of Circulatory system, circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term ...

, semen liquefaction and skin desquamation.

Occurrence

In 1934,

Eugen Werle Eugen is a masculine given name which may refer to: * Archduke Eugen of Austria (1863–1954), last Habsburg Grandmaster of the Teutonic Order from 1894 to 1923 * Prince Eugen, Duke of Närke (1865–1947), Swedish painter, art collector, and pa ...

reported finding a substance in the

pancreas The pancreas (plural pancreases, or pancreata) is an Organ (anatomy), organ of the Digestion, digestive system and endocrine system of vertebrates. In humans, it is located in the abdominal cavity, abdomen behind the stomach and functions as a ...

of humans and various animals in such large amounts that the pancreas could be taken for its site of origin. He named it kallikrein, by derivation from the Greek word καλλίκρεας (''kallíkreas'') 'pancreas'. Since then, similar enzymes have been found in the biological fluids of humans and other mammals, as well as in some snake venoms.

Venom

The caterpillar known as '' Lagoa crispata'' contains poison glands attached to hypodermic spines, which produce and inject venom that has been characterized as kallikrein in nature. The venom of

solenodon Solenodons (from , 'channel' or 'pipe' and , 'tooth') are venomous, nocturnal, burrowing, insectivorous mammals belonging to the family Solenodontidae . The two living solenodon species are the Cuban solenodon (''Atopogale cubana'') and t ...

s and some

shrews Shrews (family Soricidae) are small mole-like mammals classified in the order Eulipotyphla. True shrews are not to be confused with treeshrews, otter shrews, elephant shrews, West Indies shrews, or marsupial shrews, which belong to diffe ...

like the

northern short-tailed shrew The northern short-tailed shrew (''Blarina brevicauda'') is the largest shrew in the genus '' Blarina'', and occurs in the northeastern region of North America. It is a semifossorial, highly active, and voracious insectivore and is present in a ...

consist of multiple copies of kallikrein 1 (''KLK1'') serine proteases. KLK1 are very similar to serine protease found in venomous snakes like vipers, and have evolved in parallel from a common toxin precursor, which cause hypotensive effects ''in vivo''.

Plasma kallikrein

The ''KLKB1'' gene encoding plasma kallikrein is located on chromosome 4q34-35. It is synthesised as an inactive precursor,

prekallikrein Prekallikrein (PK), also known as Fletcher factor, is an 85,000 Mr serine protease that complexes with high-molecular-weight kininogen. PK is the precursor of plasma kallikrein, which is a serine protease that activates kinins. PK is cleaved to ...

, which must undergo proteolytic processing to become activated. This is facilitated by

factor XII Coagulation factor XII, also known as Hageman factor, is a plasma protein involved in coagulation. It is the zymogen form of factor XIIa (), an enzyme of the serine protease (or serine endopeptidase) class. In humans, factor XII is encoded by ' ...

, PRCP or other stimuli. Plasma kallikrein liberates

kinin A kinin is any of various structurally related peptides, such as bradykinin and kallidin. They are members of the autacoid family. Kinins are peptides that are cleaved from kininogens by the process of kallikreins. Kallikreins activate kinins ...

s (

bradykinin Bradykinin (BK) (from Greek ''brady-'' 'slow' + ''-kinin'', ''kīn(eîn)'' 'to move') is a peptide that promotes inflammation. It causes arterioles to dilate (enlarge) via the release of prostacyclin, nitric oxide, and endothelium-derived hyperpo ...

and kallidin) from the

kininogen Kininogens are Protein precursor, precursor proteins for Kinin, kinins, biologically active Peptide, polypeptides involved in blood coagulation, vasodilation, smooth muscle contraction, Inflammation, inflammatory regulation, and the regulation of t ...

s, peptides responsible for the regulation of blood pressure and activation of inflammation. It is also capable of generating

plasmin Plasmin is an important enzyme () present in blood that degrades many blood plasma proteins, including fibrin thrombus, clots. The degradation of fibrin is termed fibrinolysis. In humans, the plasmin protein (in the zymogen form of plasminogen) i ...

from

plasminogen Plasmin is an important enzyme () present in blood that degrades many blood plasma proteins, including fibrin clots. The degradation of fibrin is termed fibrinolysis. In humans, the plasmin protein (in the zymogen form of plasminogen) is enco ...

Structure

Kallikrein is homologous to

factor XI Factor XI, or plasma thromboplastin antecedent, is the zymogen form of factor XIa, one of the enzymes involved in coagulation. Like many other coagulation factors, it is a serine protease. In humans, factor XI is encoded by ''F11'' gene. Fu ...

and consists of four apple domains and one

domain.

Tissue kallikreins

Distinct from plasma kallikrein, tissue kallikreins (KLKs) are expressed throughout the human body and perform various physiological roles. As some kallikreins are able to catalyse the activation of other kallikreins, several cascades involving these proteases have been implicated in the regulation of homeostatic functions.

Function

Similar to KLKB1, three tissue kallikreins KLK1, KLK2 and KLK12 also participate in regulation of blood pressure via the activation of bradykinin. KLK2, KLK3,

KLK4 Kallikrein-related peptidase 4 is a protein which in humans is encoded by the ''KLK4'' gene. Kallikreins are a subgroup of serine proteases having diverse physiological functions. Growing evidence suggests that many kallikreins are implicated in ...

, KLK5 and KLK14 are expressed in the prostate and are thought to be responsible for regulating semen liquefaction through hydrolysis of semenogelin.

Desquamation Desquamation, or peeling skin, is the shedding of dead cells from the outermost layer of skin. The term is . Physiologic desquamation Keratinocytes are the predominant cells of the epidermis, the outermost layer of the skin. Living keratin ...

of the skin is likely controlled by KLK5,

KLK7 Kallikrein-related peptidase 7 (KLK7) is a serine protease that in humans is encoded by the ''KLK7'' gene. KLK7 was initially purified from the epidermis and characterised as stratum corneum chymotryptic enzyme (SCCE). It was later identified as ...

and KLK14, which are expressed in the outermost layer of the epidermis and cleave cellular adhesion proteins. Additionally, KLK6 and KLK8 are associated with neuronal plasticity in the central nervous system.

Genes

There are 15 known human tissue kallikreins: KLK1, KLK2, KLK3,

, KLK5, KLK6,

, KLK8, KLK9, KLK10, KLK11, KLK12, KLK13, KLK14, KLK15.

Clinical significance

Kallikrein-related peptidases are targets of active investigation by drug researchers as possible

biomarker In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...

s for cancer. Prostate-specific antigen (PSA; hk3, human kallikrein gene 3) and human glandular kallikrein (hK2) are used as

tumor marker A tumor marker is a biomarker that can be used to indicate the presence of cancer or the behavior of cancers (measure progression or response to therapy). They can be found in bodily fluids or tissue. Markers can help with assessing prognosis, s ...

s for prostate cancer.

Ecallantide Ecallantide (trade name Kalbitor) is a pharmaceutical drug, drug used for the treatment of hereditary angioedema (HAE) and in the prevention of blood loss in cardiothoracic surgery. It is an inhibitor of the protein kallikrein and a 60-amino acid ...

, lanadelumab, and berotralstat are FDA-approved drugs that inhibit kallikrein and can be used for managing hereditary angioedema. A missense variant on KLK15 has been associated with hypermobile Ehlers-Danlos syndrome.

References

External links

* The MEROPS online database for peptidases and their inhibitors
S01.212
* {{Portal bar, Biology, border=no EC 3.4.21 Kinin–kallikrein system Urticaria and angioedema