抗菌肽

抗菌肽（Cathelicidin），係一系列可在巨噬細胞和中性粒細胞的溶酶體中找到的具有抗菌作用的多肽。這種多肽在哺乳動物對侵襲性細菌感染的先天免疫中扮演着重要的角色。抗菌肽家族被歸爲抗微生物肽（antimicrobial peptides ，縮寫爲AMPs）的一種。防禦素則是抗微生物肽家族的另一成員。儘管抗菌肽家族與防禦素具有相同的結構特徵，但它們卻具有高度異質性。 抗菌肽家族的成員可通過一個高度穩定的區域（即凱薩林域（cathelin domain））和另一個高度可變的域來表徵。 哺乳動物的各個種的抗菌肽之間是互相孤立的。最初，科學家在中性粒細胞中發現了抗菌肽，不過，隨後，科學家發現，在經過細菌或病毒或骨化三醇（維生素D的活性形式）的刺激後，上皮細胞和巨噬細胞中亦會產生抗菌肽。 抗菌肽的長度範圍很大，其長度可從12個氨基酸殘基到80個氨基酸殘基。它們的結構也千變萬化。大部分的抗菌肽均爲摺疊成兩親性的α螺旋的長爲23-37個氨基酸的線狀肽。不過也有小部分的抗菌肽長度在12-18個氨基酸之間。這類肽有一到兩個起穩定結構作用的二硫鍵，且擁有β髮夾（英语：beta hairpin）結構。科學家也有發現長度較長的抗菌肽（長度在39-80個氨基酸殘基之間）。這些長度較長的抗菌肽呈現出重複的脯氨酸基序，形成了延長的聚脯氨酸型結構。 抗菌肽與半胱氨酸蛋白酶抑製劑（英语：Cystatin）家族有着一級同源性，儘管那些被認爲很重要的氨基酸殘基在這一蛋白酶抑制家族中往往難以找到。 抗菌肽家族的成員在人類、猴子、小鼠、大鼠、豚鼠、熊貓、豬、牛、青蛙、綿羊、山羊、雞，還有馬體內都有分佈。 如今已被確認的抗菌肽有： 人類：hCAP-18/LL-37 恆河猴：RL-37 小鼠：CRAMP-1/2 大鼠：rCRAMP 兔：CAP-18 豚鼠：CAP-11 豬：PR-39、Prophenin、PMAP-23/6/37 牛：BMAP-27/28/34（牛髓細胞抗菌肽）、Bac5、Bac7 青蛙：抗菌肽-AL（在棕點湍蛙（Amolops loloensis）體內存在） 羊： 山羊： 雞：fowlicidins 1/2/3以及抗菌肽β-1（cathelicidin Beta-1） 馬： 熊貓： 患酒渣鼻的患者體內的抗菌肽水平和角質層胰蛋白酶酵素（SCTEs）水平會升高。在激肽釋放酶7（英语：KLK7）（KLK7）和激肽釋放酶5（英语：KLK5）（KLK5）的共同作用下，抗菌肽能被切割成抗微生物肽LL-37。LL-37過量被認爲是引發酒渣鼻（無論是其哪一亞種）的罪魁禍首之一。抗生素已被用於酒渣鼻的治療，然而，抗生素之所以起作用，或許僅僅是因爲它部分抑制了角質層胰蛋白酶酵素。 維生素D能提高的人體內抗菌肽hCAP18的水平，而hCAP18據信能有效降低接受透析的患者因感染而造成的死亡風險。拥有高水平hCAP18蛋白的患者经过一年透析之后能存活并免受致命感染的概率是一般患者的3.7倍。。 維生素D能夠增強抗菌肽相關基因的表達，而抗菌肽又對細菌，真菌和病毒具有廣譜抗微生物活性。抗菌肽能在巨噬細胞內的吞噬體與溶酶體融合後快速摧毀原來吞噬體裏的微生物的脂蛋白膜。 針對抗菌胜肽，提供相關資訊的研究型資料庫，如: DRAMP [3] （页面存档备份，存于互联网档案馆）, dbAMP [4] 。 dbAMP 為一個綜合型抗菌胜肽資料庫，其中所包含的資訊有抗菌胜肽蛋白質序列、名稱、物種來源、抗菌物種分類、抗菌胜肽的物理性質、是否經實驗研究證明以及蛋白質結構分析與圖形化等資訊，此些資料庫同時也提供抗菌胜肽等預測工具，供使用者瀏覽、分析及研究應用。 抗微生物肽 先天免疫系統 理查德·加洛（英语：Richard Gallo） Entrez Gene: CAMP cathelicidin antimicrobial peptide.  Zanetti M. Cathelicidins, multifunctional peptides of the innate immunity. Journal of Leukocyte Biology. Jan 2004, 75 (1): 39–48. PMID 12960280. doi:10.1189/jlb.0403147.  Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, Ochoa MT, Schauber J, Wu K, Meinken C, Kamen DL, Wagner M, Bals R, Steinmeyer A, Zügel U, Gallo RL, Eisenberg D, Hewison M, Hollis BW, Adams JS, Bloom BR, Modlin RL. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science (New York, N.Y.). Mar 2006, 311 (5768): 1770–3. PMID 16497887. doi:10.1126/science.1123933.  Gennaro R, Zanetti M. Structural features and biological activities of the cathelicidin-derived antimicrobial peptides. Biopolymers. 2000, 55 (1): 31–49. PMID 10931440. doi:10.1002/1097-0282(2000)55:1<31::AID-BIP40>3.0.CO;2-9.  Zaiou M, Nizet V, Gallo RL. Antimicrobial and protease inhibitory functions of the human cathelicidin (hCAP18/LL-37) prosequence. The Journal of Investigative Dermatology. May 2003, 120 (5): 810–6. PMID 12713586. doi:10.1046/j.1523-1747.2003.12132.x3.  Gallo RL, Kim KJ, Bernfield M, Kozak CA, Zanetti M, Merluzzi L, Gennaro R. Identification of CRAMP, a cathelin-related antimicrobial peptide expressed in the embryonic and adult mouse. The Journal of Biological Chemistry. May 1997, 272 (20): 13088–93. PMID 9148921. doi:10.1074/jbc.272.20.13088.  Hao X, Yang H, Wei L, Yang S, Zhu W, Ma D, Yu H, Lai R. Amphibian cathelicidin fills the evolutionary gap of cathelicidin in vertebrate. Amino Acids. Aug 2012, 43 (2): 677–85. PMID 22009138. doi:10.1007/s00726-011-1116-7.  Achanta M, Sunkara LT, Dai G, Bommineni YR, Jiang W, Zhang G. Tissue expression and developmental regulation of chicken cathelicidin antimicrobial peptides. Journal of Animal Science and Biotechnology. 2012, 3 (1): 15. PMC 3436658 . PMID 22958518. doi:10.1186/2049-1891-3-15.  Reinholz M, Ruzicka T, Schauber J. Cathelicidin LL-37: an antimicrobial peptide with a role in inflammatory skin disease. Ann Dermatol. 2012, 24 (2): 126–35. PMC 3346901 . PMID 22577261. doi:10.5021/ad.2012.24.2.126.  Yamasaki K, Di Nardo A, Bardan A, Murakami M, Ohtake T, Coda A, Dorschner RA, Bonnart C, Descargues P, Hovnanian A, Morhenn VB, Gallo RL. Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. Nature Medicine. Aug 2007, 13 (8): 975–80. PMID 17676051. doi:10.1038/nm1616.  Gombart AF, Bhan I, Borregaard N, Tamez H, Camargo CA, Koeffler HP, Thadhani R. Low plasma level of cathelicidin antimicrobial peptide (hCAP18) predicts increased infectious disease mortality in patients undergoing hemodialysis. Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America. Feb 2009, 48 (4): 418–24. PMID 19133797. doi:10.1086/596314.  Zasloff M. Antimicrobial peptides of multicellular organisms. Nature. Jan 2002, 415 (6870): 389–95. PMID 11807545. doi:10.1038/415389a.  Kamen DL, Tangpricha V. Vitamin D and molecular actions on the immune system: modulation of innate and autoimmunity. Journal of Molecular Medicine (Berlin, Germany). May 2010, 88 (5): 441–50. PMC 2861286 . PMID 20119827. doi:10.1007/s00109-010-0590-9.  Shi, Guobang; Kang, Xinyue; Dong, Fanyi; Liu, Yanchao; Zhu, Ning; Hu, Yuxuan; Xu, Hanmei; Lao, Xingzhen; Zheng, Heng. DRAMP 3.0: an enhanced comprehensive data repository of antimicrobial peptides. Nucleic Acids Research. 2022-01-07, 50 (D1): D488–D496 [2022-04-25]. ISSN 0305-1048. PMC 8728287 . PMID 34390348. doi:10.1093/nar/gkab651. （原始内容存档于2022-06-20） （英语）.  Dürr UH, Sudheendra US, Ramamoorthy A. LL-37, the only human member of the cathelicidin family of antimicrobial peptides. Biochimica Et Biophysica Acta. Sep 2006, 1758 (9): 1408–25. PMID 16716248. doi:10.1016/j.bbamem.2006.03.030.  Chromek M, Slamová Z, Bergman P, Kovács L, Podracká L, Ehrén I, Hökfelt T, Gudmundsson GH, Gallo RL, Agerberth B, Brauner A. The antimicrobial peptide cathelicidin protects the urinary tract against invasive bacterial infection. Nature Medicine. Jun 2006, 12 (6): 636–41. PMID 16751768. doi:10.1038/nm1407.  Gombart AF, Borregaard N, Koeffler HP. Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3. FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology. Jul 2005, 19 (9): 1067–77. PMID 15985530. doi:10.1096/fj.04-3284com.  López-García B, Lee PH, Gallo RL. Expression and potential function of cathelicidin antimicrobial peptides in dermatophytosis and tinea versicolor. The Journal of Antimicrobial Chemotherapy. May 2006, 57 (5): 877–82. PMID 16556635. doi:10.1093/jac/dkl078.  Lehrer RI, Ganz T. Cathelicidins: a family of endogenous antimicrobial peptides. Current Opinion in Hematology. Jan 2002, 9 (1): 18–22. PMID 11753073. doi:10.1097/00062752-200201000-00004.  Niyonsaba F, Hirata M, Ogawa H, Nagaoka I. Epithelial cell-derived antibacterial peptides human beta-defensins and cathelicidin: multifunctional activities on mast cells. Current Drug Targets. Inflammation and Allergy. Sep 2003, 2 (3): 224–31. PMID 14561157. doi:10.2174/1568010033484115.  van Wetering S, Tjabringa GS, Hiemstra PS. Interactions between neutrophil-derived antimicrobial peptides and airway epithelial cells. Journal of Leukocyte Biology. Apr 2005, 77 (4): 444–50. PMID 15591123. doi:10.1189/jlb.0604367.  Agerberth B, Gunne H, Odeberg J, Kogner P, Boman HG, Gudmundsson GH. FALL-39, a putative human peptide antibiotic, is cysteine-free and expressed in bone marrow and testis. Proceedings of the National Academy of Sciences of the United States of America. Jan 1995, 92 (1): 195–9. PMC 42844 . PMID 7529412. doi:10.1073/pnas.92.1.195.  Cowland JB, Johnsen AH, Borregaard N. hCAP-18, a cathelin/pro-bactenecin-like protein of human neutrophil specific granules. FEBS Letters. Jul 1995, 368 (1): 173–6. PMID 7615076. doi:10.1016/0014-5793(95)00634-L.  Gudmundsson GH, Magnusson KP, Chowdhary BP, Johansson M, Andersson L, Boman HG. Structure of the gene for porcine peptide antibiotic PR-39, a cathelin gene family member: comparative mapping of the locus for the human peptide antibiotic FALL-39. Proceedings of the National Academy of Sciences of the United States of America. Jul 1995, 92 (15): 7085–9. PMC 41476 . PMID 7624374. doi:10.1073/pnas.92.15.7085.  Larrick JW, Hirata M, Balint RF, Lee J, Zhong J, Wright SC. Human CAP18: a novel antimicrobial lipopolysaccharide-binding protein. Infection and Immunity. Apr 1995, 63 (4): 1291–7. PMC 173149 . PMID 7890387.  Gudmundsson GH, Agerberth B, Odeberg J, Bergman T, Olsson B, Salcedo R. The human gene FALL39 and processing of the cathelin precursor to the antibacterial peptide LL-37 in granulocytes. European Journal of Biochemistry / FEBS. Jun 1996, 238 (2): 325–32. PMID 8681941. doi:10.1111/j.1432-1033.1996.0325z.x.  Larrick JW, Lee J, Ma S, Li X, Francke U, Wright SC, Balint RF. Structural, functional analysis and localization of the human CAP18 gene. FEBS Letters. Nov 1996, 398 (1): 74–80. PMID 8946956. doi:10.1016/S0014-5793(96)01199-4.  Frohm M, Agerberth B, Ahangari G, Stâhle-Bäckdahl M, Lidén S, Wigzell H, Gudmundsson GH. The expression of the gene coding for the antibacterial peptide LL-37 is induced in human keratinocytes during inflammatory disorders. The Journal of Biological Chemistry. Jun 1997, 272 (24): 15258–63. PMID 9182550. doi:10.1074/jbc.272.24.15258.  Bals R, Wang X, Zasloff M, Wilson JM. The peptide antibiotic LL-37/hCAP-18 is expressed in epithelia of the human lung where it has broad antimicrobial activity at the airway surface. Proceedings of the National Academy of Sciences of the United States of America. Aug 1998, 95 (16): 9541–6. PMC 21374 . PMID 9689116. doi:10.1073/pnas.95.16.9541.  Chen Q, Schmidt AP, Anderson GM, Wang JM, Wooters J, Oppenheim JJ, Chertov O. LL-37, the neutrophil granule- and epithelial cell-derived cathelicidin, utilizes formyl peptide receptor-like 1 (FPRL1) as a receptor to chemoattract human peripheral blood neutrophils, monocytes, and T cells. The Journal of Experimental Medicine. Oct 2000, 192 (7): 1069–74. PMC 2193321 . PMID 11015447. doi:10.1084/jem.192.7.1069.  Agerberth B, Charo J, Werr J, Olsson B, Idali F, Lindbom L, Kiessling R, Jörnvall H, Wigzell H, Gudmundsson GH. The human antimicrobial and chemotactic peptides LL-37 and alpha-defensins are expressed by specific lymphocyte and monocyte populations. Blood. Nov 2000, 96 (9): 3086–93. PMID 11049988.  Bals R, Lang C, Weiner DJ, Vogelmeier C, Welsch U, Wilson JM. Rhesus monkey (Macaca mulatta) mucosal antimicrobial peptides are close homologues of human molecules. Clinical and Diagnostic Laboratory Immunology. Mar 2001, 8 (2): 370–5. PMC 96065 . PMID 11238224. doi:10.1128/CDLI.8.2.370-375.2001.  Nagaoka I, Hirota S, Niyonsaba F, Hirata M, Adachi Y, Tamura H, Heumann D. Cathelicidin family of antibacterial peptides CAP18 and CAP11 inhibit the expression of TNF-alpha by blocking the binding of LPS to CD14(+) cells. Journal of Immunology (Baltimore, Md. : 1950). Sep 2001, 167 (6): 3329–38. PMID 11544322. doi:10.4049/jimmunol.167.6.3329.  Hase K, Eckmann L, Leopard JD, Varki N, Kagnoff MF. Cell differentiation is a key determinant of cathelicidin LL-37/human cationic antimicrobial protein 18 expression by human colon epithelium. Infection and Immunity. Feb 2002, 70 (2): 953–63. PMC 127717 . PMID 11796631. doi:10.1128/IAI.70.2.953-963.2002.  Giuliani A, Pirri G, Nicoletto S. Antimicrobial peptides: an overview of a promising class of therapeutics. Cent. Eur. J. Biol. 2007, 2 (1): 1–33. doi:10.2478/s11535-007-0010-5.  Burton MF, Steel PG. The chemistry and biology of LL-37. Natural Product Reports. Dec 2009, 26 (12): 1572–1584. PMID 19936387. doi:10.1039/b912533g.