Cyclophilins (CYPs) are a family of proteins named after their ability to bind to

ciclosporin Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is a natural product. It is taken orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease, ...

(cyclosporin A), an

immunosuppressant Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent activity of the immune system. Classification Immunosuppressive drugs can be classified in ...

which is usually used to suppress rejection after internal organ transplants. They are found in all domains of life. These proteins have peptidyl

prolyl isomerase Prolyl isomerase (also known as peptidylprolyl isomerase or PPIase) is an enzyme () found in both prokaryotes and eukaryotes that interconverts the ''cis'' and ''trans'' isomers of peptide bonds with the amino acid proline. Proline has an unusua ...

activity, which

catalyzes Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...

the

isomerization In chemistry, isomerization or isomerisation is the process in which a molecule, polyatomic ion or molecular fragment is transformed into an isomer with a different chemical structure. Enolization is an example of isomerization, as is tautomeri ...

of peptide bonds from ''trans'' form to ''cis'' form at proline residues and facilitates protein folding. Cyclophilin A is a

cytosolic The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrio ...

and highly abundant protein. The protein belongs to a family of

isozymes In biochemistry, isozymes (also known as isoenzymes or more generally as multiple forms of enzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. Isozymes usually have different kinetic parameters (e.g. dif ...

, including cyclophilins B and C, and natural killer cell cyclophilin-related protein. Major isoforms have been found within single cells, including inside the Endoplasmic reticulum, and some are even secreted.

Mammalian cyclophilins

Human genes encoding proteins containing the cyclophilin domain include: *

PPIA Peptidylprolyl isomerase A (PPIA), also known as cyclophilin A (CypA) or rotamase A is an enzyme that in humans is encoded by the ''PPIA'' gene on chromosome 7. As a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family, this protein ca ...

PPIB Peptidyl-prolyl cis-trans isomerase B is an enzyme that is encoded by the ''PPIB'' gene. As a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family, this protein catalyzes the cis-trans isomerization of proline imidic peptide bonds, w ...

, PPIC, PPID, PPIE,

PPIF Peptidyl-prolyl cis-trans isomerase, mitochondrial (PPIF) is an enzyme that in humans is encoded by the ''PPIF'' gene. It has also been referred to as, but should not be confused with, cyclophilin D (CypD), which is encoded by the '' PPID'' gene. ...

, PPIG,

PPIH Peptidyl-prolyl cis-trans isomerase H is an enzyme that in humans is encoded by the ''PPIH'' gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''ge ...

PPIL1 Peptidyl-prolyl cis-trans isomerase-like 1 is an enzyme that in humans is encoded by the ''PPIL1'' gene. This gene is a member of the cyclophilin family of peptidylprolyl isomerases (PPIases). The cyclophilins are a highly conserved, ubiquitous ...

PPIL2 Peptidyl-prolyl cis-trans isomerase-like 2 is an enzyme that in humans is encoded by the ''PPIL2'' gene. This gene is a member of the cyclophilin family of peptidylprolyl isomerases. The cyclophilins are a highly conserved ubiquitous family, membe ...

PPIL3 Peptidyl-prolyl cis-trans isomerase-like 3 is an enzyme that in humans is encoded by the ''PPIL3'' gene. Function This gene encodes a member of the cyclophilin family. Cyclophilins catalyze the cis-trans isomerization of peptidylprolyl imide bo ...

PPIL4 Peptidyl-prolyl cis-trans isomerase-like 4 is an enzyme that in humans is encoded by the ''PPIL4'' gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meanin ...

, PPIAL4, PPIL6 * PPWD1

Cyclophilin A

Cyclophilin A Peptidylprolyl isomerase A (PPIA), also known as cyclophilin A (CypA) or rotamase A is an enzyme that in humans is encoded by the ''PPIA'' gene on chromosome 7. As a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family, this protein ca ...

(CYPA) also known as peptidylprolyl isomerase A (PPIA), which is found in the

cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrio ...

, has a

beta barrel In protein structures, a beta barrel is a beta sheet composed of tandem repeats that twists and coils to form a closed toroidal structure in which the first strand is bonded to the last strand (hydrogen bond). Beta-strands in many beta-barrels are ...

structure with two

alpha helices The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues ea ...

and a

beta-sheet The beta sheet, (β-sheet) (also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a gen ...

. Other cyclophilins have similar structures to cyclophilin A. The cyclosporin-cyclophilin A complex inhibits a

calcium Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar ...

calmodulin Calmodulin (CaM) (an abbreviation for calcium-modulated protein) is a multifunctional intermediate calcium-binding messenger protein expressed in all eukaryotic cells. It is an intracellular target of the secondary messenger Ca2+, and the bind ...

-dependent

phosphatase In biochemistry, a phosphatase is an enzyme that uses water to cleave a phosphoric acid monoester into a phosphate ion and an alcohol. Because a phosphatase enzyme catalyzes the hydrolysis of its substrate, it is a subcategory of hydrolases. P ...

calcineurin Calcineurin (CaN) is a calcium and calmodulin dependent serine/threonine protein phosphatase (also known as protein phosphatase 3, and calcium-dependent serine-threonine phosphatase). It activates the T cells of the immune system and can be blo ...

, the inhibition of which is thought to suppress

organ rejection Transplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient ...

by halting the production of the pro-inflammatory molecules TNF alpha and interleukin 2. Cyclophilin A is also known to be recruited by the Gag polyprotein during

HIV-1 The subtypes of HIV include two major types, HIV type 1 (HIV-1) and HIV type 2 (HIV-2). HIV-1 is related to viruses found in chimpanzees and gorillas living in western Africa, while HIV-2 viruses are related to viruses found in the sooty mangabey ...

virus infection, and its incorporation into new virus particles is essential for HIV-1 infectivity.

Cyclophilin D

Cyclophilin D (PPIF, note that literature is confusing, the mitochondrial cyclophilin is encoded by the PPIF gene), which is located in the

matrix Matrix most commonly refers to: * ''The Matrix'' (franchise), an American media franchise ** '' The Matrix'', a 1999 science-fiction action film ** "The Matrix", a fictional setting, a virtual reality environment, within ''The Matrix'' (franchi ...

of mitochondria, is only a modulatory, but may or may not be a structural component of the

mitochondrial permeability transition pore The mitochondrial permeability transition pore (mPTP or MPTP; also referred to as PTP, mTP or MTP) is a protein that is formed in the inner membrane of the mitochondria under certain pathological conditions such as traumatic brain injury and st ...

. The pore opening raises the permeability of the mitochondrial inner membrane, allows influx of

ic molecules into the

mitochondrial matrix In the mitochondrion, the matrix is the space within the inner membrane. The word "matrix" stems from the fact that this space is viscous, compared to the relatively aqueous cytoplasm. The mitochondrial matrix contains the mitochondrial DNA, ribo ...

, increases the matrix volume, and disrupts the mitochondrial outer membrane. As a result, the mitochondria fall into a functional disorder, so the opening of the pore plays an important role in

cell death Cell death is the event of a biological cell ceasing to carry out its functions. This may be the result of the natural process of old cells dying and being replaced by new ones, as in programmed cell death, or may result from factors such as dis ...

. Cyclophilin D is thought to regulate the opening of the pore because cyclosporin A, which binds to CyP-D, inhibits the pore opening. However, mitochondria obtained from the cysts of Artemia franciscana, do not exhibit the mitochondrial permeability transition pore

Clinical significance

Diseases

Overexpression of Cyclophilin A has been linked to poor response to inflammatory diseases, the progression or metastasis of cancer, and aging.

Cyclophilins as drug targets

Cyclophilin inhibitors, such as

cyclosporin Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is a natural product. It is taken orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease, ...

, are being developed to treat

neurodegenerative disease A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...

s.J&J targets degenerative diseases in cyclophilin inhibitor partnership. Dan Stanton. 08-Dec-2015
/ref> Cyclophilin inhibition may also be a therapy for liver diseases.

References

External links

* {{Portal bar, Biology, border=no EC 5.2.1 Isomerases