头孢菌素C生物合成调控研究进展
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国家自然科学基金(31470177)


Advances in the regulation of cephalosporin C biosynthesis-A review
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    摘要:

    头孢菌素C由丝状真菌顶头孢霉产生,属于β-内酰胺类抗生素。其经改造后的7-氨基头孢烷酸是头孢类抗生素的重要中间体。头孢类抗生素在国内外抗生素市场中占有巨大的份额,是临床上的主要抗感染药物。随着分子生物学的发展,头孢菌素C的生物合成途径已基本阐明。为提高头孢菌素C的产量和降低生产成本,越来越多的研究者开始关注其较为精细、复杂的调控机制。本文重点对头孢菌素C生物合成及其调控机制的最新进展进行了简述,希望为今后头孢菌素C生产菌株的菌种改造和传统产业的升级换代提供一定的借鉴。

    Abstract:

    The beta-lactam antibiotic cephalosporin C is produced industrially by Acremonium chrysogenum. Its derivative 7-aminocephalosporanic acid (7-ACA) is the intermediate of most chemical modification cephalosporins that are the most frequently used antibiotics for the therapy of infectious diseases. Due to its importance, the biosynthetic pathway of cephalosporin C has been elucidated in Acremonium chrysogenum. To improve the yield of cephalosporin C and reduce the cost of production, recent studies have been focused on the sophisticated regulation of cephalosporin C biosynthesis. In this review, recent advances in cephalosporin C biosynthesis and regulation are summarized.

    参考文献
    [1] Abraham E. Selective reminiscences of β-lactam antibiotics: early research on penicillin and cephalosporins. BioEssays, 1990, 12(12): 601-606.
    [2] Martín JF, Ullán RV, García-Estrada C. Regulation and compartmentalization of β-lactam biosynthesis. Microbiology Biotechnology, 2010, 3(3): 285-299.
    [3] Hu YJ, Zhu BQ. Research progress on strain improvement of Acremonium chrysogenum by genetic engineering. Hereditas, 2011, 33(10): 1079-1086. (in Chinese) 胡又佳, 朱宝泉. 顶头孢霉遗传育种研究进展. 遗传, 2011, 33(10): 1079-1086.
    [4] Ozcengiz G, Demain AL. Recent advances in the biosynthesis of penicillins, cephalosporins and clavams and its regulation. Biotechnology Advances, 2013, 31(2): 287-311.
    [5] Ullán RV, Liu G, Casqueiro J, Gutiérrez S, Bañuelos O, Martín JF. The cefT gene of Acremonium chrysogenum C10 encodes a putative multidrug efflux pump protein that significantly increases cephalosporin C production. Molecular Genetics and Genomics, 2002, 267(5): 673-683.
    [6] Teijeira F, Ullán RV, Guerra SM, García-Estrada C, Vaca I, Martín JF. The transporter CefM involved in translocation of biosynthetic intermediates is essential for cephalosporin production. Biochemical Journal, 2009, 418(1): 113-124.
    [7] Ullán RV, Teijeira F, Guerra SM, Vaca I, Martín JF. Characterization of a novel peroxisome membrane protein essential for conversion of isopenicillin N into cephalosporin C. Biochemical Journal, 2010, 432(2): 227-236.
    [8] Teijeira F, Ullán RV, Fernández-Aguado M, Martín JF. CefR modulates transporters of beta-lactam intermediates preventing the loss of penicillins to the broth and increases cephalosporin production in Acremonium chrysogenum. Metabolic Engineering, 2011, 13(5): 532-543.
    [9] Behmer CJ, Demain AL. Further studies on carbon catabolite regulation of β-lactam antibiotic synthesis in Cephalosporium acremonium. Current Microbiology, 1983, 8(2): 107-114.
    [10] Jekosch K, Kück U. Glucose dependent transcriptional expression of the cre1 gene in Acremonium chrysogenum strains showing different levels of cephalosporin C production. Current Genetics, 2000, 37(6): 388-395.
    [11] Jekosch K, Kück U. Loss of glucose repression in an Acremonium chrysogenum β-lactam producer strain and its restoration by multiple copies of the cre1 gene. Applied Microbiology and Biotechnology, 2000, 54(4): 556-563.
    [12] Jekosch K, Hortschansky P, Kück U. Identification of a minimal cre1 promoter sequence promoting glucose-dependent gene expression in the β-lactam producer Acremonium chrysogenum. Current Genetics, 2008, 53(1): 35-48.
    [13] Shin HY, Lee JY, Park C, Kim SW. Utilization of glycerol as cysteine and carbon sources for cephalosporin C production by Acremonium chrysogenum M35 in methionine-unsupplemented culture. Journal of Biotechnology, 2011, 151(4): 363-368.
    [14] Shen YQ, Heim J, Solomon NA, Wolfe S, Demain AL. Repression of β-lactam production in Cephalosporium acremonium by nitrogen sources. Journal of Antibiotics, 1984, 37(5): 503-511.
    [15] Li JY, Pan YY, Liu G. Disruption of the nitrogen regulatory gene AcareA in Acremonium chrysogenum leads to reduction of cephalosporin production and repression of nitrogen metabolism. Fungal Genetics and Biology, 2013, 61: 69-79.
    [16] Esmahan C, Alvarez E, Montenegro E, Martin JF. Catabolism of lysine in Penicillium chrysogenum leads to formation of 2-aminoadipic acid, a precursor of penicillin biosynthesis. Applied and Environmental Microbiology, 1994, 60(6): 1705-1710.
    [17] Hijarrubia MJ, Aparicio JF, Casqueiro J, Martín JF. Characterization of the lys2 gene of Acremonium chrysogenum encoding a functional α-aminoadipate activating and reducing enzyme. Molecular and General Genetics, 2001, 264(6): 755-762.
    [18] Demain AL, Zhang JY. Cephalosporin C production by Cephalosporium acremonium: the methionine story. Critical Reviews in Biotechnology, 1998, 18(4): 283-294.
    [19] Liu G, Casqueiro J, Bañuelos O, Cardoza RE, Gutiérrez S, Martín JF. Targeted inactivation of the mecB gene, encoding cystathionine-γ-lyase, shows that the reverse transsulfuration pathway is required for high-level cephalosporin biosynthesis in Acremonium chrysogenum C10 but not for methionine induction of the cephalosporin genes. Journal of Bacteriology, 2001, 183(5): 1765-1772.
    [20] Kosalková K, Marcos AT, Martín JF. A moderate amplification of the mecB gene encoding cystathionine-γ-lyase stimulates cephalosporin biosynthesis in Acremonium chrysogenum. Journal of Industrial Microbiology & Biotechnology, 2001, 27(4): 252-258.
    [21] Long LK, Yang J, An Y, Liu G. Disruption of a glutathione reductase encoding gene in Acremonium chrysogenum leads to reduction of its growth, cephalosporin production and antioxidative ability which is recovered by exogenous methionine. Fungal Genetics and Biology, 2012, 49(2): 114-122.
    [22] Liu L, Long LK, An Y, Yang J, Xu XX, Hu CH, Liu G. The thioredoxin reductase-encoding gene ActrxR1 is involved in the cephalosporin C production of Acremonium chrysogenum in methionine-supplemented medium. Applied Microbiology and Biotechnology, 2013, 97(6): 2551-2562.
    [23] Calvo AM, Wilson RA, Bok JW, Keller NP. Relationship between secondary metabolism and fungal development. Microbiology and Molecular Biology Reviews, 2002, 66(3): 447-459.
    [24] Nash CH, Huber FM. Antibiotic synthesis and morphological differentiation of Cephalosporium acremonium. Applied Microbiology, 1971, 22(1): 6-10.
    [25] Sándor E, Szentirmai A, Paul GC, Thomas CR, Pócsi I, Karaffa L. Analysis of the relationship between growth, cephalosporin C production, and fragmentation in Acremonium chrysogenum. Canadian Journal of Microbiology, 2001, 47(7): 801-806.
    [26] Long LK, Wang YL, Yang J, Xu XX, Liu G. A septation related gene AcsepH in Acremonium chrysogenum is involved in the cellular differentiation and cephalosporin production. Fungal Genetics and Biology, 2013, 50: 11-20.
    [27] Hu PJ, Wang Y, Zhou J, Pan YY, Liu G. AcstuA, which encodes an APSES transcription regulator, is involved in conidiation, cephalosporin biosynthesis and cell wall integrity of Acremonium chrysogenum. Fungal Genetics and Biology, 2015, 83: 26-40.
    [28] Hoffmeister D, Keller NP. Natural products of filamentous fungi: enzymes, genes and their regulation. Natural Product Reports, 2007, 24(2): 393-416.
    [29] Schmitt EK, Kempken R, Kück U. Functional analysis of promoter sequences of cephalosporin C biosynthesis genes from Acremonium chrysogenum: specific DNA-protein interactions and characterization of the transcription factor PACC. Molecular Genetics and Genomics, 2001, 265(3): 508-518.
    [30] Schmitt EK, Kück U. The fungal CPCR1 protein, which binds specifically to β-lactam biosynthesis genes, is related to human regulatory factor X transcription factors. The Journal of Biological Chemistry, 2000, 275(13): 9348-9357.
    [31] Schmitt EK, Bunse A, Janus D, Hoff B, Friedlin E, Kürnsteiner H, Kück U. Winged helix transcription factor CPCR1 is involved in regulation of β-lactam biosynthesis in the fungus Acremonium chrysogenum. Eukaryotic Cell, 2004, 3(1): 121-134.
    [32] Schmitt EK, Hoff B, Kück U. AcFKH1, a novel member of the forkhead family, associates with the RFX transcription factor CPCR1 in the cephalosporin C-producing fungus Acremonium chrysogenum. Gene, 2004, 342(2): 269-281.
    [33] Hoff B, Schmitt EK, Kück U. CPCR1, but not its interacting transcription factor AcFKH1, controls fungal arthrospore formation in Acremonium chrysogenum. Molecular Microbiology, 2005, 56(5): 1220-1233.
    [34] Dreyer J, Eichhorn H, Friedlin E, Kürnsteiner H, Kück U. A homologue of the Aspergillus velvet gene regulates both cephalosporin C biosynthesis and hyphal fragmentation in Acremonium chrysogenum. Applied and Environmental Microbiology, 2007, 73(10): 3412-3422.
    [35] Gong GH, Zhang W, HU YJ. Over-expression of AcveA in Acremonium chrysogenum to improve cephalosporin C production. Chinese Journal of Pharmaceuticals, 2014, 45(8): 719-723. (in Chinese) 龚桂花, 张伟, 胡又佳, 朱宝泉. 顶头孢霉中过表达AcveA提高头孢菌素C产量. 中国医药工业杂志, 2014, 45(8): 719-723.
    [36] Zhang JY, Wolfe S, Demain AL. Phosphate repressible and inhibitable β-lactam synthetases in Cephalosporium acremonium strain C-10. Applied Microbiology and Biotechnology, 1988, 29(2/3): 242-247.
    [37] Wang HT, Pan YY, Hu PJ, Zhu YX, Li JY, Jiang XJ, Liu G. The autophagy-related gene Acatg1 is involved in conidiation and cephalosporin production in Acremonium chrysogenum. Fungal Genetics and Biology, 2014, 69: 65-74.
    [38] Terfehr D, Dahlmann TA, Specht T, Zadra I, Kürnsteiner H, Kück U. Genome sequence and annotation of Acremonium chrysogenum, producer of the β-lactam antibiotic cephalosporin C. Genome Announcements, 2014, 2(5): e00948.
    [39] Liu Y, Xie LP, Gong GH, Zhang W, Zhu BQ, Hu YJ. De novo comparative transcriptome analysis of Acremonium chrysogenum: high-yield and wild-type strains of cephalosporin C producer. PLoS One, 2014, 9(8): e104542.
    [40] Nødvig CS, Nielsen JB, Kogle ME, Mortensen UH. A CRISPR-Cas9 system for genetic engineering of filamentous fungi. PLoS One, 2015, 10(7): e0133085.
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刘佳佳,刘钢. 头孢菌素C生物合成调控研究进展[J]. 微生物学报, 2016, 56(3): 461-470

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  • 收稿日期:2015-11-09
  • 最后修改日期:2015-12-28
  • 在线发布日期: 2016-03-03
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