Sunflower trypsin inhibitor

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Sunflower trypsin inhibitor (SFTI) is a small, circular peptide produced in sunflower seeds, and is a potent inhibitor of trypsin. It is the smallest known member of the Bowman-Birk family of serine protease inhibitors. [1]

Contents

One example of Sunflower trypsin inhibitor is Sunflower trypsin inhibitor-1 (SFTI-1). Sunflower trypsin inhibitor-1 is a potent Bowman-Birk inhibitor. Sunflower trypsin inhibitor-1 is the simplest cysteine-rich peptide scaffold because it is a bicyclic 14 amino acid peptide and only has one disulfide bond. The disulfide bond divides the peptide into two loops. One loop is a functional trypsin inhibitory and the second loop is a nonfunctional loop. [2] The nonfunctional loop can be replaced by a bioactive loop. It is extracted from a seed of a sunflower called Helianthus annuus. The synthesis of SFTI is not known however, it can evolutionarily linked to a gene-coded product from classic Bowman-Birk inhibitors. [3] STFI is used in radiopharmaceutical, antimicrobial, and pro-angiogenic peptides. [2]

Synthetic inhibitors and the structure of SFTI

By modifying the amino acid sequence of sunflower trypsin inhibitor, more specifically, sunflower trypsin inhibitor-1 (SFTI-1), researchers have been able to develop synthetic serine protease inhibitors that have specificity and improved inhibitory activity towards certain serine proteases that are found in the human body, such as tissue kallikreins and human matriptase-1. For instance, researchers from the Institute of Child Health and the Department of Chemistry of the University College London, have created two SFTI-1 analogs (I10G and I10H) by substituting residue 10 of SFTI-1 (isoleucine, I) with glycine (G) and histidine (H), respectively. Out of the two analogs, SFTI-I10H was found to be the more potent KLK5 inhibitor. [4] Another group of researchers from the previously mentioned institute and department of the University College London, conducted further research on the development of synthetic kallikrein inhibitors by modifying the amino acid sequence of SFTI-I10H. Out of the six SFTI-I10H variants that were constructed by modifying SFTI-I10H, the first and second variant (K5R_I10H and I10H_F12W) demonstrated improved KLK5 inhibition and the sixth variant (K5R_I10H_F12W) showed dual-inhibition of KLK5 and KLK7, improved KLK5 inhibition potency, and specificity for KLK5 and KLK14. The first variant (K5R_I10H) was made by replacing residue 5 of SFTI-I10H (lysine, K) with arginine (R), and in order to get the second variant (I10H_F12W) residue 12 (phenylalanine, F) was replaced with tryptophan (W). Lastly, the sixth variant (K5R_I10H_F12W) was developed by combining the amino acid substitutions of the first and second variants. [5]

Moreover, researchers from the Clemens-Schöpf Institute of Organic Chemistry and Biochemistry and Helmholtz-Institute for Pharmaceutical Research Saarland, developed potent synthetic human matriptase-1 inhibitors based on a different SFTI-1 variant, SDMI-1. SFTI-1 derived matriptase inhibitor-1 (SDMI-1) was previously developed by replacing residue 10 of SFTI-1 (isoleucine, I) with arginine (R) and residue 12 (phenylalanine, F) with histidine (H). Further modifications of SDMI-1 resulted in synthetic matriptase-1 inhibitors with improved inhibitory activity, matriptase binding, and inhibition potency. The SDMI-1 variant that resulted in enhanced inhibitory activity was developed by replacing residue 1 of SDMI-1 (glycine, G) with lysine (K) and by keeping it as a monocyclic structure. The SDMI-1 variant that resulted in improved matriptase binding was created by using the same amino acid substitutions of the previously mentioned SDMI-1 variant and by attaching a bulky fluorescein moiety to the side chain of lysine. Lastly, the SDMI-1 variant that had enhanced inhibition potency was developed by applying the same amino acid substitutions of the previous variants, cleaving the proline-aspartic acid sequence found at the C-terminus (PD-OH), and by making it a bicyclic compound via tail-to-side-chain cyclization. [6]

See also

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Trypsin Family of digestive enzymes

Trypsin is an enzyme in the first section of the small intestine that starts the digestion of protein molecules by cutting these long chains of amino acids into smaller pieces. It is a serine protease from the PA clan superfamily, found in the digestive system of many vertebrates, where it hydrolyzes proteins. Trypsin is formed in the small intestine when its proenzyme form, the trypsinogen produced by the pancreas, is activated. Trypsin cuts peptide chains mainly at the carboxyl side of the amino acids lysine or arginine. It is used for numerous biotechnological processes. The process is commonly referred to as trypsin proteolysis or trypsinization, and proteins that have been digested/treated with trypsin are said to have been trypsinized. Trypsin was discovered in 1876 by Wilhelm Kühne and was named from the Ancient Greek word for rubbing since it was first isolated by rubbing the pancreas with glycerin.

Protease Enzyme that cleaves other proteins into smaller peptides

A protease is an enzyme that catalyzes proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the formation of new protein products. They do this by cleaving the peptide bonds within proteins by hydrolysis, a reaction where water breaks bonds. Proteases are involved in many biological functions, including digestion of ingested proteins, protein catabolism, and cell signaling.

In biology and biochemistry, protease inhibitors, or antiproteases, are molecules that inhibit the function of proteases. Many naturally occurring protease inhibitors are proteins.

Serine protease Class of enzymes

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The kinin–kallikrein system or simply kinin system is a poorly understood hormonal system with limited available research. It consists of blood proteins that play a role in inflammation, blood pressure control, coagulation and pain. Its important mediators bradykinin and kallidin are vasodilators and act on many cell types. Clinical symptoms include marked weakness, tachycardia, fever, leukocytosis and acceleration of ESR.

Trypsinogen Chemical compound

Trypsinogen is the precursor form of trypsin, a digestive enzyme. It is produced by the pancreas and found in pancreatic juice, along with amylase, lipase, and chymotrypsinogen. It is cleaved to its active form, trypsin, by enteropeptidase, which is found in the intestinal mucosa. Once activated, the trypsin can cleave more trypsinogen into trypsin, a process called autoactivation. Trypsin cleaves the peptide bond on the carboxyl side of basic amino acids such as arginine and lysine.

Mixed inhibition

Mixed inhibition is a type of enzyme inhibition in which the inhibitor may bind to the enzyme whether or not the enzyme has already bound the substrate but has a greater affinity for one state or the other. It is called "mixed" because it can be seen as a conceptual "mixture" of competitive inhibition, in which the inhibitor can only bind the enzyme if the substrate has not already bound, and uncompetitive inhibition, in which the inhibitor can only bind the enzyme if the substrate has already bound. If the ability of the inhibitor to bind the enzyme is exactly the same whether or not the enzyme has already bound the substrate, it is known as a non-competitive inhibitor. Non-competitive inhibition is sometimes thought of as a special case of mixed inhibition.

Dendrotoxin Chemical compound

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Carboxypeptidase

A carboxypeptidase is a protease enzyme that hydrolyzes (cleaves) a peptide bond at the carboxy-terminal (C-terminal) end of a protein or peptide. This is in contrast to an aminopeptidases, which cleave peptide bonds at the N-terminus of proteins. Humans, animals, bacteria and plants contain several types of carboxypeptidases that have diverse functions ranging from catabolism to protein maturation.

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KLK7 Protein-coding gene in the species Homo sapiens

Kallikrein-related peptidase 7 (KLK7) is a serine protease that in humans is encoded by the KLK7 gene. KLK7 was initially purified from the epidermis and characterised as stratum corneum chymotryptic enzyme (SCCE). It was later identified as the seventh member of the human kallikrein family, which includes fifteen homologous serine proteases located on chromosome 19 (19q13).

KLK14 Protein-coding gene in the species Homo sapiens

Kallikrein-14 is a protein that in humans is encoded by the KLK14 gene.

Kunitz STI protease inhibitor

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Kunitz domain

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SSI protease inhibitor

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Bowman–Birk protease inhibitor

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References

  1. ↑ Luckett S, Garcia RS, Barker JJ, Konarev AV, Shewry PR, Clarke AR, Brady RL (July 1999). "High-resolution structure of a potent, cyclic proteinase inhibitor from sunflower seeds". Journal of Molecular Biology. 290 (2): 525–33. doi:10.1006/jmbi.1999.2891. PMID   10390350.
  2. 1 2 Qiu Y, Taichi M, Wei N, Yang H, Luo KQ, Tam JP (January 2017). "1 Receptor Antagonist Engineered as a Bifunctional Chimera of Sunflower Trypsin Inhibitor". Journal of Medicinal Chemistry. 60 (1): 504–510. doi:10.1021/acs.jmedchem.6b01011. PMID   27977181.
  3. ↑ Korsinczky ML, Schirra HJ, Craik DJ (October 2004). "Sunflower trypsin inhibitor-1". Current Protein & Peptide Science. 5 (5): 351–64. doi:10.2174/1389203043379594. PMID   15544530.
  4. ↑ Shariff, Leila; Zhu, Yanan; Cowper, Ben; Di, Wei-Li; Macmillan, Derek (2014-10-21). "Sunflower trypsin inhibitor (SFTI-1) analogues of synthetic and biological origin via N→S acyl transfer: potential inhibitors of human Kallikrein-5 (KLK5)". Tetrahedron. 70 (42): 7675–7680. doi: 10.1016/j.tet.2014.06.059 .
  5. ↑ Chen W, Kinsler VA, Macmillan D, Di WL (2016-11-08). "Tissue Kallikrein Inhibitors Based on the Sunflower Trypsin Inhibitor Scaffold - A Potential Therapeutic Intervention for Skin Diseases". PLOS ONE. 11 (11): e0166268. Bibcode:2016PLoSO..1166268C. doi: 10.1371/journal.pone.0166268 . PMC   5100903 . PMID   27824929.
  6. ↑ Fittler H, Avrutina O, Empting M, Kolmar H (June 2014). "Potent inhibitors of human matriptase-1 based on the scaffold of sunflower trypsin inhibitor". Journal of Peptide Science. 20 (6): 415–20. doi:10.1002/psc.2629. PMID   24723440. S2CID   21635664.
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