Citrullination
Encyclopedia
Citrullination or deimination is the term used for the post-translational modification of the amino acid
arginine
in a protein into the amino acid citrulline
. This reaction, shown below, is performed by enzymes called peptidylarginine deiminases (PADs). Note that citrullination of proteins is distinct from the formation of the free amino acid citrulline as part of the urea cycle
or as a byproduct of enzymes of the nitric oxide synthase
family.
The conversion of arginine into citrulline can have important consequences for the structure and function of proteins, since arginine is positively charged at a neutral pH, whereas citrulline is uncharged. This increases the hydrophobicity of the protein, leading to changes in protein folding
.
Proteins that normally contain citrulline residues include MBP
, fillagrin, and several histone
proteins, while other proteins, like fibrin and vimentin
, can get citrullinated during cell-death and tissue inflammation. Fibrin and fibrinogen may be favored sites for arginine deimination within rheumatoid joints. Test for presence of anti-citrullinated protein (ACP) antibodies are highly specific (88-96%) for rheumatoid arthritis
(RA), about as sensitive as Rheumatoid factor
(70-78%) for diagnosis of RA, and are detectable from even before the onset of clinical disease.
Citrullinated vimentin is a very promising autoantigen in RA, and, more important, a very suitable tool for studying this systemic autoimmune disease. Moreover, anti-MCV antibodies may be useful for monitoring effects of RA therapy. A newly developed ELISA
system utilises genetically modified citrullinated vimentin (MCV
), a naturally occurring isoform of vimentin to improve the performance of the test.
In the reaction from arginine to citrulline, one of the terminal nitrogen
atoms of the arginine sidechain is replaced by an oxygen
. The reaction uses one water
molecule and yields ammonia
as a side-product:
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
arginine
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
in a protein into the amino acid citrulline
Citrulline
The organic compound citrulline is an α-amino acid. Its name is derived from citrullus, the Latin word for watermelon, from which it was first isolated in 1930.It has the idealized formula H2NCNH3CHCO2H...
. This reaction, shown below, is performed by enzymes called peptidylarginine deiminases (PADs). Note that citrullination of proteins is distinct from the formation of the free amino acid citrulline as part of the urea cycle
Urea cycle
The urea cycle is a cycle of biochemical reactions occurring in many animals that produces urea from ammonia . This cycle was the first metabolic cycle discovered , five years before the discovery of the TCA cycle...
or as a byproduct of enzymes of the nitric oxide synthase
Nitric oxide synthase
Nitric oxide synthases are a family of enzymes that catalyze the production of nitric oxide from L-arginine. NO is an important cellular signaling molecule, having a vital role in many biological processes...
family.
The conversion of arginine into citrulline can have important consequences for the structure and function of proteins, since arginine is positively charged at a neutral pH, whereas citrulline is uncharged. This increases the hydrophobicity of the protein, leading to changes in protein folding
Protein folding
Protein folding is the process by which a protein structure assumes its functional shape or conformation. It is the physical process by which a polypeptide folds into its characteristic and functional three-dimensional structure from random coil....
.
Proteins that normally contain citrulline residues include MBP
Myelin basic protein
Myelin basic protein is a protein believed to be important in the process of myelination of nerves in the central nervous system .MBP was initially sequenced in 1971 after isolation from myelin membranes...
, fillagrin, and several histone
Histone
In biology, histones are highly alkaline proteins found in eukaryotic cell nuclei that package and order the DNA into structural units called nucleosomes. They are the chief protein components of chromatin, acting as spools around which DNA winds, and play a role in gene regulation...
proteins, while other proteins, like fibrin and vimentin
Vimentin
Vimentin is a type III intermediate filament protein that is expressed in mesenchymal cells. IF proteins are found in all metazoan cells as well as bacteria. IF, along with tubulin-based microtubules and actin-based microfilaments, comprise the cytoskeleton...
, can get citrullinated during cell-death and tissue inflammation. Fibrin and fibrinogen may be favored sites for arginine deimination within rheumatoid joints. Test for presence of anti-citrullinated protein (ACP) antibodies are highly specific (88-96%) for rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
(RA), about as sensitive as Rheumatoid factor
Rheumatoid factor
Rheumatoid factor is an autoantibody most relevant in rheumatoid arthritis. It is defined as an antibody against the Fc portion of IgG. RF and IgG join to form immune complexes that contribute to the disease process...
(70-78%) for diagnosis of RA, and are detectable from even before the onset of clinical disease.
Citrullinated vimentin is a very promising autoantigen in RA, and, more important, a very suitable tool for studying this systemic autoimmune disease. Moreover, anti-MCV antibodies may be useful for monitoring effects of RA therapy. A newly developed ELISA
ELISA
Enzyme-linked immunosorbent assay , is a popular format of a "wet-lab" type analytic biochemistry assay that uses one sub-type of heterogeneous, solid-phase enzyme immunoassay to detect the presence of a substance in a liquid sample."Wet lab" analytic biochemistry assays involves detection of an...
system utilises genetically modified citrullinated vimentin (MCV
Mutated citrullinated Vimentin
Detection of autoantibodies against mutated citrullinated vimentin is part of RA diagnostics , especially in sera negative for rheumatoid factor . Anti-MCV antibodies are member of ACPA family, a group of the so called antibodies to citrullinated protein/peptide antigens.Rheumatoid arthritis is an...
), a naturally occurring isoform of vimentin to improve the performance of the test.
In the reaction from arginine to citrulline, one of the terminal nitrogen
Nitrogen
Nitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...
atoms of the arginine sidechain is replaced by an oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
. The reaction uses one water
Water
Water is a chemical substance with the chemical formula H2O. A water molecule contains one oxygen and two hydrogen atoms connected by covalent bonds. Water is a liquid at ambient conditions, but it often co-exists on Earth with its solid state, ice, and gaseous state . Water also exists in a...
molecule and yields ammonia
Ammonia
Ammonia is a compound of nitrogen and hydrogen with the formula . It is a colourless gas with a characteristic pungent odour. Ammonia contributes significantly to the nutritional needs of terrestrial organisms by serving as a precursor to food and fertilizers. Ammonia, either directly or...
as a side-product: