Kallikreins are a subgroup of serine proteases, enzymes 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, semen liquefaction and skin desquamation.
In 1934, Eugen Werle reported finding a substance in the pancreas 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. [1]
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. [2]
The venom of solenodons and some shrews like the northern short-tailed shrew consist of multiple copies of kallikrein 1 (KLK1) serine proteases. [3] KLK1 are very similar to serine protease found in venomous snakes like vipers, and have evolved in parallel from a common toxin precursor, [4] which cause hypotensive effects in vivo. [5]
The KLKB1 gene encoding plasma kallikrein is located on chromosome 4q34-35. It is synthesised as an inactive precursor, prekallikrein, which must undergo proteolytic processing to become activated. This is facilitated by factor XII, PRCP or other stimuli.[ citation needed ]
Plasma kallikrein liberates kinins (bradykinin and kallidin) from the kininogens, [6] [7] peptides responsible for the regulation of blood pressure and activation of inflammation. It is also capable of generating plasmin from plasminogen:
Kallikrein is homologous to factor XI and consists of four apple domains and one serine protease domain.[ citation needed ]
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.[ citation needed ]
Similar to KLKB1, three tissue kallikreins KLK1, KLK2 and KLK12 also participate in regulation of blood pressure via the activation of bradykinin. [8] KLK2, KLK3, KLK4, KLK5 and KLK14 are expressed in the prostate and are thought to be responsible for regulating semen liquefaction through hydrolysis of semenogelin. [9] [10] Desquamation of the skin is likely controlled by KLK5, KLK7 and KLK14, which are expressed in the outermost layer of the epidermis and cleave cellular adhesion proteins. [11] Additionally, KLK6 and KLK8 are associated with neuronal plasticity in the central nervous system. [12]
There are 15 known human tissue kallikreins: KLK1, KLK2, KLK3, KLK4, KLK5, KLK6, KLK7, KLK8, KLK9, KLK10, KLK11, KLK12, KLK13, KLK14, KLK15.[ citation needed ]
Kallikrein-related peptidases are targets of active investigation by drug researchers as possible biomarkers for cancer. [13] [14]
Prostate-specific antigen (PSA; hk3, human kallikrein gene 3) and human glandular kallikrein (hK2) are used as tumor markers for prostate cancer.[ citation needed ]
Ecallantide, 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 [15] .
The kinin–kallikrein system or simply kinin system is a poorly understood hormonal system with limited available research. It consists of blood proteins that play a role in inflammation, blood pressure control, coagulation and pain. Its important mediators bradykinin and kallidin are vasodilators and act on many cell types. Clinical symptoms include marked weakness, tachycardia, fever, leukocytosis and acceleration of ESR.
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 produce kallikrein by activated Factor XII.
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.
Renal tissue kallikrein is an enzyme.
Kallikrein-1 is a protein that in humans is encoded by the KLK1 gene. KLK1 is a member of the peptidase S1 family.
Kallikrein-2 is a protein that in humans is encoded by the KLK2 gene, and is particularly associated with prostatic tissue.
Kallikrein-6 is a protein that in humans is encoded by the KLK6 gene. Kallikrein-6 is also referred to as neurosin, protease M, hK6, or zyme. It is a 223 amino acid sequence, derived from its 244 original form, which contains a 16 residue presignal and 5 residue activation peptide.
Kallikrein-10 is a protein that in humans is encoded by the KLK10 gene.
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 cluster on chromosome 19. Its expression is up-regulated by estrogens and progestins. Alternative splicing results in multiple transcript variants encoding the same protein.
Kallikrein-related peptidase 4 is a protein which in humans is encoded by the KLK4 gene.
Lympho-epithelial Kazal-type-related inhibitor (LEKTI) also known as serine protease inhibitor Kazal-type 5 (SPINK5) is a protein that in humans is encoded by the SPINK5 gene.
Kallikrein-11 is a protein that in humans is encoded by the KLK11 gene.
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 the seventh member of the human kallikrein family, which includes fifteen homologous serine proteases located on chromosome 19 (19q13).
Kallikrein-13 is a protein that in humans is encoded by the KLK13 gene.
Kallikrein-8 is a protein that in humans is encoded by the KLK8 gene.
Kallikrein-14 is a protein that in humans is encoded by the KLK14 gene.
Kallikrein-15 is a protein that in humans is encoded by the KLK15 gene.
Kallikrein-12 is a protein that in humans is encoded by the KLK12 gene.
Kallikrein-related peptidase 9 also known as KLK9 is an enzyme which in humans is encoded by the KLK9 gene.
Serine protease inhibitor Kazal-type 6 (SPINK6) is a protein encoded by the SPINK6 gene in humans. It is a potent inhibitor of epidermal proteases involved in maintaining skin homeostasis, including KLK5, KLK7 and KLK14. SPINK6 is a member of a gene family cluster located on chromosome 5q33.1, which includes SPINK5 and SPINK9.