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. ...

enzymes Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...

capable of cleaving peptide bonds in proteins. In humans,

plasma kallikrein Plasma kallikrein (, ''serum kallikrein'', ''kininogenin'', ''kallikrein I'', ''kallikrein II'', ''kininogenase'', ''kallikrein'', ''callicrein'', ''glumorin'', ''padreatin'', ''padutin'', ''kallidinogenase'', ''bradykininogenase'', ''panceatic ka ...

(encoded by ''

KLKB1 KLKB1 is a gene that, in humans, encodes the ''Plasma kallikrein'' protein. Function Plasma prekallikrein is a glycoprotein that participates in the surface-dependent activation of blood coagulation, fibrinolysis, kinin generation and inflamm ...

gene'') has no known

paralogue Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a s ...

, 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, 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 pat ...

reported finding a substance in the

pancreas The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an end ...

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 for 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 solenodons 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 different ...

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 v ...

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

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 pr ...

, 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. 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 the ''F12'' gene. Struc ...

PRCP Lysosomal Pro-X carboxypeptidase is an enzyme that in humans is encoded by the ''PRCP'' gene. The protein encoded by this gene is a lysosomal prolylcarboxypeptidase, which cleaves C-terminal amino acids linked to proline in peptides such as ang ...

or other stimuli. Plasma kallikrein liberates

kinin A kinin is any of various structurally related polypeptides, 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) (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 hyperpolarizing factor and ...

and

kallidin Kallidin is a bioactive kinin formed in response to injury from kininogen precursors through the action of kallikreins. Kallidin is a decapeptide whose sequence is H-Lys-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH. It can be converted to bradykinin b ...

) from the

kininogen Kininogens are precursor proteins for kinins, biologically active polypeptides involved in blood coagulation, vasodilation, smooth muscle contraction, inflammatory regulation, and the regulation of the cardiovascular and renal systems. Types o ...

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 clots. The degradation of fibrin is termed fibrinolysis. In humans, the plasmin protein (in the zymogen form of plasminogen) is encode ...

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 encode ...

Structure

Kallikrein is homologous to

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

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 Kallikrein-1 is a protein that in humans is encoded by the ''KLK1'' gene. KLK1 is a member of the peptidase S1 family. Kallikreins are a subgroup of serine proteases having diverse physiological functions. Growing evidence suggests that many kall ...

KLK2 Kallikrein-2 is a protein that in humans is encoded by the ''KLK2'' gene, and is particularly associated with prostatic tissue. References Further reading * * * * * * * * * * * * * * * * * * * External links * The MEROPS MEROPS is an onli ...

and

KLK12 Kallikrein-12 is a protein that in humans is encoded by the ''KLK12'' gene. Kallikreins are a subgroup of serine proteases having diverse physiological functions. Growing evidence suggests that many kallikreins are implicated in carcinogenesis an ...

also participate in regulation of blood pressure via the activation of bradykinin. KLK2,

KLK3 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 ...

, KLK4,

KLK5 Kallikrein-5, formerly known as stratum corneum tryptic enzyme (SCTE), is a serine protease expressed in the epidermis. In humans it is encoded by the ''KLK5'' gene. This gene is one of the fifteen kallikrein subfamily members located in a clust ...

and

KLK14 Kallikrein-14 is a protein that in humans is encoded by the ''KLK14'' gene. Kallikreins are a subgroup of serine proteases having diverse physiological functions. Growing evidence suggests that many kallikreins are implicated in carcinogenesis an ...

are expressed in the prostate and are thought to be responsible for regulating semen liquefaction through hydrolysis of

semenogelin Semenogelin is a protein that is involved in the formation of a gel matrix that encases ejaculated spermatozoa, preventing capacitation. It blocks capacitation mainly via inhibition of reactive oxygen species In chemistry, reactive oxygen species ...

Desquamation Desquamation occurs when the outermost layer of a tissue, such as the skin, is shed. The term is . Physiologic desquamation Keratinocytes are the predominant cells of the epidermis, the outermost layer of the skin. Living keratinocytes reside in ...

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 t ...

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:

, KLK4,

, KLK6,

, KLK8,

KLK9 Kallikrein-related peptidase 9 also known as KLK9 is an enzyme which in humans is encoded by the ''KLK9'' gene. Function KLK9 belongs to the kallikrein subgroup of serine proteases, which have diverse physiologic functions in many tissues. KL ...

, KLK10, KLK11,

KLK13 Kallikrein-13 is a protein that in humans is encoded by the ''KLK13'' gene. Function Kallikreins are a subgroup of serine proteases having diverse physiological functions. As of 2022, the precise physiological functions of Kallikrein 13 remai ...

, 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, p ...

s for cancer.

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 ...

(PSA; hk3, human kallikrein gene 3) and human glandular kallikrein (hK2) are used as

tumor marker A tumor marker is a biomarker found in blood, urine, or body tissues that can be elevated by the presence of one or more types of cancer. There are many different tumor markers, each indicative of a particular disease process, and they are used in ...

s for prostate cancer.

Ecallantide Ecallantide (trade name Kalbitor) is a 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 polypeptide which wa ...

lanadelumab Lanadelumab, sold under the brand name Takhzyro, is a human monoclonal antibody (class IgG1 kappa) that targets plasma kallikrein (pKal) in order to promote prevention of angioedema in people with hereditary angioedema. Lanadelumab, was approved ...

, and

berotralstat Berotralstat, sold under the brand name Orladeyo, is a medication used to prevent attacks of hereditary angioedema (HAE) in people aged twelve years and older. The most common side effects include abdominal pain, vomiting, diarrhea, back pain, ...

are FDA-approved drugs that inhibit kallikrein and can be used for managing

Hereditary Angioedema Hereditary angioedema (HAE) is a disorder that results in recurrent attacks of severe swelling. The swelling most commonly affects the arms, legs, face, intestinal tract, and airway. If the intestinal tract is affected, abdominal pain and vomitin ...

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
S01.212
* {{Portal bar, Biology, border=no EC 3.4.21 Kinin–kallikrein system Urticaria and angioedema