抗菌肽
抗菌肽（Cathelicidin），系一系列可在巨噬细胞和中性粒细胞的溶酶体中找到的具有抗菌作用的多肽[1]。这种多肽在哺乳动物对侵袭性细菌感染的先天免疫中扮演着重要的角色[2]。抗菌肽家族被归为抗微生物肽（antimicrobial peptides ，缩写为AMPs）的一种。防御素则是抗微生物肽家族的另一成员。尽管抗菌肽家族与防御素具有相同的结构特征，但它们却具有高度异质性[2]。
| 抗菌肽 Cathelicidin antimicrobial peptide | |||||||||||||
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| 标识 | |||||||||||||
| 代号 | CAMP; CAP-18; CAP18; CRAMP; FALL-39; FALL39; HSD26; LL37 | ||||||||||||
| 扩展标识 | 遗传学：600474 鼠基因：108443 同源基因：110678 GeneCards: CAMP Gene | ||||||||||||
| RNA表达模式 | |||||||||||||
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| 更多表达数据 | |||||||||||||
| 直系同源体 | |||||||||||||
| 物种 | 人类 | 小鼠 | |||||||||||
| Entrez | 820 | 12796 | |||||||||||
| Ensembl | ENSG00000164047 | ENSMUSG00000038357 | |||||||||||
| UniProt | P49913 | P51437 | |||||||||||
| mRNA序列 | NM_004345 | NM_009921 | |||||||||||
| 蛋白序列 | NP_004336 | NP_034051 | |||||||||||
| 基因位置 |
Chr 3: 48.22 – 48.23 Mb |
Chr 9: 109.85 – 109.85 Mb | |||||||||||
| PubMed查询 | [1] | [2] | |||||||||||
抗菌肽家族的成员可通过一个高度稳定的区域（即凯萨林域（cathelin domain））和另一个高度可变的域来表征[2]。
哺乳动物的各个种的抗菌肽之间是互相孤立的。最初，科学家在中性粒细胞中发现了抗菌肽，不过，随后，科学家发现，在经过细菌或病毒或骨化三醇（维生素D的活性形式）的刺激后，上皮细胞和巨噬细胞中亦会产生抗菌肽[3]。
特征
| 抗菌肽 Cathelicidin | |||||||||
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 内源性抗微生物多肽的抗菌肽基序（the Cathelicidin Motif of Protegrins）的晶体结构分析 | |||||||||
| 鉴定 | |||||||||
| 标志 | Cathelicidin | ||||||||
| Pfam | PF00666（旧版） | ||||||||
| Pfam宗系 | CL0121（旧版） | ||||||||
| InterPro | IPR001894 | ||||||||
| PROSITE | PDOC00729 | ||||||||
| SCOP | 1lyp / SUPFAM | ||||||||
| OPM家族 | 236 | ||||||||
| OPM蛋白 | 2k6o | ||||||||
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抗菌肽的长度范围很大，其长度可从12个氨基酸残基到80个氨基酸残基。它们的结构也千变万化[4]。大部分的抗菌肽均为折叠成两亲性的α螺旋的长为23-37个氨基酸的线状肽。不过也有小部分的抗菌肽长度在12-18个氨基酸之间。这类肽有一到两个起稳定结构作用的二硫键，且拥有β发夹结构。科学家也有发现长度较长的抗菌肽（长度在39-80个氨基酸残基之间）。这些长度较长的抗菌肽呈现出重复的脯氨酸基序，形成了延长的聚脯氨酸型结构[2]。
抗菌肽与半胱氨酸蛋白酶抑制剂家族有着一级同源性[5]，尽管那些被认为很重要的氨基酸残基在这一蛋白酶抑制家族中往往难以找到。
种类
抗菌肽家族的成员在人类、猴子、小鼠、大鼠、豚鼠、熊猫、猪、牛、青蛙、绵羊、山羊、鸡，还有马体内都有分布。
如今已被确认的抗菌肽有：[2]
临床意义
患酒渣鼻的患者体内的抗菌肽水平和角质层胰蛋白酶酵素（SCTEs）水平会升高。在激肽释放酶7（KLK7）和激肽释放酶5（KLK5）的共同作用下，抗菌肽能被切割成抗微生物肽LL-37。LL-37过量被认为是引发酒渣鼻（无论是其哪一亚种）的罪魁祸首之一[9]。抗生素已被用于酒渣鼻的治疗，然而，抗生素之所以起作用，或许仅仅是因为它部分抑制了角质层胰蛋白酶酵素[10]。
维生素D能提高的人体内抗菌肽hCAP18的水平，而hCAP18据信能有效降低接受透析的患者因感染而造成的死亡风险。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。[11]。
维生素D能够增强抗菌肽相关基因的表达，而抗菌肽又对细菌，真菌和病毒具有广谱抗微生物活性[12][13]。抗菌肽能在巨噬细胞内的吞噬体与溶酶体融合后快速摧毁原来吞噬体里的微生物的脂蛋白膜。
数据库
针对抗菌胜肽，提供相关资讯的研究型数据库，如: DRAMP[14] [3] （页面存档备份，存于互联网档案馆）, dbAMP [4] 。 dbAMP 为一个综合型抗菌胜肽数据库，其中所包含的资讯有抗菌胜肽蛋白质序列、名称、物种来源、抗菌物种分类、抗菌胜肽的物理性质、是否经实验研究证明以及蛋白质结构分析与图形化等资讯，此些数据库同时也提供抗菌胜肽等预测工具，供使用者浏览、分析及研究应用。
参见
参考
- ^ Entrez Gene: CAMP cathelicidin antimicrobial peptide.
- ^ 2.0 2.1 2.2 2.3 2.4 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）.
拓展阅读
- 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.
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- 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.