Dipeptidyl peptidase-4 (DPP4), also known as adenosine deaminase complexing protein 2 or CD26 (
cluster of differentiation
The cluster of differentiation (also known as cluster of designation or classification determinant and often abbreviated as CD) is a protocol used for the identification and investigation of cell surface molecules providing targets for immunophen ...
26) is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
that, in humans, is encoded by the ''DPP4''
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
.
DPP4 is related to
FAP,
DPP8
Dipeptidyl peptidase 8 is an enzyme that in humans is encoded by the ''DPP8'' gene.
This gene encodes a member of the peptidase S9B family, a small family of dipeptidyl peptidases that are able to cleave peptide substrates at a prolyl bond. The e ...
, and
DPP9
Dipeptidyl peptidase 9 is an enzyme that in humans is encoded by the ''DPP9'' gene.
This gene encodes a protein that is a member of the S9B family in clan SC of the serine proteases. The protein has been shown to have post-proline dipeptidyl ami ...
. The enzyme was discovered in 1966 by Hopsu-Havu and Glenner, and as a result of various studies on chemism, was called dipeptidyl peptidase IV
P IV
P, or p, is the sixteenth letter of the Latin alphabet, used in the modern English alphabet, the alphabets of other western European languages and others worldwide. Its name in English is ''pee'' (pronounced ), plural ''pees''.
History
The ...
Function
The protein encoded by the ''DPP4'' gene is an
enzyme
Enzymes () are proteins that act as biological catalysts 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 products ...
expressed on the surface of most cell types and is associated with immune regulation,
signal transduction, and
apoptosis. It is a type II transmembrane
glycoprotein, but a soluble form, which lacks the intracellular and transmembrane part, is present in blood plasma and various body fluids. DPP-4 is a
serine exopeptidase
An exopeptidase is any peptidase that catalyzes the cleavage of the terminal (or the penultimate) peptide bond; the process releases a single amino acid, dipeptide or a tripeptide from the peptide chain. Depending on whether the amino acid is rel ...
that cleaves X-proline or X-alanine
dipeptide A dipeptide is an organic compound derived from two amino acids. The constituent amino acids can be the same or different. When different, two isomers of the dipeptide are possible, depending on the sequence. Several dipeptides are physiologicall ...
s from the
N-terminus of
polypeptides. Peptide bonds involving the cyclic amino acid proline cannot be cleaved by the majority of proteases and an N-terminal X-proline "shields" various biopeptides. Extracellular proline-specific proteases therefore play an important role in the regulation of these biopeptides.
DPP-4 is known to cleave a broad range of
substrates including
growth factor
A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for regul ...
s,
chemokine
Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In additio ...
s,
neuropeptide
Neuropeptides are chemical messengers made up of small chains of amino acids that are synthesized and released by neurons. Neuropeptides typically bind to G protein-coupled receptors (GPCRs) to modulate neural activity and other tissues like the ...
s, and
vasoactive peptides.
The cleaved substrates lose their biological activity in the majority of cases, but in the case of the chemokine RANTES and neuropeptide Y, DPP-4 mediated cleavage leads to a shift in the receptor subtype binding.
DPP4 plays a major role in
glucose
Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, u ...
metabolism. It is responsible for the degradation of
incretin
Incretins are a group of metabolic hormones that stimulate a decrease in blood glucose levels. Incretins are released after eating and augment the secretion of insulin released from pancreatic beta cells of the islets of Langerhans by a blood-gl ...
s such as
GLP-1
Glucagon-like peptide-1 (GLP-1) is a 30- or 31-amino-acid-long peptide hormone deriving from the tissue-specific posttranslational processing of the proglucagon peptide. It is produced and secreted by intestinal enteroendocrine L-cells and certa ...
.
Furthermore, it appears to work as a suppressor in the development of some
tumors
A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
.
DPP-4 also binds the enzyme
adenosine deaminase
Adenosine deaminase (also known as adenosine aminohydrolase, or ADA) is an enzyme () involved in purine metabolism. It is needed for the breakdown of adenosine from food and for the turnover of nucleic acids in tissues.
Its primary function ...
specifically and with high affinity. The significance of this interaction has yet to be established.
Animal studies
Animal studies suggest its pathogenetic role in development of
fibrosis
Fibrosis, also known as fibrotic scarring, is a pathological wound healing in which connective tissue replaces normal parenchymal tissue to the extent that it goes unchecked, leading to considerable tissue remodelling and the formation of perma ...
of various organs, such as liver and kidney.
Clinical significance
CD26/DPPIV plays an important role in tumor biology, and is useful as a marker for various cancers, with its levels either on the cell surface or in the serum increased in some
neoplasm
A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
s and decreased in others.
A class of
oral hypoglycemics
Drugs used in diabetes treat diabetes mellitus by altering the glucose level in the blood. With the exceptions of insulin, most GLP receptor agonists ( liraglutide, exenatide, and others), and pramlintide, all are administered orally and are th ...
called
dipeptidyl peptidase-4 inhibitors
Inhibitors of dipeptidyl peptidase 4 (DPP-4 inhibitors or gliptins) are a class of oral hypoglycemics that block the enzyme dipeptidyl peptidase-4 (DPP-4). They can be used to treat diabetes mellitus type 2.
The first agent of the class – sit ...
works by inhibiting the action of this enzyme, thereby prolonging
incretin
Incretins are a group of metabolic hormones that stimulate a decrease in blood glucose levels. Incretins are released after eating and augment the secretion of insulin released from pancreatic beta cells of the islets of Langerhans by a blood-gl ...
effect ''in vivo''.
Middle East respiratory syndrome coronavirus
''Middle East respiratory syndrome–related coronavirus'' (''MERS-CoV''), or EMC/2012 ( HCoV-EMC/2012), is the virus that causes Middle East respiratory syndrome (MERS). It is a species of coronavirus which infects humans, bats, and camels. Th ...
has been found to bind to DPP4. It is found on the surface of cells in the airways (such as the lungs) and kidneys. Scientists may be able to use this to their advantage by blocking the virus's entry into the cell.
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See also
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Development of dipeptidyl peptidase-4 inhibitors Dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) are enzyme inhibitors that inhibit the enzyme dipeptidyl peptidase-4 (DPP-4). They are used in the treatment of type 2 diabetes mellitus. Inhibition of the DPP-4 enzyme prolongs and enhances the a ...
*
Berberine
Berberine is a quaternary ammonium salt from the protoberberine group of benzylisoquinoline alkaloids found in such plants as ''Berberis vulgaris'' (barberry), '' Berberis aristata'' (tree turmeric), '' Mahonia aquifolium'' (Oregon grape), '' Hyd ...
References
Further reading
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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 inhibit ...
online database for peptidases and their inhibitors
S09.003*
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EC 3.4.14
Proteases