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. S ...

s, enzymes capable of cleaving peptide bonds in proteins. In humans, plasma kallikrein (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 infla ...

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 spec ...

, 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 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 "blood pressur ...

semen liquefaction A semen analysis (plural: semen analyses), also called seminogram or spermiogram, evaluates certain characteristics of a male's semen and the sperm contained therein. It is done to help evaluate male fertility, whether for those seeking pregnancy ...

and

skin 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 ...

Occurrence

In 1934, Eugen Werle 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 en ...

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 ''Megalopyge crispata'', the black-waved flannel moth, crinkled flannel moth or white flannel moth, is a moth of the Megalopygidae family. It is found along the east coast of the United States, and as far inland as Oklahoma. This wingspan is 25� ...

'' 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 like the northern short-tailed shrew 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. 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 a ...

or other stimuli. Plasma kallikrein liberates kinins (

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 m ...

and kallidin) 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 ...

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 encod ...

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'' gen ...

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,

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 clus ...

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

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: KLK1, KLK2, KLK3, KLK4,

, KLK6,

, KLK8, KLK9,

KLK10 Kallikrein-10 is a protein that in humans is encoded by the ''KLK10'' gene. Kallikreins are a subgroup of serine proteases having diverse physiological functions. Growing evidence suggests that many kallikreins are implicated in carcinogenesis an ...

KLK11 Kallikrein-11 is a protein that in humans is encoded by the ''KLK11'' gene. Kallikreins are a subgroup of serine proteases having diverse physiological functions. Growing evidence suggests that many kallikreins are implicated in carcinogenesis an ...

, 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, 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 ...

(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, lanadelumab, and berotralstat are FDA-approved drugs that inhibit kallikrein and can be used for managing Hereditary Angioedema.

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 inhibi ...

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