Chymase and Chymosin – Rumored To Be Synonyms (and a little renin and rennin)

Chymase Alternative name for chymosin [“chymase .” A Dictionary of Food and Nutrition. . Encyclopedia.com. 25 Aug. 2022 https://www.encyclopedia.com]

Mast Cell Chymase and Tryptase and some MMPs

Chymase and tryptase are packaged in secretory granules together with histamine and other mediators in mast cells, which are infiltrated in rheumatoid synovium. Chymase is a chymotrypsin-like proteinase with a broad spectrum of activity against ECM components such as type VI collagen⁷ and aggrecan. It also activates proMMPs such as proMMP-1, 3, and 9.⁶ Although prochymase is activated intra-cellularly and stored in the granules, the activity in the granules is limited at low pH and becomes fully active when released extra-cellularly. Tryptase is a trypsin-like proteinase that degrades type VI collagen⁷ and fibronectin; it also activates proMMP-3.⁶ [Proteinases and Matrix Degradation, Yasunori Okada, in Kelley and Firestein’s Textbook of Rheumatology (Tenth Edition), 2017]

Chymase at Wikipedia (page last updated March 27, 2022)

• Chymases (EC 3.4.21.39, mast cell protease 1, skeletal muscle protease, skin chymotryptic proteinase, mast cell serine proteinase, skeletal muscle protease) are a family of serine proteases found primarily in mast cells, though also present in basophil granulocytes (e.g. alpha chymase mcpt8). Recently, Derakhshan et al. reported that a specific mast cell population expressed trascripts for Mcpt8.^{[Derakhshan, Tahereh; Samuchiwal, Sachin K.; Hallen, Nils; Bankova, Lora G.; Boyce, Joshua A.; Barrett, Nora A.; Austen, K. Frank; Dwyer, Daniel F. (2021-01-04). “Lineage-specific regulation of inducible and constitutive mast cells in allergic airway inflammation”. Journal of Experimental Medicine. 218 (1): e20200321. doi:10.1084/jem.20200321. ISSN 0022-1007. PMC 7953627. PMID 32946563]} 
• They show broad peptidolytic activity and are involved in a variety of functions. For example, chymases are released by mucosal mast cells upon challenge with parasites and parasite antigens promoting an inflammatory response, and chymase mcp1 and mcp2 are used for marker for mast cell degranulation in parasite infection such as: 
  • Nematode,^{[McDermott JR, Bartram RE, Knight PA, Miller HR, Garrod DR, Grencis RK (June 2003). “Mast cells disrupt epithelial barrier function during enteric nematode infection”. Proceedings of the National Academy of Sciences of the United States of America. 100 (13): 7761–6. Bibcode:2003PNAS..100.7761M. doi:10.1073/pnas.1231488100. PMC 164661. PMID 12796512]} 
  • Trichuris muris^{[Betts CJ, Else KJ (January 1999). “Mast cells, eosinophils and antibody-mediated cellular cytotoxicity are not critical in resistance to Trichuris muris”. Parasite Immunology. 21 (1): 45–52. doi:10.1046/j.1365-3024.1999.00200.x. PMID 10081771. S2CID 31343469][Blackwell NM, Else KJ (June 2001). “B cells and antibodies are required for resistance to the parasitic gastrointestinal nematode Trichuris muris”. Infection and Immunity. 69 (6): 3860–8. doi:10.1128/IAI.69.6.3860-3868.2001. PMC 98409. PMID 11349052.]} 
• Chymases are also known to convert angiotensin I to angiotensin II and thus play a role in hypertension and atherosclerosis.^{[Caughey GH (June 2007). “Mast cell tryptases and chymases in inflammation and host defense”. Immunological Reviews. 217: 141–54. doi:10.1111/j.1600-065X.2007.00509.x. PMC 2275918. PMID 17498057.]}
• Because of its role in inflammation it has been investigated as a target in the treatment of asthma.^{[de Garavilla L, Greco MN, Sukumar N, Chen ZW, Pineda AO, Mathews FS, et al. (May 2005). “A novel, potent dual inhibitor of the leukocyte proteases cathepsin G and chymase: molecular mechanisms and anti-inflammatory activity in vivo”. The Journal of Biological Chemistry. 280 (18): 18001–7. doi:10.1074/jbc.M501302200. PMID 15741158]}
• Categories: 
  • Genes on human chromosome 14
  • EC 3.4.21
  • Hydrolase stubs

Chymosin at Wikipedia (page last updated April 5, 2022)

Not to be confused with renin, an enzyme which takes part in regulation of arterial blood pressure.

• Chymosin or rennin is a protease found in rennet. It is an aspartic endopeptidase belonging to MEROPS A1 family. It is produced by newborn ruminant animals in the lining of the abomasum to curdle the milk they ingest, allowing a longer residence in the bowels and better absorption. It is widely used in the production of cheese. Bovine chymosin is now produced recombinantly in E. coli, Aspergillus niger var awamori, and K. lactis as alternative resource.

Occurrence

• The chymosin is found in a wide range of tetrapods,^{[Lopes-Marques M, Ruivo R, Fonseca E, Teixeira A, Castro LF (November 2017). “Unusual loss of chymosin in mammalian lineages parallels neo-natal immune transfer strategies”. Molecular Phylogenetics and Evolution. 116: 78–86. doi:10.1016/j.ympev.2017.08.014. PMID 28851538.]} although it is best known to be produced by ruminant animals in the lining of the abomasum.
  • Chymosin is produced by gastric chief cells in newborn mammals^{[Kitamura N, Tanimoto A, Hondo E, Andrén A, Cottrell DF, Sasaki M, Yamada J (August 2001). “Immunohistochemical study of the ontogeny of prochymosin–and pepsinogen-producing cells in the abomasum of sheep”. Anatomia, Histologia, Embryologia. 30 (4): 231–5. doi:10.1046/j.1439-0264.2001.00326.x. PMID 11534329. S2CID 7552821]} to curdle the milk they ingest, allowing a longer residence in the bowels and better absorption.
    • A few words about gastric chief cells
      • A gastric chief cell (or peptic cell, or gastric zymogenic cell) is a type of gastric gland cell that releases pepsinogen and gastric lipase and is the cell responsible for secretion of chymosin in ruminants.^{[Kitamura N, Tanimoto A, Hondo E, Andrén A, Cottrell DF, Sasaki M, Yamada J (2001). “Immunohistochemical study of the ontogeny of prochymosin–and pepsinogen-producing cells in the abomasum of sheep”. Anatomia, Histologia, Embryologia. 30 (4): 231–235. doi:10.1046/j.1439-0264.2001.00326.x. PMID 11534329. S2CID 7552821]} 
      • The cell stains basophilic upon H&E staining due to the large proportion of rough endoplasmic reticulum in its cytoplasm. Gastric chief cells are generally located deep in the mucosal layer of the stomach lining, in the fundus and body of the stomach.^{[Kelsey E. McHugh, M.D., Thomas P. Plesec, M.D. “Stomach – General – Histology”. PathologyOutlines. Topic Completed: 28 May 2020. Minor changes: 28 December 2020]}
      • Chief cells release the zymogen (enzyme precursor) pepsinogen when stimulated by a variety of factors including cholinergic activity from the vagus nerve and acidic condition in the stomach. Gastrin and secretin may also act as secretagogues.^{[ Johnson, Leonard R. (2001). Gastrointestinal Physiology. ISBN 0323012396.]}
      • It works in conjunction with the parietal cell, which releases gastric acid, converting the pepsinogen into pepsin.
      • See also
        • Gastric acid
        • Fundic glands
        • List of human cell types derived from the germ layers
        • Anatomy Atlases – Microscopic Anatomy, plate 01.05
        • Histology image: 22201loa – Histology Learning System at Boston University – “Ultrastructure of the Cell: chief cells and enteroendocrine cell”
        • Histology image: 11304loa – Histology Learning System at Boston University – “Digestive System: Alimentary Canal: fundic stomach, gastric glands, base”
        • “chief cell” at Dorland’s Medical Dictionary
        • Nosek, Thomas M. “Section 6/6ch4/s6ch4_8”. Essentials of Human Physiology. Archived from the original on 2016-03-24.
      • NOMENCLATURE: The terms chief cell and zymogenic cell are often used without the word “gastric” to name this type of cell. However those terms can also be used to describe other cell types (for example, parathyroid chief cells). Chief cells are also known as peptic cells.
  • Non-ruminant species that produce chymosin include pigs, cats, seals,^{[Staff, Online Mendelian Inheritance in Man (OMIM) Database. Last updated February 21, 1997 Chymosin pseudogene; CYMP prochymosin, included, in the OMIM]} and chicks.^{[Lopes-Marques M, Ruivo R, Fonseca E, Teixeira A, Castro LF (November 2017). “Unusual loss of chymosin in mammalian lineages parallels neo-natal immune transfer strategies”. Molecular Phylogenetics and Evolution. 116: 78–86. doi:10.1016/j.ympev.2017.08.014. PMID 28851538.]}
  • One study reported finding a chymosin-like enzyme in some human infants,^{[Henschel MJ, Newport MJ, Parmar V (1987). “Gastric proteases in the human infant”. Biology of the Neonate. 52 (5): 268–72. doi:10.1159/000242719. PMID 3118972.]} but others have failed to replicate this finding.^{[Szecsi PB, Harboe M (2013). “Chapter 5: Chymosin”. In Rawlings ND, Salvesen G (eds.). Handbook of Proteolytic Enzymes. Vol. 1. pp. 37–42. doi:10.1016/B978-0-12-382219-2.00005-3.]} 
  • Humans have a pseudogene for chymosin that does not generate a protein, found on chromosome 1.^{[4][Fox PF (28 February 1999). Cheese: Chemistry, Physics and Microbiology. ISBN 9780834213388.]} 
  • Humans have other proteins to digest milk, such as pepsin and lipase.^{[Sanderson IR, Walker WA (1999). Development of the gastrointestinal tract. Hamilton, Ontario: B.C. Decker. ISBN 978-1-55009-081-9.]: 262}
  • In addition to the primate lineage leading up to humans, some other mammals have also lost the chymosin gene.^[2]

Enzymatic reaction

• Chymosin is used to bring about the extensive precipitation and curd formation in cheese-making. The native substrate of chymosin is K-casein which is specifically cleaved at the peptide bond between amino acid residues 105 and 106, phenylalanine and methionine.^[9] 
• The resultant product is calcium phosphocaseinate.^{[citation needed]} When the specific linkage between the hydrophobic (para-casein) and hydrophilic (acidic glycopeptide) groups of casein is broken, the hydrophobic groups unite and form a 3D network that traps the aqueous phase of the milk.
• Charge interactions between histidines on the kappa-casein and glutamates and aspartates of chymosin initiate enzyme binding to the substrate.^{[Gilliland GL, Oliva MT, Dill J (1991). “Functional implications of the three-dimensional structure of bovine chymosin”. Advances in Experimental Medicine and Biology. 306: 23–37. doi:10.1007/978-1-4684-6012-4_3. ISBN 978-1-4684-6014-8. PMID 1812710.]} 
• When chymosin is not binding substrate, a beta-hairpin, sometimes referred to as “the flap,” can hydrogen bond with the active site, therefore covering it and not allowing further binding of substrate.^{[Groves MR, Dhanaraj V, Badasso M, Nugent P, Pitts JE, Hoover DJ, Blundell TL (October 1998). “A 2.3 A resolution structure of chymosin complexed with a reduced bond inhibitor shows that the active site beta-hairpin flap is rearranged when compared with the native crystal structure” (PDF). Protein Engineering. 11 (10): 833–40. doi:10.1093/protein/11.10.833. PMID 9862200.} PDB: 1CZI​; ^]

Examples

Listed below are the ruminant Cym gene and corresponding human pseudogene:

Chymosin [Precursor]

chymosin pseudogene (human)

Identifiers:

Symbol – CYMP

NCBI gene – 643160

HGNC – 2588

OMIM – 118943

RefSeq – NR_003599

Other data

Locus – Chr. 1 p13.3

Recombinant chymosin

• Because of the imperfections and scarcity of microbial and animal rennets, producers sought replacements. With the development of genetic engineering, it became possible to extract rennet-producing genes from animal stomach and insert them into certain bacteria, fungi or yeasts to make them produce chymosin during fermentation.^{[Emtage JS, Angal S, Doel MT, Harris TJ, Jenkins B, Lilley G, Lowe PA (June 1983). “Synthesis of calf prochymosin (prorennin) in Escherichia coli”. Proceedings of the National Academy of Sciences of the United States of America. 80 (12): 3671–5. Bibcode:1983PNAS…80.3671E. doi:10.1073/pnas.80.12.3671. PMC 394112. PMID 6304731][Harris TJ, Lowe PA, Lyons A, Thomas PG, Eaton MA, Millican TA, et al. (April 1982). “Molecular cloning and nucleotide sequence of cDNA coding for calf preprochymosin”. Nucleic Acids Research. 10 (7): 2177–87. doi:10.1093/nar/10.7.2177. PMC 320601. PMID 6283469]} 
• The genetically modified microorganism is killed after fermentation and chymosin is isolated from the fermentation broth, so that the fermentation-produced chymosin (FPC) used by cheese producers does not contain any GM component or ingredient.^{[“Chymosin”. GMO Compass. Archived from the original on 2015-03-26. Retrieved 2011-03-03.]} 
• FPC contains the identical chymosin as the animal source, but produced in a more efficient way. FPC products have been on the market since 1990 and are considered the ideal milk-clotting enzyme.^{[Law BA (2010). Technology of Cheesemaking. UK: Wiley-Blackwell. pp. 100–101. ISBN 978-1-4051-8298-0.]}
• FPC was originally created by biotechnology company Pfizer ^{[“FDA Approves 1st Genetically Engineered Product for Food”. Los Angeles Times. 24 March 1990. Retrieved 1 May 2014.][Staff, National Centre for Biotechnology Education, 2006. Case Study: Chymosin]}
• FPC was the first artificially produced enzyme to be registered and allowed by the US Food and Drug Administration. In 1999, about 60% of US hard cheese was made with FPC^{[ “Food Biotechnology in the United States: Science, Regulation, and Issues”. U.S. Department of State. Retrieved 2006-08-14.]} and it has up to 80% of the global market share for rennet.^{[Johnson ME, Lucey JA (April 2006). “Major technological advances and trends in cheese”. Journal of Dairy Science. 89 (4): 1174–8. doi:10.3168/jds.S0022-0302(06)72186-5. PMID 16537950.]}
• By 2008, approximately 80% to 90% of commercially made cheeses in the US and Britain were made using FPC.^{[“Chymosin”. GMO Compass. Archived from the original on 2015-03-26. Retrieved 2011-03-03.]} 
• The most widely used fermentation-produced chymosin is produced either using the fungus Aspergillus niger or using Kluyveromyces lactis.
• FPC contains only chymosin B,^{[Bovine chymosins A and B differ by one amino acid residue. This is probably an alleic variant, according to Uniprot:P00794. The two isoforms have identical catalytic activity, so any improvement in the product is due to the elimination of other impurities.]} achieving a higher degree of purity compared with animal rennet. FPC can deliver several benefits to the cheese producer compared with animal or microbial rennet, such as higher production yield, better curd texture and reduced bitterness.^{[Law BA (2010). Technology of Cheesemaking. UK: Wiley-Blackwell. pp. 100–101. ISBN 978-1-4051-8298-0.]}
• Further reading
  • Foltmann B (1966). “A review on prorennin and rennin”. Comptes-Rendus des Travaux du Laboratoire Carlsberg. 35 (8): 143–231. PMID 5330666.
  • Visser S, Slangen CJ, van Rooijen PJ (June 1987). “Peptide substrates for chymosin (rennin). Interaction sites in kappa-casein-related sequences located outside the (103-108)-hexapeptide region that fits into the enzyme’s active-site cleft”. The Biochemical Journal. 244 (3): 553–8. doi:10.1042/bj2440553. PMC 1148031. PMID 3128264.
• External links
  • The MEROPS online database for peptidases and their inhibitors: A01.006
• Categories: 
  • Genes on human chromosome 1
  • EC 3.4.23

Proteases: aspartate proteases (EC 3.4.23)

Enzymes

• Renin gets another page
  • The name renin = ren + -in, “kidney” + “compound“. Renin was discovered, characterized, and named in 1898 by Robert Tigerstedt, Professor of Physiology, and his student, Per Bergman, at the Karolinska Institute in Stockholm.^{[Tigerstedt R, Bergman PG (1898). “Niere und Kreislauf” [Kidney and Circulation]. Skandinavisches Archiv für Physiologie (in German). 8: 223–271. doi:10.1111/j.1748-1716.1898.tb00272.x][Phillips MI, Schmidt-Ott KM (Dec 1999). “The Discovery of Renin 100 Years Ago”. News in Physiological Sciences. 14 (6): 271–274. doi:10.1152/physiologyonline.1999.14.6.271. PMID 11390864]}
  • Renin, also known as an angiotensinogenase, is an aspartic protease protein and enzyme secreted by the kidneys that participates in the body’s renin–angiotensin–aldosterone system (RAAS)—also known as the renin–angiotensin–aldosterone axis—that mediates the volume of extracellular fluid (blood plasma, lymph and interstitial fluid) and arterial vasoconstriction. Thus, it regulates the body’s mean arterial blood pressure.
  • Renin is not commonly referred to as a hormone, albeit it having a receptor, the (pro)renin receptor, also known as the renin receptor and prorenin receptor (see also below),^{[Nguyen G (Mar 2011). “Renin, (pro)renin and receptor: an update”. Clin Sci (Lond). 120 (5): 169–178. doi:10.1042/CS20100432. PMID 21087212]} as well as enzymatic activity with which it hydrolyzes angiotensinogen to angiotensin I.
  • See also
    • Angiotensin-converting enzyme
    • Plasma renin activity
    • Renin inhibitor
    • Renin stability regulatory element (REN-SRE)

Rennet gets another page