Citrullination

Citrullination or deimination is the conversion of the amino acid arginine in a protein into the amino acid citrulline. Citrulline is not one of the 20 standard amino acids encoded by DNA in the genetic code. Instead, it is the result of a post-translational modification. Citrullination 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.

Enzymes called arginine deiminases (ADIs) catalyze the deimination of free arginine, while protein arginine deiminases or peptidylarginine deiminases (PADs) replace the primary ketimine group (=NH) by a ketone group (=O). Arginine is positively charged at a neutral pH, whereas citrulline is has no net charge. This increases the hydrophobicity of the protein, which can lead to changes in protein folding, affecting the structure and function.

In eukaryotes, citrullination controls the expression of genes, particularly in the developing embryo. The immune system often attacks citrullinated proteins, leading to autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. 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.[1]

Citrullinated vimentin may be an autoantigen in RA and other autoimmune diseases, and is used to study RA. Moreover, antibodies against mutated citrullinated vimentin (MCV) may be useful for monitoring effects of RA therapy.[2] An ELISA system utilises genetically modified citrullinated vimentin (MCV), a naturally occurring isoform of vimentin to improve the performance of the test.[3]

In the reaction from arginine to citrulline, one of the terminal nitrogen atoms of the arginine side chain is replaced by an oxygen. The reaction uses one water molecule and yields ammonia as a side-product:

The chemical conversion of arginine to citrulline, known as citrullination or deimination.

In the nervous system

PADs are found in mammals but not in lower animals. Five PADs – PAD1, PAD2, PAD3, PAD4 and PAD6 – have been found.[4]

PAD2 is expressed at a high level in the central nervous system (CNS), including the eye and brain. PAD transcripts have been found in the C57BL6/J mouse eyes as early as embryonic day 14.5.[5]

The PAD isotypes differ in terms of their tissue and cellular distributions. The PAD2 isotype has the broadest tissue distribution and is found in myelinating cells of the CNS and in myelin, where one of its target substrates is myelin basic protein. In the normal retina, deimination is found in nearly all the retinal layers, including the photoreceptors. Deimination has been also reported in neuronal cells, such as astrocytes, microglia and oligodendrocytes, Schwann cells and neurons.[6]

Deimination regulates gene expression through histone modifications. DNA is wrapped around histones, and the histone proteins can control DNA expression when chemical groups are added and removed. This process is known as post-translational processing or post-translational modification, because it takes place on the protein after the DNA is translated. The role of post-translational processing in gene regulation is the subject of the growing field of study, epigenetics.

One mechanism is methylation. A methyl group (CH3) binds to an arginine on the histone protein, which can induce transcription of the DNA. When PAD converts arginine to citrulline, it no longer induces transcription.[7] The main isotype for this is PAD4, which deiminates arginines and/or monomethylated arginines on histones 3 and 4, turning off the effects of arginine methylation.[8]

Myelin basic protein, the main protein in myelin sheath stability, is modified this way during normal embryonic central nervous system formation, and also during myelin degeneration in demyelinating diseases such as multiple sclerosis.

Methylation and phosphorylation of MBP are active during the process of myelinogenesis. In the embryo, in early CNS development, MBP deimination plays a major role in myelin assembly. In adults, MBP deamination is found in demyelination diseases. MBP may affect different cell types in each case.[9]

Autoimmune diseases

In rheumatoid arthritis and other autoimmune diseases, such as psoriatic arthritis, systemic lupus erythematosus and Sjögren's syndrome, autoantibodies often attack citrullinated proteins. The presence of anti-citrullinated protein antibody is a standard test for rheumatoid arthritis, and it is associated with more severe disease. Citrullinated proteins are also found in the cellular debris accompanying the destruction of cells in alzheimer disease, and after smoking cigarettes. So citrullination seems to be part of the mechanism that stimulates the immune system in autoimmune disease.[10][11][12][13][14]

The first comprehensive textbook on deimination was published in 2014.[15]

References

  1. ↑ Coenen D, Verschueren P, Westhovens R, Bossuyt X (March 2007). "Technical and diagnostic performance of 6 assays for the measurement of citrullinated protein/peptide antibodies in the diagnosis of rheumatoid arthritis". Clin. Chem. 53 (3): 498–504. doi:10.1373/clinchem.2006.078063. PMID 17259232.
  2. ↑ Nicaise Roland P, Grootenboer Mignot S, Bruns A, et al. (2008). "Antibodies to mutated citrullinated vimentin for diagnosing rheumatoid arthritis in anti-CCP-negative patients and for monitoring infliximab therapy". Arthritis Research & Therapy. 10 (6): R142. doi:10.1186/ar2570. PMC 2656247Freely accessible. PMID 19077182.
  3. ↑ Soós L, Szekanecz Z, Szabó Z, et al. (August 2007). "Clinical evaluation of anti-mutated citrullinated vimentin by ELISA in rheumatoid arthritis". J. Rheumatol. 34 (8): 1658–63. PMID 17611988.
  4. ↑ Vossenaar, Erik R.; Albert J.W. Zendman; Walther J. van Venrooij; Ger J.M. Pruijn (November 2003). "PAD, a growing family of citrullinating enzymes: genes, features and involvement in disease". BioEssays. 25 (11): 1106–1118. doi:10.1002/bies.10357. PMID 14579251.
  5. ↑ Visel, Axel; Thaller, Eichele (January 2004). "GenePaint.org: an atlas of gene expression patterns in the mouse embryo". Nucleic Acids Res. 32 (Database issue): D552–6. doi:10.1093/nar/gkh029. PMC 308763Freely accessible. PMID 14681479.
  6. ↑ Bhattacharya, Sanjoy (May 2009). "Retinal deimination in aging and disease". IUBMB Life. 61 (5): 504–509. doi:10.1002/iub.184. PMID 19391158.
  7. ↑ Cuthbert, Graeme; Daujat, Snowden; Erdjument-Bromage, Hagiwara; Yamada, Schneider; Gregory, Tempst; Bannister, Kouzarides (September 2, 2004). "Histone deimination antagonizes arginine methylation.". Cell. 118 (5): 545–553. doi:10.1016/j.cell.2004.08.020. PMID 15339660.
  8. ↑ Kouzarides, T (November 2007). "SnapShot: Histone-modifying enzymes". Cell. 131 (4): 822–822.e1. doi:10.1016/j.cell.2007.11.005. PMID 18022374.
  9. ↑ Harauz, G; Mussee (February 2007). "A tale of two citrullines--structural and functional aspects of myelin basic protein deimination in health and disease.". Neurochemical Research. 32 (2): 137–158. doi:10.1007/s11064-006-9108-9. PMID 16900293.
  10. ↑ Enzyme-activating antibodies revealed as marker for most severe form of rheumatoid arthritis, Science Daily, May 22, 2013
  11. ↑ Autoantibodies: Double Agents in Human Disease, Sci Transl Med, May 22, 2013
  12. ↑ Erosive Rheumatoid Arthritis Is Associated with Antibodies That Activate PAD4 by Increasing Calcium Sensitivity, Sci Transl Med, May 22, 2013
  13. ↑ "Anti-citrullinated protein/peptide antibodies (ACPA) in rheumatoid arthritis: Specificity and relation with rheumatoid factor". Autoimmunity Reviews. 4 (7): 468–474. 2005. doi:10.1016/j.autrev.2005.04.018.
  14. ↑ Can Smoking Trigger Autoimmunity in RA? Scientists seek to connect the dots between smoking and rheumatoid arthritis, By Debra Dreger
  15. ↑ Nicholas, AP; Bhattacharya, SK (2014). Protein Deimination in Human Health and Disease. New York: Springer. ISBN 978-1-4614-8317-5.
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