Anti-inflammatory tablets with Aceclofenac, Paracetamol & Serratiopeptidase
Serratiopeptidase (other names: Serratia E-15 protease, Serralysin, Serrapeptase, Serratiapeptase, Serratia extracellular protease) is a proteolytic enzyme belonging to the metalloprotease family of enzymes. Serratiopeptidase is produced most commonly by Serratia Marcescens (other names: Bacillus prodigiosus, Serratia sp. E-15 Monas prodigiosus), a species of enterobacteria belonging to the Yersiniaceae family of gram-negative bacteria.[1] Although this enzyme has no isozymes, Serratiopeptidase have different strains that can be produced, varying between wild, mutated, or recombined origins of production. In production, due to Serratiopeptidase being produced naturally by a bacteria (Serratia Mercescens) that is pathogenic and is able to spread in most environments, E. Coli is used as a means of recombinant expression to produce Serratiopeptidase in order to acquire higher yields of the enzyme than from its native source. These strains of E. Coli are engineered to produce high yields of recombined gene expression, and are also a way to sidestep the risks of using a pathogenic bacteria in mass scale production to produce enzymes like Serratiopeptidase.[2] The enzyme is used as a treatment for inflammation both internal and external, as well as having fibrinolytic (dissolves blood clots) properties, though it is most commonly known as a treatment for carpal tunnel, arthritis, fibrocystic breast disease, bronchitis, and sinusitis.[3][1][4]
Although the discovery of Serratia Marcescens would be made in 1819 by Italian pharmacist Bartolomeo Bizio,[5] with the bacteria coming from a silk moth known as Bombyx Mori that uses the bacteria stored in its gut as a means of dissolving its cocoon, the enzyme Serratiopeptidase would be discovered over a century later in the late 1950s (some sites say 1960s) by unnamed Japanese researchers.[3][4][1] This was after America had discovered and had been testing other anti-inflammatory enzymes of their own, using enzymes like Bromelain, Trypsin, and Chymotrypsin as a means of anti-inflammation for patients recovering from surgery. Soon after 1967, the enzyme formula used as treatment for patients would be replaced by a successor. Originally, treatment would only be done parenterally (applied anywhere other than orally). With this successor, treatment could be administered in powder form through a pill covered in enteric coating that would prevent premature digestion and allow for treatment to be done in a more convenient form. In the 1980s and the 1990s, separate research taking place in Europe and Japan would conclude that Serratiopeptidase was the most effective anti-inflammation enzyme out of all other enzyme formulations available at the time, and continues to be a treatment option in stores as a product to this day.[4]
Structure
Serratiopeptidase has a molecular weight of 45-60 kDa and is made up of 470 amino acids,[3][4][1][1] with it uniquely not consisting of any amino acids containing sulphur. As a proteolytic enzyme, it cleaves dead/damaged proteins that are consumed or within the body to create smaller amino acids and peptides as products.[1][4] As a metalloprotease enzyme, it also has zinc located within its active site. When this enzyme interacts with its substrate (proteins, polypeptides), the zinc atom uses the catalytic triad that it helps bind to the active site to perform catalytic hydrolysis to cleave peptide bonds and break down proteins.[6] The enzyme also contains calcium ions within its binding sites, which it uses alongside the zinc atom it contains as integral components to its structure stability.[7] Domain-wise when it comes to structure, it has two domains: an N-terminal Catalytic Domain (Ncat) and a C-terminal Repeat-In-Toxin Domain Crtx. The proteolytic enzyme's ability to break down proteins and peptides through proteolysis and hydrolysis are done in the Ncat domain, with the active site holding Serratiopeptidase's zinc atom also residing within this domain. Crtx on the other hand is responsible for the exporting of this enzyme from the bacteria that produces it, as well as the domain that contains most of the Calcium ions that it uses to maintain proper folding and stability as the enzyme is secreted out of Serratia Marcescens and the extracellular milieu.[8] Although Crtx is irrelevant during laboratory production of Serratiopeptidase once it is purified, it is essential for initial high-yield production of the enzyme.[4][7] In terms of solubility, Serratiopeptidase in powder form is water-soluble. It is this water solubility that makes its medical characteristics possible for oral consumption, and is a key trait for pharmaceutical testing. It is insoluble in organic solvents like alcohol.[9] Peak productivity of this enzyme takes place in conditions at pH 9.0 at 40 degrees Celsius, however at >55 degrees Celsius, enzyme gradually slows to no productivity and becomes inactive.[3][4]
Absorption and distribution
Once a user of a Serratiopeptidase product takes a pill containing the enzyme, the enteric coating covering the pill will cause the pill to not dissolve in the stomach acid of the user, but will instead dissolve in the more alkaline environment found in the small intestines where the enzyme will be released and consumed.[9] The large 45-60 kDa enzyme shouldn't cross the intestinal barrier and absorbed into the bloodstream so easily, but the enzyme is found in the bloodstreams of subject animal in clinical trials regardless. The mechanism behind this absorption is still debated and not fully understood, but some theories include the use of paracellular transport, where the enzyme reversibly increases the permeability of the tight intersections between intestinal epithelial cells for a short time, allowing the enzyme to slip into the lamina propria. The evidence corroborating this theory are mainly due to this mechanism of absorption being responsible for increased absorption of other drugs when co-administered with Serratiopeptidase. Other theories include the use of enterocytes binding to the enzyme via enterocytosis to be transported across cell to be released into the lamina propria, a process known as Transcytosis. Once inside the lamina propria, the enzyme is then flowed into the lymphatic capillaries in the intestinal villi to then enter thoracic that will finally lead into the circulatory system.[10][11][9]
Once in the bloodstream, Serratiopeptidase is quickly bound to Alpha-2-Macroglobulin, a large protein in plasma that acts as a protease inhibitor that is designed to neutralize harmful enzymes in the body. Serratiopeptidase is then physically encapsulated by the protein, where the enzyme is safe from deterioration while in the circulatory system, is able to be cleared reticuloendothethial system (system of phagocytes specializing in devouring harmful entities and foreign particles in the body)(RES), and is safe from other plasma protease inhibitors and antibodies.[11] Cells within sites of inflammation and RES cells express receptors for Alpha-2-Macroglobulin, causing the large protein to have a high affinity for these cells and may lead these Alpha-2-Macroglobulin to concentrate at sites of inflammation.[10][3][6]
Crystal structure of alpha-2-macroglobulin. Rendered from PDB 2P9R
Activation
As the Alpha-2-Macroglobulin reaches to the site of inflammation, Serratiopeptidase may completely disassociate from the Alpha-2-Macroglobulin or even act while partially complexed in the large protein, where it will begin to break down its designed substrate. Serratiopeptidase will break down fibrin found in edematous fluid (trapped fluid that causes swelling), bradykinin (peptide that mediates inflammatory response and stimulates pain), and dead tissue.[11][6]
Clearance
The Serratiopeptidase-Alpha-2-Macroglobulin partial complexes are quickly cleared by phagocyte cells in the RES of the lymph nodes, liver, and spleen, while free-roaming enzymes left from the inflammation cite are eventually rendered inactive due to other non-Alpha-2-Macroglobulin plasma protease inhibitors and eventually degraded into amino acids through normal catabolic protein pathways.[6][3]
Clinical significance
Pharmacologically, in addition to being a prominent anti-inflammatory and fibrinolytic, some trends indicate Serratiopeptidase to also have analgesic (pain relieving) effects as well, although done indirectly by reducing swelling and clearing pain-induced body reactions. Important to note that this property is supported mainly by trends in research, not high-quality evidence.[1] Similarly speculative as well is the property of being able to inhibit the formation of biofilm found on bacteria that protects from antibiotics. This is mechanically supported by Serratiopeptidase's ability to break down peptide bonds and proteins which make up bacterial biofilm, and though this in-vitro study is a compelling mechanical find to fight against the formation of antibiotic super-bugs, there are no substantive clinical trials that have replicated this process consistently.[6][3]
Serratiopeptidase is a clinically plausible treatment and has seen strong evidence of effectiveness with the consistent ability to manage post surgical swelling and inflammation, as well as showing trends of other health benefits like its ability to degrade bacteria biofilm production which could help in the ever-increasing amount of antibiotic-resistant bacteria.[3] It has even been able to see proof-of-concept clinical experiments be successful where cocktail mixtures of Serratiopeptidase and Lumbrokinase enzymes were able to significantly reduce amyloid masses after injection, something that many diabetics suffer from. With this treatment being able to work, Serratiopeptidase could be another enzyme to be added to a growing list of enzyme treatments for bodily health and probiotic immunity.[12]
With the current status of clinical trials surrounding Serratiopeptidase, evidence is not robust enough to meet high medical standards for further validation of its medicinal capabilities. It remains a promising enzyme for its capabilities, but is currently only seen as a potentially useful but not essential second-line treatment.[4][6]
12345678Bhagat S, Agarwal M, Roy V (April 2013). "Serratiopeptidase: a systematic review of the existing evidence". International Journal of Surgery. 11 (3): 209–217. doi:10.1016/j.ijsu.2013.01.010. PMID23380245.
12Srivastava V, Bandhu S, Mishra S, Chaudhuri TK (May 2024). "Calcium-induced structural transitions are central to the folding, function, and processing of serratiopeptidase zymogen into mature form". The FEBS Journal. 291 (9): 1958–1973. doi:10.1111/febs.17090. PMID38700222.
↑Srivastava V, Bandhu S, Mishra S, Chaudhuri TK (January 2025). "Serratiopeptidase exhibits antibiofilm activity through the proteolytic function of N-terminal domain and versatile function of the C-terminal domain". Biochimica et Biophysica Acta. Proteins and Proteomics. 1873 (1) 141046. doi:10.1016/j.bbapap.2024.141046. PMID39241938.
123Mazzone A, Catalani M, Costanzo M, Drusian A, Mandoli A, Russo S, etal. (September 1990). "Evaluation of Serratia peptidase in acute or chronic inflammation of otorhinolaryngology pathology: a multicentre, double-blind, randomized trial versus placebo". The Journal of International Medical Research. 18 (5): 379–388. doi:10.1177/030006059001800506. PMID2257960.
↑Metkar SK, Girigoswami A, Vijayashree R, Girigoswami K (November 2020). "Attenuation of subcutaneous insulin induced amyloid mass in vivo using Lumbrokinase and Serratiopeptidase". International Journal of Biological Macromolecules. 163: 128–134. doi:10.1016/j.ijbiomac.2020.06.256. PMID32615214.
External links
The MEROPS online database for peptidases and their inhibitors: M10.051
This page is based on this Wikipedia article Text is available under the CC BY-SA 4.0 license; additional terms may apply. Images, videos and audio are available under their respective licenses.
