Proteolipid

(Redirected from Proteolipids)

A proteolipid is a protein covalently linked to lipid molecules, which can be fatty acids, isoprenoids or sterols. The process of such a linkage is known as protein lipidation, and falls into the wider category of acylation and post-translational modification. Proteolipids are abundant in brain tissue, and are also present in many other animal and plant tissues. They include ghrelin, a peptide hormone associated with feeding. Many proteolipids have bound fatty acid chains,[1] which often provide an interface for interacting with biological membranes[2] and act as lipidons that direct proteins to specific zones.[3]

Proteolipids were discovered serendipitously in 1951 by Jordi Folch Pi and Marjorie Lees while extracting sulfatides from brain lipids.[4]

They are not to be confused with lipoproteins, a kind of spherical assembly made up of many molecules of lipids and some apolipoproteins.

Structure

edit

Depending on the type of fatty acid attached to the protein, a proteolipid can often contain myristoyl, palmitoyl, or prenyl groups. These groups each serve different functions and have different preferences as to which amino acid residue they attach to. The processes are respectively named myristoylation (usually at N-terminal Gly), palmitoylation (to cysteine), and prenylation (also to cysteine). Despite the seemingly specific names, N-myristoylation and S-palmitoylation can also involve some other fatty acids, most commonly in plants and viral proteolipids.[2][5] The article on lipid-anchored proteins has more information on these canonical classes.

Lipidated peptides are a type of peptide amphiphile that incorporate one or more alkyl/lipid chains, attached to a peptide head group. As with peptide amphiphiles, they self-assemble depending on the hydrophilic/hydrophobic balance, as well interactions between the peptide units, which is dependent on the charge of the amino acid residues.[6] Lipidated peptides combine the structural features of amphiphilic surfactants with the functions of bioactive peptides, and they are known to assemble into a variety of nanostructures.[7][8]

Function and application

edit

Due to the desirable properties of peptides such as high receptor affinity and bioactivity, and low toxicity, the use of peptides in therapeutics (i. e. as peptide therapeutics) has great potential; shown by a fast growing market with over 100 approved peptide-based drugs.[9] The disadvantages are that peptides have low oral bioavailability and stability. Lipidation as a chemical modification tool in the development of therapeutic agents has proven to be useful in overcoming these issues, with four lipidized peptide drugs currently approved for use in humans, and various others in clinical trials.[10] Two of the approved drugs are long-acting anti-diabetic GLP-1 analogues liraglutide (Victoza®), and insulin detemir (Levemir®). The other two are the antibiotics daptomycin and polymyxin B.

Lipidated peptides also have applications in other areas, such as use in the cosmetic industry.[6] A commercially available lipidated peptide, Matrixyl, is used in anti-wrinkle creams. Matrixyl is a pentapeptide and has the sequence KTTKS, with an attached palmitoyl lipid chain, that is able to stimulate collagen and fibronectin production in fibroblasts.[11] Several studies have shown promising results of palmitoyl-KTTKS, and topical formulations have been found to significantly reduce fine lines and wrinkles, helping to delay the aging process in the skin.[12] The Hamley group have also carried out investigations of palmitoyl-KTTKS, and found it so self-assemble into nano tapes in the pH range 3-7, in addition to stimulating human dermal and corneal fibroblasts in a concentration dependant manner, suggesting that stimulation occurs above the critical aggregation concentration.[13]

There exist some rarer forms of protein acylation that may not have a membrane-related function. They include serine O-octanoylation in ghrelin, serine O-palmitoleoylation in Wnt proteins, and O-palmitoylation in histone H4 with LPCAT1. Hedgehog proteins are double-modified by (N-)palmitate and cholesterol. Some skin ceramides are proteolipids.[2] The amino group on lysine can also be myristoylation via a poorly-understood mechanism.[14]

In bacteria

edit

All bacteria use proteolipids, sometimes confusingly referred to as bacterial lipoproteins, in their cell membrane. A common modification consists of N-acyl- and S‑diacylglycerol attached to an N-terminal cystine residue. Braun's lipoprotein, found in gram-negative bacteria, is a representative of this group. In addition, Mycobacterium O-mycolate proteins destined for the outer membrane.[15] The plant chloroplast is capable of many of the same modifications that bacteria perform to proteolipids.[16] One database for such N-Acyl Diacyl Glycerylated cell wall proteolipids is DOLOP.[17]

Pathogenic spirochetes, including B. burgdorferi and T. pallidum, use their proteolipid adhesins to stick to victim cells.[18] These proteins are also potent antigens, and are in fact the main immunogens of these two species.[19]

Proteolipids include bacterial antibiotics that aren't synthesised in the ribosome.[10] Products of nonribosomal peptide synthase may also involve a peptide structure linked to lipids. These are usually referred to as "lipopeptides".[15] Bacterial "lipoproteins" and "lipopeptides" (LP) are potent inducers of sepsis, second only to lipopolysaccharide (LPS) in its ability to cause an inflammation response. While LPS is detected by the toll-like receptor TLR4, LPs are detected by TLR2.[20]

Bacillus

edit

Many proteolipids are produced by the Bacillus subtilis family, and are composed of a cyclic structure made up of 7-10 amino acids, and a β-hydroxy fatty acid chain of varying length ranging from 13-19 carbon atoms.[21] These can be divided into three families depending on the structure of the cyclic peptide sequence: surfactins, iturins, and fengycins.[22][23][24] Lipidated peptides produced by Bacillus strains have many useful bio-activities such as anti-bacterial, anti- viral, anti-fungal, and anti-tumour properties,[21][22] making them very attractive for use in a wide range of industries.

Surfactins

edit

As the name implies, surfactins are potent biosurfactants (surfactants produced by bacteria, yeast, or fungi), and they have been shown to reduce the surface tension of water from 72 to 27 mN/m at very low concentrations.[25] Furthermore, surfactins are also able to permeabilize lipid membranes, allowing them to have specific antimicrobial and antiviral activities.[22][26][27] Since surfactins are biosurfactants, they have diverse functional properties. These include low toxicity, biodegradability and a higher tolerance towards variation of temperature and pH,[22] making them very interesting for use in a wide range of applications.

Iturins

edit

Iturins are pore‐forming lipopeptides with antifungal activity, and this is dependent on the interaction with the cytoplasmic membrane of the target cells.[22][23][28] Mycosubtilin is an iturin isoform that can interact with membranes via its sterol alcohol group, to target ergosterol (a compound found in fungi) to give it antifungal properties.[21][29]

Fengycins

edit

Fengycins are another class of biosurfactant produced by Bacillus subtilis, with antifungal activity against filamentous fungi.[24][28][30] There are two classes of Fengycins, Fengycin A and Fengycin B, with the two only differing by one amino acid at position 6 in the peptide sequence, with the former having an alanine residue, and the latter having valine.[31]

Streptomyces

edit

Daptomycin is another naturally occurring lipidated peptide, produced by the Gram positive bacterium Streptomyces roseoporous. The structure of Daptomycin consists of a decanoyl lipid chain attached to a partially cyclised peptide head group.[6] It has very potent antimicrobial properties and is used as an antibiotic to treat life-threatening conditions caused by Gram positive bacteria including MRSA (methicillin-resistant Staphylococcus aureus) and vancomycin resistant Enterococci.[8][32][33] As with the Bacillus subtilis lipidated peptides, the permeation of the cell membrane is what gives it its properties, and the mechanism of action with daptomycin is thought to involve the insertion of the decanoyl chain into the bacterial membrane to cause disruption. This then causes a serious depolarization resulting in the inhibition of various synthesis processes including those of DNA, protein and RNA, leading to apoptosis.[34][35][36]

See also

edit

References

edit

  This article incorporates text by Jessica Hutchinson available under the CC BY-SA 3.0 license.

  1. ^ "MeSH Browser". meshb.nlm.nih.gov. Retrieved 11 March 2018.
  2. ^ a b c "Proteolipids - proteins modified by covalent attachment to lipids - N-myristoylated, S-palmitoylated, prenylated proteins, ghrelin, hedgehog proteins". The LipidWeb. Retrieved 18 July 2019.
  3. ^ Kervin, Troy A.; Overduin, Michael (2024-02-27). "Membranes are functionalized by a proteolipid code". BMC Biology. 22 (1): 46. doi:10.1186/s12915-024-01849-6. ISSN 1741-7007. PMC 10898092. PMID 38414038.
  4. ^ Lees, Marjorie B. (1998-03-01). "A History of Proteolipids: A Personal Memoir". Neurochemical Research. 23 (3): 261–271. doi:10.1023/A:1022488912996. ISSN 1573-6903. PMID 9482238. S2CID 523291.
  5. ^ Li Y, Qi B (2017). "Progress toward Understanding Protein S-acylation: Prospective in Plants". Frontiers in Plant Science. 8: 346. doi:10.3389/fpls.2017.00346. PMC 5364179. PMID 28392791.
  6. ^ a b c Hamley IW (May 2015). "Lipopeptides: from self-assembly to bioactivity". Chemical Communications. 51 (41): 8574–83. doi:10.1039/C5CC01535A. PMID 25797909.
  7. ^ Cui H, Webber MJ, Stupp SI (2010). "Self-assembly of peptide amphiphiles: from molecules to nanostructures to biomaterials". Biopolymers. 94 (1): 1–18. doi:10.1002/bip.21328. PMC 2921868. PMID 20091874.
  8. ^ a b Löwik DW, van Hest JC (May 2004). "Peptide based amphiphiles" (PDF). Chemical Society Reviews. 33 (4): 234–45. doi:10.1039/B212638A. hdl:2066/13849. PMID 15103405. S2CID 1517441.
  9. ^ Bruno BJ, Miller GD, Lim CS (November 2013). "Basics and recent advances in peptide and protein drug delivery". Therapeutic Delivery. 4 (11): 1443–67. doi:10.4155/tde.13.104. PMC 3956587. PMID 24228993.
  10. ^ a b Zhang L, Bulaj G (2012-03-31). "Converting peptides into drug leads by lipidation". Current Medicinal Chemistry. 19 (11): 1602–18. doi:10.2174/092986712799945003. PMID 22376031.
  11. ^ Katayama K, Armendariz-Borunda J, Raghow R, Kang AH, Seyer JM (May 1993). "A pentapeptide from type I procollagen promotes extracellular matrix production". The Journal of Biological Chemistry. 268 (14): 9941–4. doi:10.1016/S0021-9258(18)82153-6. PMID 8486721.
  12. ^ Robinson LR, Fitzgerald NC, Doughty DG, Dawes NC, Berge CA, Bissett DL (June 2005). "Topical palmitoyl pentapeptide provides improvement in photoaged human facial skin". International Journal of Cosmetic Science. 27 (3): 155–60. doi:10.1111/j.1467-2494.2005.00261.x. PMID 18492182. S2CID 70695.
  13. ^ Jones RR, Castelletto V, Connon CJ, Hamley IW (March 2013). "Collagen stimulating effect of peptide amphiphile C16-KTTKS on human fibroblasts". Molecular Pharmaceutics. 10 (3): 1063–9. doi:10.1021/mp300549d. PMID 23320752.
  14. ^ Lanyon-Hogg T, Faronato M, Serwa RA, Tate EW (July 2017). "Dynamic Protein Acylation: New Substrates, Mechanisms, and Drug Targets". Trends in Biochemical Sciences. 42 (7): 566–581. doi:10.1016/j.tibs.2017.04.004. hdl:10044/1/48121. PMID 28602500.
  15. ^ a b "Microbial Proteolipids and Lipopeptides - glycopeptidolipids, surfactin, iturnins, polymyxins, daptomycin". The LipidWeb. Retrieved 21 July 2019.
  16. ^ Glenz K, Bouchon B, Stehle T, Wallich R, Simon MM, Warzecha H (January 2006). "Production of a recombinant bacterial lipoprotein in higher plant chloroplasts". Nature Biotechnology. 24 (1): 76–7. doi:10.1038/nbt1170. PMID 16327810. S2CID 7029129.
  17. ^ "DOLOP - A Database of Bacterial Lipoproteins". cam.ac.uk. Retrieved 2 January 2017.
  18. ^ Chan K, Nasereddin T, Alter L, Centurion-Lara A, Giacani L, Parveen N (May 2016). "Treponema pallidum Lipoprotein TP0435 Expressed in Borrelia burgdorferi Produces Multiple Surface/Periplasmic Isoforms and mediates Adherence". Scientific Reports. 6: 25593. Bibcode:2016NatSR...625593C. doi:10.1038/srep25593. PMC 4861935. PMID 27161310.
  19. ^ Porcella SF, Schwan TG (March 2001). "Borrelia burgdorferi and Treponema pallidum: a comparison of functional genomics, environmental adaptations, and pathogenic mechanisms". The Journal of Clinical Investigation. 107 (6): 651–6. doi:10.1172/JCI12484. PMC 208952. PMID 11254661.
  20. ^ de Tejada, Guillermo Martinez; Heinbockel, Lena; Ferrer-Espada, Raquel; Heine, Holger; Alexander, Christian; Bárcena-Varela, Sergio; Goldmann, Torsten; Correa, Wilmar; Wiesmüller, Karl-Heinz; Gisch, Nicolas; Sánchez-Gómez, Susana; Fukuoka, Satoshi; Schürholz, Tobias; Gutsmann, Thomas; Brandenburg, Klaus (November 2015). "Lipoproteins/peptides are sepsis-inducing toxins from bacteria that can be neutralized by synthetic anti-endotoxin peptides". Scientific Reports. 5 (1): 14292. Bibcode:2015NatSR...514292D. doi:10.1038/srep14292. PMC 4585737. PMID 26390973.
  21. ^ a b c Zhao H, Shao D, Jiang C, Shi J, Li Q, Huang Q, et al. (August 2017). "Biological activity of lipopeptides from Bacillus". Applied Microbiology and Biotechnology. 101 (15): 5951–5960. doi:10.1007/s00253-017-8396-0. PMID 28685194. S2CID 3756911.
  22. ^ a b c d e Mnif I, Ghribi D (May 2015). "Review lipopeptides biosurfactants: Mean classes and new insights for industrial, biomedical, and environmental applications". Biopolymers. 104 (3): 129–47. doi:10.1002/bip.22630. PMID 25808118. S2CID 25521354.
  23. ^ a b Singh P, Cameotra SS (March 2004). "Potential applications of microbial surfactants in biomedical sciences". Trends in Biotechnology. 22 (3): 142–6. doi:10.1016/j.tibtech.2004.01.010. PMID 15036865.
  24. ^ a b Steller S, Vollenbroich D, Leenders F, Stein T, Conrad B, Hofemeister J, et al. (January 1999). "Structural and functional organization of the fengycin synthetase multienzyme system from Bacillus subtilis b213 and A1/3". Chemistry & Biology. 6 (1): 31–41. doi:10.1016/S1074-5521(99)80018-0. PMID 9889147.
  25. ^ Ohno A, Ano T, Shoda M (July 1995). "Production of a lipopeptide antibiotic, surfactin, by recombinant Bacillus subtilis in solid state fermentation". Biotechnology and Bioengineering. 47 (2): 209–14. doi:10.1002/bit.260470212. PMID 18623394. S2CID 30547894.
  26. ^ Heerklotz H, Seelig J (September 2001). "Detergent-like action of the antibiotic peptide surfactin on lipid membranes". Biophysical Journal. 81 (3): 1547–54. Bibcode:2001BpJ....81.1547H. doi:10.1016/S0006-3495(01)75808-0. PMC 1301632. PMID 11509367.
  27. ^ Carrillo C, Teruel JA, Aranda FJ, Ortiz A (April 2003). "Molecular mechanism of membrane permeabilization by the peptide antibiotic surfactin". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1611 (1–2): 91–7. doi:10.1016/S0005-2736(03)00029-4. PMID 12659949.
  28. ^ a b Hamley IW, Dehsorkhi A, Jauregi P, Seitsonen J, Ruokolainen J, Coutte F, et al. (October 2013). "Self-assembly of three bacterially-derived bioactive lipopeptides". Soft Matter. 9 (40): 9572–8. Bibcode:2013SMat....9.9572H. doi:10.1039/c3sm51514a. PMID 26029764.
  29. ^ Nasir MN, Besson F (May 2012). "Interactions of the antifungal mycosubtilin with ergosterol-containing interfacial monolayers". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1818 (5): 1302–8. doi:10.1016/j.bbamem.2012.01.020. PMID 22306791.
  30. ^ Deleu M, Paquot M, Nylander T (April 2008). "Effect of fengycin, a lipopeptide produced by Bacillus subtilis, on model biomembranes". Biophysical Journal. 94 (7): 2667–79. Bibcode:2008BpJ....94.2667D. doi:10.1529/biophysj.107.114090. PMC 2267117. PMID 18178659.
  31. ^ Meena KR, Kanwar SS (2015). "Lipopeptides as the antifungal and antibacterial agents: applications in food safety and therapeutics". BioMed Research International. 2015: 473050. doi:10.1155/2015/473050. PMC 4303012. PMID 25632392.
  32. ^ Woodworth JR, Nyhart EH, Brier GL, Wolny JD, Black HR (February 1992). "Single-dose pharmacokinetics and antibacterial activity of daptomycin, a new lipopeptide antibiotic, in healthy volunteers". Antimicrobial Agents and Chemotherapy. 36 (2): 318–25. doi:10.1128/AAC.36.2.318. PMC 188435. PMID 1318678.
  33. ^ Baltz RH, Miao V, Wrigley SK (December 2005). "Natural products to drugs: daptomycin and related lipopeptide antibiotics". Natural Product Reports. 22 (6): 717–41. doi:10.1039/b416648p. PMID 16311632.
  34. ^ Silverman JA, Perlmutter NG, Shapiro HM (August 2003). "Correlation of daptomycin bactericidal activity and membrane depolarization in Staphylococcus aureus". Antimicrobial Agents and Chemotherapy. 47 (8): 2538–44. doi:10.1128/aac.47.8.2538-2544.2003. PMC 166110. PMID 12878516.
  35. ^ Alborn WE, Allen NE, Preston DA (November 1991). "Daptomycin disrupts membrane potential in growing Staphylococcus aureus". Antimicrobial Agents and Chemotherapy. 35 (11): 2282–7. doi:10.1128/AAC.35.11.2282. PMC 245372. PMID 1666494.
  36. ^ Kirkham S, Castelletto V, Hamley IW, Inoue K, Rambo R, Reza M, Ruokolainen J (July 2016). "Self-Assembly of the Cyclic Lipopeptide Daptomycin: Spherical Micelle Formation Does Not Depend on the Presence of Calcium Chloride" (PDF). ChemPhysChem. 17 (14): 2118–22. doi:10.1002/cphc.201600308. PMID 27043447.
edit