微生物学报

HK	Type	RR	Family	HK	Type	RR	Family
SCO0203	Classic	SCO0204	NarL	SCO0211	Classic	-	-
SCO0422	Classic	SCO0421	NarL	SCO0551	Classic	SCO0552	OmpR
SCO0588	Classic	-	-	SCO0599	Classic	-	-
SCO0946	Classic	-	-	SCO1071	Classic	SCO1070	NarL
SCO1137	Classic	SCO1136	IclR	SCO1160	Classic	-	-
SCO1217	Classic	-	-	-	-	SCO1220	LytTR
SCO1259	Classic	SCO1260	NarL	SCO1369	Classic	SCO1370	NarL
SCO1402	Classic	-	-	SCO1596	Classic	-	-
SCO1630	Classic	-	-	-	-	SCO1654	NarL
SCO1744	Classic	SCO1745	NarL	SCO1802	Classic	SCO1801	NarL
-	-	SCO2013	AmiR_NasR	SCO2121	Classic	SCO2120	NarL
SCO2142	Classic	SCO2143	OmpR	SCO2166	Classic	SCO2165	NarL
SCO2215	Classic	SCO2216	NarL	-	-	SCO2281	NarL
SCO2307	Classic	SCO2308	NarL	SCO2359	Classic	SCO2358	NarL
SCO2518	Classic	SCO2517	NarL	SCO2800	Classic	SCO2801	OmpR
SCO2879	Classic	-	-	-	-	SCO3008	NarL
SCO3012	Classic	SCO3013	OmpR	SCO3062	Classic	SCO3063	OmpR
SCO3119	Classic	-	-	-	-	SCO3134	NarL
-	-	SCO3144	NarL	SCO3225	Classic	SCO3226	NarL
SCO3284	Classic	-	-	SCO3359	Classic	SCO3358	OmpR
SCO3390	Classic	SCO3389	NarL	SCO3589	Classic	SCO3590	OmpR
SCO3654	Classic	SCO3653	NarL	SCO3740	Classic	SCO3741	OmpR
SCO3750	Classic	-	-	SCO3757	Classic	SCO3756	NarL
SCO3796	Classic	-	-	-	-	SCO3818	NarL
SCO3948	Classic	-	-	-	-	SCO4009	Unclassified
SCO4021	Classic	SCO4020	OmpR	SCO4073	Classic	SCO4072	NarL
SCO4120	Classic	-	-	SCO4124	Classic	SCO4123	NarL
SCO4155	Classic	SCO4156	OmpR	-	-	SCO4201	RsbU
SCO4229	Classic	SCO4230	OmpR	SCO4275	Classic	SCO4276	NarL
SCO4362	Classic	SCO4363	NarL	-	-	SCO4596	NarL
SCO4597	Classic	-	-	SCO4598	Classic	-	-
SCO4667	Classic	SCO4668	NarL		-	SCO4768	NarL
SCO4791	Classic	SCO4792	NarL	SCO4906	Classic	SCO4907	OmpR
-	-	SCO5006	Unclassified	SCO5131	Classic	SCO5132	NarL
SCO5239	Classic	-	-	SCO5282	Classic	SCO5283	OmpR
SCO5289	Classic	-	-	SCO5304	Classic	-	-
-	-	SCO5351	CheY	SCO5378	Classic	SCO5377	NarL
SCO5404	Classic	SCO5403	OmpR	SCO5435	Classic	SCO5434	IclR
SCO5454	Classic	SCO5455	NarL	SCO5460	Classic	-	-
SCO5540	Classic	-	-	SCO5544	Classic	-	-
-	-	SCO5567	Unclassified	SCO5683	Classic	SCO5684	NarL
SCO5748	Hybrid	-	-	-	-	SCO5749	Unclassified
SCO5779	Classic	SCO5778	OmpR	SCO5784	Classic	SCO5785	NarL
SCO5824	Classic	SCO5825	NarL	SCO5829	Classic	SCO5828	Unclassified
SCO5863	Classic	SCO5862	OmpR	SCO5871	Classic	SCO5872	OmpR
-	-	SCO5881	NarL	-	-	SCO6029	NarL
SCO6069	Classic	-	-	SCO6139	Classic	SCO6140	NarL
SCO6163	Classic	SCO6162	NarL	SCO6253	Classic	SCO6254	NarL
SCO6268	Classic	-	-	SCO6353	Classic	SCO6354	OmpR
SCO6362	Classic	SCO6363	NarL	-	-	SCO6364	OmpR
SCO6369	Classic	-	-	SCO6421	Classic	SCO6422	NarL
SCO6424	Classic	-	-	SCO6668	Classic	SCO6667	NarL
-	-	SCO6685	NarL	SCO6794	Classic	-	-
SCO6943	Classic	-	-	SCO7076	Classic	SCO7075	OmpR
SCO7089	Classic	SCO7088	NarL	SCO7231	Classic	SCO7230	OmpR
SCO7297	Classic	SCO7298	TrxB	SCO7327	Hybrid	-	-
SCO7422	Classic	-	-	SCO7463	Classic	-	-
SCO7534	Classic	SCO7533	OmpR	SCO7649	Classic	SCO7648	NarL
SCO7711	Classic	SCO7712	NarL	-	-	-	-

HK	Type	RR	Family	HK	Type	RR	Family
SCO0203	Classic	SCO0204	NarL	SCO0211	Classic	-	-
SCO0422	Classic	SCO0421	NarL	SCO0551	Classic	SCO0552	OmpR
SCO0588	Classic	-	-	SCO0599	Classic	-	-
SCO0946	Classic	-	-	SCO1071	Classic	SCO1070	NarL
SCO1137	Classic	SCO1136	IclR	SCO1160	Classic	-	-
SCO1217	Classic	-	-	-	-	SCO1220	LytTR
SCO1259	Classic	SCO1260	NarL	SCO1369	Classic	SCO1370	NarL
SCO1402	Classic	-	-	SCO1596	Classic	-	-
SCO1630	Classic	-	-	-	-	SCO1654	NarL
SCO1744	Classic	SCO1745	NarL	SCO1802	Classic	SCO1801	NarL
-	-	SCO2013	AmiR_NasR	SCO2121	Classic	SCO2120	NarL
SCO2142	Classic	SCO2143	OmpR	SCO2166	Classic	SCO2165	NarL
SCO2215	Classic	SCO2216	NarL	-	-	SCO2281	NarL
SCO2307	Classic	SCO2308	NarL	SCO2359	Classic	SCO2358	NarL
SCO2518	Classic	SCO2517	NarL	SCO2800	Classic	SCO2801	OmpR
SCO2879	Classic	-	-	-	-	SCO3008	NarL
SCO3012	Classic	SCO3013	OmpR	SCO3062	Classic	SCO3063	OmpR
SCO3119	Classic	-	-	-	-	SCO3134	NarL
-	-	SCO3144	NarL	SCO3225	Classic	SCO3226	NarL
SCO3284	Classic	-	-	SCO3359	Classic	SCO3358	OmpR
SCO3390	Classic	SCO3389	NarL	SCO3589	Classic	SCO3590	OmpR
SCO3654	Classic	SCO3653	NarL	SCO3740	Classic	SCO3741	OmpR
SCO3750	Classic	-	-	SCO3757	Classic	SCO3756	NarL
SCO3796	Classic	-	-	-	-	SCO3818	NarL
SCO3948	Classic	-	-	-	-	SCO4009	Unclassified
SCO4021	Classic	SCO4020	OmpR	SCO4073	Classic	SCO4072	NarL
SCO4120	Classic	-	-	SCO4124	Classic	SCO4123	NarL
SCO4155	Classic	SCO4156	OmpR	-	-	SCO4201	RsbU
SCO4229	Classic	SCO4230	OmpR	SCO4275	Classic	SCO4276	NarL
SCO4362	Classic	SCO4363	NarL	-	-	SCO4596	NarL
SCO4597	Classic	-	-	SCO4598	Classic	-	-
SCO4667	Classic	SCO4668	NarL		-	SCO4768	NarL
SCO4791	Classic	SCO4792	NarL	SCO4906	Classic	SCO4907	OmpR
-	-	SCO5006	Unclassified	SCO5131	Classic	SCO5132	NarL
SCO5239	Classic	-	-	SCO5282	Classic	SCO5283	OmpR
SCO5289	Classic	-	-	SCO5304	Classic	-	-
-	-	SCO5351	CheY	SCO5378	Classic	SCO5377	NarL
SCO5404	Classic	SCO5403	OmpR	SCO5435	Classic	SCO5434	IclR
SCO5454	Classic	SCO5455	NarL	SCO5460	Classic	-	-
SCO5540	Classic	-	-	SCO5544	Classic	-	-
-	-	SCO5567	Unclassified	SCO5683	Classic	SCO5684	NarL
SCO5748	Hybrid	-	-	-	-	SCO5749	Unclassified
SCO5779	Classic	SCO5778	OmpR	SCO5784	Classic	SCO5785	NarL
SCO5824	Classic	SCO5825	NarL	SCO5829	Classic	SCO5828	Unclassified
SCO5863	Classic	SCO5862	OmpR	SCO5871	Classic	SCO5872	OmpR
-	-	SCO5881	NarL	-	-	SCO6029	NarL
SCO6069	Classic	-	-	SCO6139	Classic	SCO6140	NarL
SCO6163	Classic	SCO6162	NarL	SCO6253	Classic	SCO6254	NarL
SCO6268	Classic	-	-	SCO6353	Classic	SCO6354	OmpR
SCO6362	Classic	SCO6363	NarL	-	-	SCO6364	OmpR
SCO6369	Classic	-	-	SCO6421	Classic	SCO6422	NarL
SCO6424	Classic	-	-	SCO6668	Classic	SCO6667	NarL
-	-	SCO6685	NarL	SCO6794	Classic	-	-
SCO6943	Classic	-	-	SCO7076	Classic	SCO7075	OmpR
SCO7089	Classic	SCO7088	NarL	SCO7231	Classic	SCO7230	OmpR
SCO7297	Classic	SCO7298	TrxB	SCO7327	Hybrid	-	-
SCO7422	Classic	-	-	SCO7463	Classic	-	-
SCO7534	Classic	SCO7533	OmpR	SCO7649	Classic	SCO7648	NarL
SCO7711	Classic	SCO7712	NarL	-	-	-	-

TCS名称 TCS name	编号 No.	功能 Function	调控机制 Regulatory mechanism	文献 References
AbrA1/A2	SCO1744/1745	Negatively regulates ACT, RED, CDA biosynthesis and morphological differentiation	Strains deficient in AbrA1/A2 serve as host bacteria with a significantly improved ability to produce the heterologous compound oviedomycin. Fe may be the activation signal for this system, and the self-regulation of AbrA1/A2 is dependent on the concentration of ferric ions	[51]
AbrB1/B2	SCO2165/2166	Negative regulation of ACT and RED biosynthesis and positive regulation of vancomycin resistance	Mechanisms not yet clear	[52]
AbrC1/C2/C3	SCO4598/4597/4596	Positive regulation of ACT, RED, and CDA biosynthesis and morphological differentiation	AbrC3 directly activates actII-ORF4 transcription and positively regulates ACT biosynthesis AbrC3 may indirectly regulate RED biosynthesis by affecting AfsS. The regulatory mechanism of CDA is unclear	[53-54]
CagR/S	-	Regulating the biosynthesis of clavulanic acid	CagR binds directly to the promoter regions of the key genes in the CA biosynthesis pathway, ceaS1, oat1, oat2, as well as claR. CagRS also extensively regulates genes involved in primary metabolism, particularly metabolic pathways related to the biosynthesis of the CA precursors glyceraldehyde-3-phosphate (G3P) and arginine	[55]
EcrA1/A2	SCO2518/2517	Located near the RED locus, it positively regulates the biosynthesis of RED	It regulates the biosynthesis of RED by affecting the transcription of redD and redZ	[56]
EcrE1/E2	SCO6421/6422	Located near the RED site and is regulating RED biosynthesis	Regulates RED biosynthesis by affecting redD and redZ transcription	[57]
OsaA/B	SCO5748/5749	Negatively regulates ACT and RED biosynthesis and is involved in morphological differentiation and osmotic pressure regulation	In R2YE containing 10.3% sucrose, deletion of OsaB resulted in impaired aerial mycelium formation, phenotypic baldness (no effect of deletion of OsaA), as well as a 3- to 5-fold increase in ACT and RED production	[58]
RapA1/A2	SCO5403/5404	Positive regulation of ACT and coelimycin biosynthesis	Deletion of RapA1/A2 decreased CpkI protein abundance and reduced the transcript levels of actII-ORF4 and kasO	[59]
-	SCO3134	May be involved in the regulation of carbon sources, secondary metabolites, and morphogenesis	Mechanisms not yet clear	[60]
-	SCO4020/4021	May be involved in the regulation of carbon sources, secondary metabolites, and morphogenesis	SCO4020 (RR) expression is up-regulated under glucose-containing culture conditions. Mechanisms not yet clear	[61]
-	SCO5351	Positively regulates ACT and CDA biosynthesis, aerial mycelium development and spore production	ActII-orf4 and cdaR expression are down-regulated in the Δsco5351 mutant	[62]

TCS名称 TCS name	编号 No.	功能 Function	调控机制 Regulatory mechanism	文献 References
AbrA1/A2	SCO1744/1745	Negatively regulates ACT, RED, CDA biosynthesis and morphological differentiation	Strains deficient in AbrA1/A2 serve as host bacteria with a significantly improved ability to produce the heterologous compound oviedomycin. Fe may be the activation signal for this system, and the self-regulation of AbrA1/A2 is dependent on the concentration of ferric ions	[51]
AbrB1/B2	SCO2165/2166	Negative regulation of ACT and RED biosynthesis and positive regulation of vancomycin resistance	Mechanisms not yet clear	[52]
AbrC1/C2/C3	SCO4598/4597/4596	Positive regulation of ACT, RED, and CDA biosynthesis and morphological differentiation	AbrC3 directly activates actII-ORF4 transcription and positively regulates ACT biosynthesis AbrC3 may indirectly regulate RED biosynthesis by affecting AfsS. The regulatory mechanism of CDA is unclear	[53-54]
CagR/S	-	Regulating the biosynthesis of clavulanic acid	CagR binds directly to the promoter regions of the key genes in the CA biosynthesis pathway, ceaS1, oat1, oat2, as well as claR. CagRS also extensively regulates genes involved in primary metabolism, particularly metabolic pathways related to the biosynthesis of the CA precursors glyceraldehyde-3-phosphate (G3P) and arginine	[55]
EcrA1/A2	SCO2518/2517	Located near the RED locus, it positively regulates the biosynthesis of RED	It regulates the biosynthesis of RED by affecting the transcription of redD and redZ	[56]
EcrE1/E2	SCO6421/6422	Located near the RED site and is regulating RED biosynthesis	Regulates RED biosynthesis by affecting redD and redZ transcription	[57]
OsaA/B	SCO5748/5749	Negatively regulates ACT and RED biosynthesis and is involved in morphological differentiation and osmotic pressure regulation	In R2YE containing 10.3% sucrose, deletion of OsaB resulted in impaired aerial mycelium formation, phenotypic baldness (no effect of deletion of OsaA), as well as a 3- to 5-fold increase in ACT and RED production	[58]
RapA1/A2	SCO5403/5404	Positive regulation of ACT and coelimycin biosynthesis	Deletion of RapA1/A2 decreased CpkI protein abundance and reduced the transcript levels of actII-ORF4 and kasO	[59]
-	SCO3134	May be involved in the regulation of carbon sources, secondary metabolites, and morphogenesis	Mechanisms not yet clear	[60]
-	SCO4020/4021	May be involved in the regulation of carbon sources, secondary metabolites, and morphogenesis	SCO4020 (RR) expression is up-regulated under glucose-containing culture conditions. Mechanisms not yet clear	[61]
-	SCO5351	Positively regulates ACT and CDA biosynthesis, aerial mycelium development and spore production	ActII-orf4 and cdaR expression are down-regulated in the Δsco5351 mutant	[62]

No.	Plant disease	Pathogen	R&M
1	Wheat sharp eyespot	Rhizoctonia cerealis	2.05	7.44	6.18	27.17
2	Wheat scab	Fusarium graminearum	2.14	4.32	2.50	12.42
3	Apple and pear fruit ring rot	Botryosphaeria berengeriana	2.21	6.67	4.27	12.38
4	Wheat common rot	Bipolaris sorokiniana	2.49	19.87	1.62	3.59
5	Potato early blight	Alternaria soari	3.27	32.56	2.81	8.03
6	Apple and pear Valsa canker	Valsa ceratosperma	3.37	7.06	5.81	22.68
7	Pear black spot	Alternaria alternate	4.16	16.06	2.76	7.45
8	Potato mole	Rhizoctonia solani	4.24	26.87	0.50	5.20
9	Cotton Fusarium wilt	Fusarium oxysporum	4.43	14.27	4.61	14.44
10	Apple Alternaria blotch	Alternaria brassicae	4.51	14.88	3.22	12.62
11	Celery Septoria leaf spot	Septoria apicola	4.73	24.93	3.69	13.59
12	Tomato early blight	Alternaria solani	5.72	23.13	2.97	10.63
13	Cotton Verticillium wilt	Verticillium dahliae	5.80	22.01	12.45	32.44
14	Crucifers Alternaria leaf spot	Alternaria oleracea	5.95	16.60	3.46	12.54
15	Cotton pink smut	Cephalothecium roseum	6.79	16.11	2.25	6.31
16	Chrysanthemum root rot	Fusarium solani	6.89	54.45	3.04	23.35
17	Grape gray mold	Botrytis cinerea	7.09	22.48	2.29	14.91

No.	Plant disease	Pathogen	R&M
1	Wheat sharp eyespot	Rhizoctonia cerealis	2.05	7.44	6.18	27.17
2	Wheat scab	Fusarium graminearum	2.14	4.32	2.50	12.42
3	Apple and pear fruit ring rot	Botryosphaeria berengeriana	2.21	6.67	4.27	12.38
4	Wheat common rot	Bipolaris sorokiniana	2.49	19.87	1.62	3.59
5	Potato early blight	Alternaria soari	3.27	32.56	2.81	8.03
6	Apple and pear Valsa canker	Valsa ceratosperma	3.37	7.06	5.81	22.68
7	Pear black spot	Alternaria alternate	4.16	16.06	2.76	7.45
8	Potato mole	Rhizoctonia solani	4.24	26.87	0.50	5.20
9	Cotton Fusarium wilt	Fusarium oxysporum	4.43	14.27	4.61	14.44
10	Apple Alternaria blotch	Alternaria brassicae	4.51	14.88	3.22	12.62
11	Celery Septoria leaf spot	Septoria apicola	4.73	24.93	3.69	13.59
12	Tomato early blight	Alternaria solani	5.72	23.13	2.97	10.63
13	Cotton Verticillium wilt	Verticillium dahliae	5.80	22.01	12.45	32.44
14	Crucifers Alternaria leaf spot	Alternaria oleracea	5.95	16.60	3.46	12.54
15	Cotton pink smut	Cephalothecium roseum	6.79	16.11	2.25	6.31
16	Chrysanthemum root rot	Fusarium solani	6.89	54.45	3.04	23.35
17	Grape gray mold	Botrytis cinerea	7.09	22.48	2.29	14.91

链霉菌中双组分系统调控次级代谢产物合成的研究进展

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刘子越 ¹ , 王娇 ¹ , 赵乐 ¹ , 刘大群 ¹^,² , 李亚宁 ¹^,^*

微生物学报 | 综述 2025,65(8): 3468-3491

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微生物学报 | 综述 2025, 65(8): 3468-3491

链霉菌中双组分系统调控次级代谢产物合成的研究进展

全屏

刘子越¹, 王娇¹, 赵乐¹, 刘大群¹^,², 李亚宁¹^,^*

作者信息

^1.河北农业大学植物保护学院，河北省农作物病虫害生物防治技术创新中心，国家北方山区农业工程技术研究中心，河北保定

^2.中国农业科学院研究生院，北京

Research progress in regulation of secondary metabolite synthesisby two-component systems in Streptomyces

Ziyue LIU¹, Jiao WANG¹, Le ZHAO¹, Daqun LIU¹^,², Yaning LI¹^,^*

Affiliations

^1.Technological Innovation Center for Biological Control of Crop Diseases and Insect Pests of Hebei Province, National Engineering Research Center for Agriculture in Northern Mountainous Areas, College of Plant Protection, Hebei Agricultural University, Baoding, Hebei, China

^2.Graduate School, Chinese Academy of Agricultural Sciences, Beijing, China

出版时间: 2025-08-04 doi: 10.13343/j.cnki.wsxb.20250042

文章导航

摘要

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链霉菌能够产生多种活性次级代谢产物，可广泛应用于医疗、工业、农业等领域。链霉菌调控次级代谢产物的基因包括途径特异性、多效性以及全局性调控基因。其中，双组分系统作为原核生物中的主要信号转导系统，参与链霉菌的多种生理生化反应，并可对次级代谢产物进行全局性调控。特定双组分系统基因的缺失或过表达可显著影响次级代谢产物的生物合成。鉴定双组分系统的功能并揭示其调控机制，有助于通过基因工程手段提高次级代谢产物的生产效率。本文总结了近年来微白黄链霉菌等多种链霉菌中双组分系统的研究现状，尤其对其次级代谢产物合成的调控机制进行了总结和阐述。

关键词

链霉菌 / 双组分系统 / 次级代谢产物 / 调控机制

Abstract

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Streptomyces can produce various active secondary metabolites, which can be widely used in medical, industrial, agricultural, and other fields. The secondary metabolite synthesis in Streptomyces is regulated by pathway-specific, pleiotropic, and global regulatory genes. The two-component system, as the main signal transduction system in prokaryotes, participates in various physiological and biochemical reactions of Streptomyces and can globally regulate secondary metabolites. The deletion or overexpression of specific two-component system genes can significantly affect the biosynthesis of secondary metabolites. Identifying the functions of two-component systems and elucidating their regulatory mechanisms can contribute to enhancing the production efficiency of secondary metabolites by genetic engineering. This paper reviews the research trends of two-component systems in various Streptomyces species such as Streptomyces albidoflavus in recent years and particularly summarizes and elaborates on the regulatory mechanisms of their secondary metabolite synthesis.

Key words

Streptomyces / two-component system / secondary metabolites / regulatory mechanism

引用本文

刘子越, 王娇, 赵乐, 刘大群, 李亚宁. 链霉菌中双组分系统调控次级代谢产物合成的研究进展. 微生物学报, 2025 , 65 (8) : 3468 -3491 . DOI: 10.13343/j.cnki.wsxb.20250042

Ziyue LIU, Jiao WANG, Le ZHAO, Daqun LIU, Yaning LI. Research progress in regulation of secondary metabolite synthesisby two-component systems in Streptomyces[J]. Acta Microbiologica Sinica, 2025 , 65 (8) : 3468 -3491 . DOI: 10.13343/j.cnki.wsxb.20250042

正文

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放线菌是一类具有巨大经济价值的微生物群体，是细菌域分类的30个主要门中最大的门之一^[1]。其中链霉菌属(Streptomyces)是放线菌中规模最大且物种多样性极为丰富的一类丝状革兰氏阳性细菌(G⁺)^[2]，可通过复杂的代谢网络合成众多具有生物活性的次级代谢产物，包括抗生素、免疫抑制剂、抗真菌药物等，在农业、工业和医学领域具有重要地位^[3-4]，是目前生物活性化合物的主要生产者之一^[5]。近几十年来，链霉菌被用于抵御植物病原体的侵染，并提高作物产量^[6]，在生态系统的维持和恢复方面具有关键作用^[7]。

链霉菌在陆地和海洋环境中无处不在，在土壤这一动态复杂的环境中分布最为广泛^[8]。这使得链霉菌不断应对来自环境条件变化与养分稀缺的挑战，推动着链霉菌在进化过程中形成极强的适应能力^[9]。无论栖息地如何，链霉菌在正常和极端条件下产生的天然产物都表现出丰富的结构多样性和显著的生物活性^[10]。在基因组水平上，链霉菌通常具有6-12 Mb的线性染色体，G+C含量约为69%-78%，是已知G+C含量最高的生物类群之一^[11]。

1 双组分系统简介

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细菌面临着来自环境和内部的大量信号，因此其必须具备检测、整合及处理这些复杂信号的能力，以便迅速做出相应反应，这种高效的信号感知与转导机制是细菌维持生存和适应动态环境的重要保障。信号转导在此过程中扮演着关键角色，而在原核生物中主要由双组分系统(two-component systems, TCS)来执行这一功能^[12]。作为一种全局性的调控系统，TCS不仅能感知内外部的刺激，引发细胞响应，还能调控细菌绝大多数的生理过程，包括细菌生长、趋化性、初级代谢、渗透压调节、次级代谢产物的生物合成，也能参与病原菌的毒力和群体感应等致病过程^[13]。

典型的双组分系统由2部分构成：一是作为传感器的组氨酸激酶(histidine kinase, HK)负责感知特定的信号；二是作为效应器的应答调控蛋白(response regulator, RR)负责产生针对这些信号进行的细胞响应^[14]。

1.1 组氨酸激酶

HK通常为跨膜蛋白，嵌入质膜中形成同型二聚体，其功能结构域主要包括信号感受域(sensor domain)、二聚体化及磷酸转移结构域(dimerization/phosphotransfer domain, DHp)及具有激酶活性的ATP结合结构域(catalytic and ATP-binding domain, CA)。信号感受域高度可变，主要在周质中或胞外参与信号识别；DHp通过自磷酸化将外部刺激转化为内部信号；CA含有N、G1、F、G2这4个相对保守的序列^[15]，用于特异性结合ATP，并将磷酸基团转移到组氨酸残基上。DHp和CA这2个结构域高度保守，共同构成HK的催化核心。HK能够感知的物理和化学刺激种类繁多，包括温度、光照、氧浓度、抗生素和各类营养物质等^[16]。

1.2 应答调控蛋白

RR通常为细胞质蛋白，负责传递来自HK的化学信号，其核心结构包括N端的信号接受域(receiver domain, REC)和C端的效应结构域(effector domain, ED)^[17]。REC高度保守，包含关键的天冬氨酸残基(Asp)，该残基在磷酸转移过程中被HK磷酸化，从而激活RR。效应结构域通常为DNA结合域，通过与目的基因启动子序列结合调节基因表达，触发细胞反应^[18]。

1.3 双组分系统的信号转导过程

细胞信号转导起始于HK感知外界环境信号刺激，DHp结构域中保守的组氨酸残基发生自磷酸化，将磷酸基团转移到REC结构域中的天冬氨酸残基上，激活结构域并引起蛋白构象的改变^[19]。磷酸化后的RR与DNA结合能力显著增强，形成同源二聚体参与下游靶基因的转录调控(图1)。在信号转导过程中，每个HK通常与一个特定的RR相关联。基因组层面上，HK-RR对通常在同一操纵子中相邻排列，从而确保信号转导的准确性和高效性。此外，不同TCS之间可能存在交叉调控，使细菌更好地适应复杂环境^[20]。

作为重要的工业微生物，链霉菌生产了近60%的微生物来源的天然抗生素^[21]。在原始菌株中，由于抗生素自身较强的毒性对菌体产生抑制作用，其产量很低，有些仅有几微克。明确链霉菌中次级代谢产物的调控网络，有助于后续设计更高效的菌株，改进抗生素的生产。双组分系统接收并传递信号分子给下游的调控基因包括某些全局调控因子，实现次级代谢产物的多级调控。目前，双组分系统主要在模式菌微白黄链霉菌(Streptomyces albidoflavus)中进行研究。本文总结了当前链霉菌中TCS调控抗生素合成的研究现状，并作图分别描述了TCS直接(图2)或间接(图3)调控次级代谢产物合成的机制，以及这些TCS在未来改进抗生素生产的可能。

2 微白黄链霉菌中的双组分系统

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微白黄链霉菌(S. albidoflavus) 是链霉菌研究的主要模式菌株，其全基因组测序已于2002年完成。基因组分析发现其含有编码次级代谢产物合成酶的基因400多个，可产生29种次级代谢产物，包括蓝色的放线紫红素(actinorhodin, ACT)、红色的十一烷基灵菌红素(undecylprodigiosin, RED)、黄色色素(coelimycin P2, yCPK)、钙依赖抗生素(calcium-dependent antibiotic, CDA)等。基于P2CS数据库(http://www.p2cs.org/，于2025年2月19日访问)发现，S. albidoflavus中含有100个HK和87个RR，其中63对HK-RR相匹配组成典型的双组分系统，另有1个三联体(SCO0870/0871/0872, RR-HK-RR)、1个四连体(SCO3638/3639/3640/3641, RR-HK-RR-HK)、34个孤儿HK和20个孤儿RR (表1)。目前，S. albidoflavus中已有34对双组分系统被鉴定研究^[20]。本文对已有研究报道的双组分系统作简要总结，重点对近5年S. albidoflavus TCS的研究进展按字母顺序进行了总结，尤其是主要调控次级代谢的双组分系统。

2.1 AbsA1/A2 (SCO3225/SCO3226)

AbsA1/A2位于CDA生物合成基因簇内部，AbsA1通过自我磷酸化启动信号传导链，磷酸化的AbsA2分别结合于途径特异性调控基因actII-ORF4、redZ以及cdaR的启动子区域抑制转录，负调控放线紫红素(actinorhodin, ACT)、十一烷基灵菌红素(undecylprodigiosin, RED)和钙依赖抗生素(calcium-dependent antibiotic, CDA)的生物合成。AbsA1的跨膜结构域与典型的HK不同，在N端附近缺少大的胞外感知结构域，因此将其排除在常见的胞外感知组氨酸激酶之外，通过构建AbsA1 C-末端缺失融合蛋白EGFP，检测发现胞外C末端结构域对信号响应很重要^[22]。AbsA2还与CDA生物合成基因簇内的多个位点(SCO3215、SCO3217和SCO3230)结合，表明它通过负向调节cdaR的活性抑制转录^[23]。AbsA1同时具有激酶和磷酸酶活性，AbsA2的磷酸化状态由AbsA1的激酶和磷酸酯酶活性之间的平衡决定，并且AbsA2-P直接或间接地抑制抗生素生物合成基因的表达^[24]。在异源链霉菌中表达AbsA1可显著改变次级代谢，如果异源链霉菌含有内源性AbsA操纵子，在表达来自S. albidoflavus的AbsA1时，会使内源性AbsA2蛋白的磷酸化水平下降，从而减轻其对目标启动子的抑制作用^[25]。

2.2 AfsQ1/Q2 (SCO4907/SCO4906)

AfsQ1/Q2参与S. albidoflavus的初级代谢、次级代谢和形态发育的调控。在正常条件下培养时，ΔafsQ1/Q2的表型及抗生素产量均未受到影响；然而，在含0.075 mol/L谷氨酸钠的基本培养基(minimal medium, MM)中培养时，ΔafsQ1/Q2表现出气生菌丝较早地发育，ACT、RED、CDA和yCPK的产量显著降低；凝胶迁移实验(electrophoretic mobility shift assay, EMSA)和逆转录实时定量聚合酶链式反应(quantitative reverse transcription polymerase chain reaction, RT-qPCR)分析显示，AfsQ1/Q2通过与actII-ORF4、redZ和cdaR相互作用激活抗生素的生物合成；AfsQ1还可激活假定的sigma因子sigQ作为抗生素产生的负调节因子，与AfsQ1/Q2相互拮抗，平衡菌体抗生素的合成；此外，体外磷酸化实验分析发现，σQ的拮抗作用是通过调控下游靶点——跨膜蛋白AfsQ4来间接实现的，AfsQ4又反过来影响AfsQ2的自磷酸化水平，进而拮抗TCS AfsQ1/Q2的功能^[26]。利用Dnase I足迹分析法，确定了AfsQ1的保守结合位点为GTnAC-n₆-GTnAC。AfsQ1/Q2也能作为氮同化过程的抑制因子发挥作用，AfsQ1与GlnR竞争glnA和nirB的启动子区域，表明AfsQ1/Q2与GlnR在氮代谢中存在交叉调控^[27]。在ΔafsQ1/Q2突变株中，colimycin P2基因簇中的cpkO、cpkN和scbR2这3个簇内调控因子(cluster-situated regulator, CSR)的转录均下调，表明AfsQ1/Q2正调控colimycin P2的生物合成^[28]。AfsQ1/Q2在直接调控coelimycin P2生物合成过程中起到关键作用，这种调控并非通过位于基因簇内的调控基因而是通过直接作用于结构基因实现的。

2.3 CutS/R (SCO5862/SCO5863)

CutS/R是链霉菌中发现的第一对双组分系统，高度保守，并负调控ACT的生物合成。染色质免疫共沉淀(chromatin immunoprecipitation, ChIP-seq)发现其结合位点并不位于ACT生物合成基因簇内，表明其调控作用是间接的。在添加额外葡萄糖的情况下，∆cutR/S突变株中的actinorhodin生物合成酶显著上调，但其机制尚不清楚。此外，CutR/S还参与细胞的分泌应激反应，并直接调控HtrA3、HtrB (HtrA家族折叠酶)以及SCO1507 [维生素K环氧化物还原酶(vitamin K epoxide reductase, VKOR)]的产生^[29]。

2.4 DevS/R (SCO0203/SCO0204)

DevS/R (又称OsdK/R)可感知S. albidoflavus中一氧化氮(NO)的浓度，作为正调控因子在ACT合成中起重要作用，缺失DevS/R会导致ACT产量下降。内源性NO可作为信号分子通过DevS/R正负双向调节ACT的产生，当NO浓度达到一定水平时，激活的DevR直接与actII-ORF4的启动子结合，正调控ACT生物合成；而低浓度的NO可能不足以有效激活DevS；过高浓度的NO则可能抑制DevS的自磷酸化活性，从而降低ACT的生物合成，这种调节机制类似于结核分枝杆菌(Mycobacteriumtuberculosis)中的DosS-T/R双组分系统^[30]。同时，构建NO生成能力降低的突变株表现出抗生素产量和孢子形成显著减少，而添加外源性NO能恢复这些表型^[31]，进一步表明NO对DevS/R的信号调节作用。在缺氧条件下，OsdK可通过激活nar2操作子的表达促使菌丝体中NarG2硝酸还原酶的合成^[32]。

2.5 DraR/K (SCO3063/SCO3062)

DraR/K在S. albidoflavus的生理和形态分化、初级代谢及次级代谢中发挥多效性及全局性的调节作用，是次级代谢产物ACT的正调控因子，RED和yCPK的负调控因子。在含有高浓度氮源(0.075 mol/L谷氨酸钠)的培养条件下，DraR/K可直接激活途径特异性调控基因actII-ORF4的转录促进ACT的生物合成；与ΔdraR相比，双敲除突变株(ΔdraR/afsQ1)的actII-ORF4转录显著减少，证明DraR/K与AfsQ1/Q2协调激活actII-ORF4转录，促进ACT的合成^[33]。DraR/K与kasO基因的启动子区域相互作用，抑制yCPK的生成；对RED的负调控并不依赖于途径特异性基因redD/redZ。DraR/K还间接影响其他次级代谢产物基因簇的表达，包括激活铁载体和四羟基萘的产生，抑制锌离子载体、土臭素和类胡萝卜素的生物合成；DraR/K的缺失导致锌响应抑制因子Zur及其靶基因强烈上调表达，表明DraR/K在锌吸收和调动中起着关键作用^[34]。在工业模型菌株阿维菌素链霉菌(S. avermitilis) NRRL-8165中，DraR-KsaV与S. albidoflavus中的DraR/K同源，突变株ΔdraR-ksaV中olmRI、olmRII和olmA4 (寡霉素合成基因)的转录水平显著下降，而aveR和aveC (阿维菌素合成基因)的转录水平上升^[33]，表明DraR-KsaV正调控寡霉素并负调控阿维菌素。

2.6 GarR/S (SCO6162/SCO6163)

GarR/S是S. albidoflavus在葡萄糖存在时ACT和RED生物合成的重要负调控因子。葡萄糖作为常用碳源，在促进链霉菌生长的同时，通过碳源代谢抑制(carbon catabolite repression, CCR)途径抑制次级代谢产物的合成^[35]。在葡萄糖抑制条件下，GarR/S的表达受到抑制。GarR/S与SCO5784/SCO5785有很高的相似性(HK 58.86%，RR 77.52%)；在0.5%葡萄糖抑制条件下，GarR/S缺失突变株中actII-ORF4和redD/redZ的表达出现上调，表现出更高的ACT和RED产量，而通过向突变株中回补带有标签的GarR和GarS蛋白，可以恢复到接近野生型的抗生素产量水平^[36]，因此为通过基因工程手段提升抗生素产量提供了潜在的靶点。

2.7 GluK/R (SCO5779/SCO5778)

GluK/R位于与编码谷氨酸摄取系统(gluABCD操纵子)反向平行的位置，参与谷氨酸的感知和摄取。谷氨酸可作为GluK的直接信号，在高谷氨酸浓度下磷酸化的GluR直接与启动子区域相互作用促进gluABCD基因(编码谷氨酸摄取系统)的表达，从而促进从环境中摄取谷氨酸；在低谷氨酸浓度下，即使GluK/R被激活，其活性仅可调节抗生素的生物合成；GluK/R是ACT合成的负调节因子，也是yCPK和RED合成的正调节因子，EMSA显示GluR并不与actII-ORF4、redZ/redD和kasO的启动子区域结合，表明GluK/R调控抗生素合成的方式是间接的^[37]。

2.8 MacS/R (SCO2121/SCO2120)

MacR/S是S. albidoflavus中的全局性调控系统，是形态发育的负调控因子和ACT、RED、CDA生物合成的正调控因子。突变株ΔmacR/S中编码ACT和CDA的基因簇表达量显著下降，而RED基因簇表达未产生差异；研究发现MacR并未在体内与actII-ORF4和cdaR的启动子直接相互作用^[38]。在actII-ORF4的上游设计一个更强的MacR位点，可提高ACT的产量，这种通过修饰预测的识别序列来调节目标基因表达的策略，为调节抗生素生物合成提供了新思路；MacR/S还能参与锌稳态调控，突变株ΔmacR中Zur调控基因和基因簇的转录明显减少^[39]。编码假定膜蛋白的mmpA-C (mmpA-mmpC的6个基因)是MacR的直接靶标，缺失mmpA-C可导致气生菌丝体的形成加速。MacR通过2个7 nt反向重复序列组成的识别位点(TGAGTACnnGTACTCA)激活或抑制该基因；在突变株ΔmacR中，mmpA-C的转录显著下调，表现为促进气生菌丝早期生长^[40]。

2.9 MtrA/B (SCO3013/SCO3012)

MtrA/B参与调控S. albidoflavus的形态分化、磷酸盐代谢和抗生素生物合成，在其他放线菌的抗生素生产中具有重要调控作用，并在多种链霉菌中保守存在(图4)。MtrA/B通过直接调控actII-ORF4、redZ、cdaR和cpkAD，抑制ACT和RED的生物合成，并激活CDA和yCPK的生物合成。MtrA可以通过结合预测的aveR上游的MtrA位点，调控阿维菌素链霉菌(S. avermitilis)中阿维菌素的生产；还可以特异性地结合井冈霉素基因簇中valA和valK之间的特定序列，调控吸水链霉菌(S. hygroscopicus) 5008中井冈霉素的生物合成^[41]。在S. albidoflavus中，MtrA可激活chpA-chpH、rdlA、rdlB、ramB、ramC、ramS和ramR的转录，并上调whiH和whiI，从而调控气生菌丝的发育；突变株ΔmtrA表现出典型的光秃表型^[42]。GlnR与MtrA竞争结合部分识别结合位点，在富营养条件下MtrA抑制氮代谢基因和GlnR的转录表达，同时激活包括phoP在内的磷代谢基因，维持细胞内的氮磷平衡；生物信息学分析显示，在链霉菌属和其他放线菌的多个抗生素生物合成基因簇中发现了很多MtrA识别位点，表明MtrA是一个多效性抗生素生物合成调控因子^[43]。

2.10 PhoR/P (SCO4229/SCO4230)

PhoP/R在链霉菌的磷酸盐代谢、氮代谢、形态分化和次级代谢等生理过程中发挥全局性作用^[44]。在缺磷培养基中培养时，PhoP (RR)可作为主要的调节因子抑制中心代谢、次级代谢和发育途径，直到吸收足够的磷酸盐以支持进一步的生长和最终的形态发育^[45]。PhoP/R能够激活与磷代谢相关的基因，同时抑制氮代谢的主要调控因子的表达，以维持菌体内氮磷的平衡；PhoR/P对抗生素生物合成的调控并不是直接结合途径特异性调控基因，而是与全局性转录激活蛋白AfsR拮抗，竞争性结合afsS的启动子，影响AfsS的表达，从而影响抗生素的合成^[46]。此外PhoP还可以抑制RNA聚合酶ω因子rpoZ的转录^[47]，使S. albidoflavus中ACT和RED的产量剧烈下降。

2.11 SCO4155/SCO4156

SCO4155/SCO4156与结核分枝杆菌(M. tuberculosis)中的MprA/B序列一致性较高，可调控S. albidoflavus中气生菌丝形成和ACT的生物合成，还参与多种酶编码基因的调控。在突变株Δsco4155/4156中，ACT生物合成基因簇相关基因sco5082 (酰基载体蛋白)、sco5083 (酮还原酶)、sco5086 (聚酮合酶)和sco5087 (β-酮酰基合酶)在36 h和48 h时均表现出显著上调；EMSA证实SCO4156蛋白可直接结合sco4157基因启动子区，直接抑制SCO4157的表达；sco4157编码一种HtrA-like丝氨酸蛋白酶，该酶属于HtrA家族，通常在细菌中参与细胞膜压力应激响应等环境应激反应^[48]。

2.12 SCO5282/SCO5283

在研究S. albidoflavus 2L12时发现该菌株在液体培养中呈现分散生长的形态，其菌丝分散性生长特性有效抑制了传统培养中常见的菌丝团聚现象，改善了氧气和营养物质的利用效率。基因组分析揭示，这一表型变化与组氨酸激酶SCO5282 (HK)的HAMP结构域中天冬氨酸残基(D125)被甘氨酸取代的突变密切相关，表明SCO5282在调控液体培养菌丝形态发育中发挥关键作用；进一步代谢组学分析显示，突变菌株的碳源利用策略发生改变：糖酵解途径关键基因表达受到抑制；而糖异生途径的核心调控酶——磷酸烯醇式丙酮酸羧化激酶(phosphoenolpyruvate carboxykinase, PEPCK)活性显著增强；同时，菌体展现出对氨基酸和嘌呤等非典型碳源的高效利用能力^[49]。这种代谢重编程不仅缓解了深层菌丝因氧气和营养扩散受限导致的生长抑制，还通过优化胞内能量分配显著提升了目标蛋白的合成效率。上述发现为工业发酵中通过靶向调控双组分系统改善丝状菌形态及代谢特性提供了新的理论依据，同时揭示了SCO5282/SCO5283信号通路在链霉菌环境适应中的潜在调控网络。

2.13 SCO5784/SCO5785

SCO5784/5785直接影响S. albidoflavus从初级代谢向次级代谢转变的过程，对ACT和RED的生物合成、气生菌丝分化及孢子形成具有正调控作用，同时显著影响分泌蛋白的表达。SCO5784/5785可通过对次级代谢的时间调节来响应环境变化。当SCO5785表达水平下降时，ACT和RED合成及孢子形成会暂时性延迟，而且核糖体基因簇SCO4701-4721 (编码50S核糖体蛋白L23、L29等)表达上调2-5倍，表明S. albidoflavus可能在抑制次级代谢相关通路的同时，转向对初级代谢产物的快速合成；当SCO5785过表达时，ACT和RED合成及孢子形成提前且增强，上述核糖体基因显著下调，表明在生长早期或比正常情况下更早的时间点，菌体就开始投入资源进行抗生素的生物合成并启动孢子形成^[50]。这种代谢重编程可使菌体在竞争激烈的环境中尽早建立防御屏障，更有效地繁殖和扩散。RT-qPCR显示，一些分泌蛋白编码基因(如sco0762，编码枯草杆菌蛋白酶抑制剂)在过表达SCO5785菌株中显著上调表达^[50]。该发现为通过基因工程改造SCO5785表达水平来优化工业菌株的外泌蛋白生产能力提供了新思路，特别是在丝状放线菌作为异源蛋白表达宿主的应用中。

本文将其他已研究的与次级代谢相关的双组分系统总结于表2。

3 其他链霉菌中的双组分系统

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3.1 AflQ1/Q2 (SLINC_5291/SLINC_5290)

林肯链霉菌(S. lincolnensis)中的AflQ1/Q2与S. albidoflavus中的AfsQ1/Q2同源，且AflQ1 (RR)可通过抑制自身表达并下调林可霉素生物合成基因簇中8个基因(lmbA、lmbJ、lmbK、lmbV、lmbW、lmbU、lmrA和lmrC)的转录水平负调控林可霉素的合成^[63]。AflQ1通过其C端HTH (螺旋-旋转-螺旋)结构域特异性识别并结合一个16 bp的回文序列motif (GTCAC-N₆-GTCAC)，直接抑制上述靶基因的转录；同时lmb基因簇内的其他基因lmbC、lmrB和调控基因bldA、SLCG_Lrp及SLCG_2919也受到AflQ1的间接控制；另外，AflQ2 (HK)通过信号分子天冬氨酸激活下游的AflQ1，AflQ1通过上调天冬氨酸代谢通路基因ask-asd、asd2和thrA的表达加速天冬氨酸代谢，间接影响林可霉素的生物合成^[64]。AflQ1的HTH结构域在放线菌中具有极高的序列保守性(>95%)，表明针对AflQ1/Q2的操作策略可能广泛适用于其他抗生素高产菌株的代谢工程改造，对多种抗生素的生产都有潜在的优化效果。

3.2 AfrQ1/Q2

龟裂链霉菌(S. rimosus) M4018中的AfrQ1/Q2与S. albidoflavus中的AfsQ1/Q2同源，可作为全局性调控因子通过下调土霉素(oxytetracycline, OTC)生物合成和调节相关基因(oxyB、otrB、otcG、otcR和otrC)来负调控OTC产生^[65]。ΔafrQ1在TSB或MS中培养时，OTC产量并未表现出明显差异，这一表型与S. albidoflavus中的AfsQ1/Q2^[66]和DraR/K^[33]相似；在以50 mmol/L Gly为唯一氮源时，OTC的产量显著提高。另外，在氧化胁迫和高糖浓度的压力环境下，缺失AfrQ1/Q2可减小OTC产量下降的幅度^[65]。

3.3 CepR/S (BB341_RS13780/BB341_RS13785)

带小棒链霉菌(S. clavuligerus) F613-1中的CepR/S正调控头霉素(cephamycin C, cep)的生物合成，对克拉维酸(clavulanic acid, CA)的生物合成无显著影响。突变株ΔcepR (RR)、ΔcepS (HK)及ΔcepRS的头霉素产量均显著降低，但并不影响菌体表型和菌株生长；CepR/S调控大多数头霉素生物合成基因的表达，RT-qPCR显示，突变株ΔcepRS中头霉素生物合成基因簇基因pcbC、pcbAB、lab (早期)、cefD、cefE (中期)以及cmcI、cmcJ、cefF、cmcH (晚期)均下调表达；突变株ΔcepRS中克拉维酸生物合成相关基因(cla、blp、orf10等)表达水平未发生显著变化；过表达CepR/S对头霉素生物合成基因的转录水平无显著调控作用，但可能通过翻译后修饰或协同调控等机制小幅促进头霉素的合成；EMSA显示，CepR能与cefD-cmcI基因区间(P3区域)特异性结合，直接与cefD和cmcI的启动子相互作用^[67]，这为通过代谢工程策略优化抗生素生产提供了新靶点。

3.4 CseB-C_SR (M271_22640/M271_22645)

在雷帕霉素链霉菌(S. rapamycinicus)NRRL5491中，CseB-C_SR通过正调控sigE_SR 、cseA_SR 、rapA、rapP、rapG、rapH和elaI等生物合成基因簇中基因的转录，促进雷帕霉素的生物合成。同时，它通过负调控rapS/R、rapY、elaA、elaB、ela3和M271_22625等基因的转录，减少洋橄榄叶素的生物合成。EMSA显示，CseB_SR蛋白可与sigE_SR 的启动子区域结合，调控sigE_SR 的转录从而影响雷帕霉素和洋橄榄叶素的生物合成^[68]。在S. albidoflavus中，CseC/B(SCO3359/3358)中的RR CseB可在镁离子(Mg²⁺)浓度较低的条件下激活sigE的转录，以维持细胞壁完整性；突变株∆cseB中ACT产量显著增加，表明CseB在ACT合成中起负调控作用^[69]。

3.5 CutS/R

在洛蒙德链霉菌(S. lomondensis) S015中，TCS CutR/S对洛蒙真菌素的生物合成起负调控作用。通过qPCR分析发现，在cutR和cutS单基因敲除突变株中，与洛蒙真菌素侧链羟基化相关的基因lomo14和lomo10，以及涉及前体物质生物合成的关键基因lphzB、lphzC、lphzE和lphzG的表达水平均有显著上调^[70]，表明CutR和CutS对吩嗪中间产物的合成路径及洛蒙真菌素侧链修饰过程中的基因表达具有抑制效应，从而间接降低了洛蒙真菌素的产量。

3.6 KasW/X

KasW/X是春日井链霉菌(S. kasugaensis)中的全局性调控因子，负调控春雷霉素生物合成^[71]。在低产菌株LY中，KasW/X通过调控下游基因kasT的转录水平间接调控春雷霉素生物合成基因的表达，缺失KasW/X使春雷霉素产量相较于LY提高了19%；在高产菌株HY中，缺失RR KasW可显著提高kasJKLMNO、kasQP和kasRABCDEF (春霉素生物合成相关基因的转录单元)的转录水平，且途径特异性正调控基因kasT和MerR家族的负调控因子kasV的表达均显著增加；在HY中敲除KasW/X，春雷霉素产量提高了58%^[72]。

3.7 MtrA/Bsbh (SBI_06494/06495)

冰城链霉菌(S. bingchenggensis)中的MtrA/B_sbh与S. albidoflavus中的MtrA/B同源，其中全局性调控子MtrA_sbh是米尔贝霉素产生的关键激活子。MtrAsbh可通过影响米尔贝霉素基因簇和前体合成相关基因的表达间接正调控米尔贝霉素的产生。米尔贝霉素生物合成基因簇中的代表性基因milA2、milA4、milF、milR和milA1在突变株ΔmtrA_sbh 中大幅下调甚至不表达，而在过表达时则表现出不同程度的显著上调；负责丙二酸单酰辅酶A合成的sbi_02769、sbi_02770和sbi_08290，以及甲基丙二酸单酰辅酶A合成基因sbi_4601在过表达MtrA_sbh时也显著上调^[73]，表明MtrA_sbh能够通过影响前体合成相关基因的表达进而调控米尔贝霉素的合成。

3.8 RimA1/A2

RimA1/A2是S. rimosus M4018中响应不同环境胁迫并以培养基依赖性方式负调控土霉素(oxytetracycline, OTC)生产的全局调节因子，与S. albidoflavus中的RapA1/A2同源。RapA1/A2分别通过调控actII-ORF4、actIII和kasO，作为ACT和coelimycin生物合成的正调控因子^[74]。RimA1/A2可通过下调otcR负向调节OTC生产，在以Gly为唯一氮源的MM条件下，突变株ΔrimA1中参与OTC生物合成的部分基因(oxyB、otrB、otcG、otcR和otrC)转录增加，OTC产量显著提高^[75]。RimA1/A2在渗透胁迫和氧化胁迫下参与OTC生产的调节。在氧化胁迫条件下，突变株ΔrimA1/A2的OTC产量下降幅度缩小；而在高渗条件(氯化钾)下，OTC生产水平下降幅度反而增大，过表达RimA1/A2更有利于维持OTC的生物合成^[76]。

3.9 RspA1/A2

白色链霉菌(S. albus)中的RspA1/A2与S. albidoflavus中的AfsQ1/Q2同源，正调控盐霉素的生物合成。RR RspA1可以特异性地结合在途径特异性激活基因slnR的启动子区域，正调控其转录，从而促进盐霉素的生物合成。EMSA表明，RspA1可作为氮同化相关基因(gdhA、amtB、glnA等)的转录抑制因子直接与上游启动子区域结合，负调控氮代谢；sigW编码一种胞质外功能的sigma因子，位于RspA1/A2下游，被RspA1直接激活，负调控盐霉素的生物合成并促进细胞生长，与RspA1/A2的作用相拮抗^[77]。

3.10 SmrA/B

SmrA/B是在S. avermitilis中发现的一对双组分调控系统，位于σ25 (编码ECF σ因子σ25)的上游，通过σ25因子调控阿维菌素和寡霉素A的生物合成。缺失smrA/B基因会导致阿维菌素产量提高约1倍，而回补smrAB后，阿维菌素的产量基本恢复到野生型水平；此外，SmrA的活化严格依赖于感应激酶SmrB，而SmrB还可以磷酸化除SmrA外的应答调控蛋白^[78]。SmrA结合到sig25基因上游区域的2个直接重复序列(CTGTGA-n5-CTGTGA)，激活σ25的表达，σ25通过抑制aveR (阿维菌素途径特异性激活基因)的转录和激活olmRI (寡霉素途径特异性激活基因)的转录来实现其调控作用^[79]。

3.11 SRO293/294

弗氏链霉菌(S. fradiae) Men-myco-93-63是本课题组筛选并多年研究的一株生防链霉菌(中国普通微生物菌种保藏管理中心编号CGMCC NO.1471)^[80]。近年来，该生防菌被发现产生一组五烯大环内酯类抗生素——roflamycoin & men-myco-A (R&M，图5)，对镰孢菌属、链格孢属等9个属17种常见植物病原真菌具有较好的抑制作用；抑菌谱检测发现，roflamycoin具有广谱的抗真菌特性，对棉花黄萎病菌、葡萄灰霉病菌等9个属17种常见植物病原真菌都有较好的抑制作用，EC₅₀介于1.82-12.18 mg/L之间^[81] (表3)。

SRO293/294是S. fradiae Men-myco-93-63中一对典型的双组分系统，与S. albidoflavus中的MtrA/B相似度较高，负调控R&M等多种次级代谢产物的生物合成。Δsro293对辣椒疫霉(Phytophthora capsica)的抑菌活性与野生株无差异，而Δsro293/294的抑菌活性明显降低，其HK SRO294的敲除突变株Δsro294则对辣椒疫霉基本丧失了抑菌活性。进一步对突变株进行HPLC检测，发现Δsro294中R&M产量高于野生株；Δsro293中R&M产量与野生株无差异；Δsro293/294不产R&M。由此推测，该TCS与S. fradiae Men-myco-93-63拮抗疫霉的活性有关，且在R&M及其他次级代谢产物中起到至关重要的调控作用^[82]。

4 非典型的双组分系统

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非典型的双组分系统是指在结构、功能或调控机制上与传统TCS存在显著差异的细菌信号传导系统，包括孤儿HK和孤儿RR、多联体、杂合型HK、非典型效应结构域等，其特性主要体现在：(1) 基因层面上出现独立表达的HK或RR，打破经典基因对的共定位原则，其间存在交叉调控和非磷酸化直接互作^[83]；(2) 形成杂合系统(hybrid systems)，即HK与RR的结构域或其他功能域(如环化酶、甲基转移酶)融合为单一多肽链，形成功能高度整合的信号转导模块，有利于信号的高效和特异性传递，实现信号感知、传递与基因调控的高效耦合^[84]；(3) “绕过”磷酸化限制进行磷酸化非依赖性调控。部分RR因关键磷酸化位点保守天冬氨酸突变或缺失而无法通过磷酸化激活，转而依赖与配体直接结合(如代谢物或抗生素)、与蛋白质互作调控(如支架蛋白结合)或翻译后修饰(post-translational modifications, PTMs)等替代途径激活功能，这有益于菌体在营养胁迫或应激条件下提高响应效率，快速整合多重信号，动态平衡基因表达^[85]。这些创新机制赋予细菌更高的信号可塑性与环境响应效率，也为合成生物学设计模块化调控工具提供了天然的分子框架。

4.1 Aor1 (SCO2281)

Aor1是孤立的应答调节蛋白，在S. albidoflavus中正调控ACT、RED、CDA的生物合成和形态分化过程，缺失aor1会导致突变株ACT、RED和CDA产量显著下降，且形态发育出现延迟。转录组分析显示，在突变株Δaor1中，包括actII-ORF4、cdaR和cpkO在内的27个基因的表达水平显著下调；过表达aor1未显著提升抗生素产量，可能因其对AbsA2 (SCO3226，全局性负调控因子)的负调控已达阈值(absA2在突变株Δaor1中上调1.8倍)；Aor1通过SigB途径参与渗透压应激反应，在突变株Δaor1中，sigma因子SigB调控的基因簇(SigL、SigM等)上调表达，一些间接或直接与SigB相关的靶基因(whiB和dpsA)也有所上调，表明当aor1功能缺失时，细胞可能激活了SigB调控下的渗透压防护机制以应对环境变化；Aor1还参与sigma因子SigU介导的分泌蛋白调控^[86]。

4.2 AtcR/K (SBI_06838/SBI_06839)

冰城链霉菌(S. bingchenggensis)中的AtcR (RR)和AtcK (HK)位于不同操纵子中，其开放阅读框呈头对头排列，因此被定义为非典型的双组分系统。AtcR通过MilR3介导的级联反应正调控米尔贝霉素的生物合成，负调控南昌霉素的生物合成；磷酸化的AtcR特异性激活MilR3转录，MilR3直接激活mil和kel簇的转录，同时通过激活nanR4 (nan簇中的抑制因子编码基因)抑制nan簇的转录；通过在ΔatcR突变株中引入由PkasO*启动子驱动的NanR1和NanR2 (南昌霉素生物合成的关键激活因子)，南昌霉素的产量相较于对照菌株TMB-C提高了大约45倍，达到6.08 g/L；过表达MilR和MilR3，并缺失PKS基因(sbi_06843-sbi_06845)，同时抑制黄色化合物和南昌霉素的生物合成，使米尔贝霉素的产量显著增加，从基础水平提升至1.34 g/L，具备了工业化生产的潜力^[87]。

4.3 JadR1

JadR1是链霉菌中发现的首个非典型双组分系统，是委内瑞拉链霉菌(S. venezuelae)中杰多霉素(jadomycin B, JdB)生物合成基因簇的关键调控蛋白。JadR1缺失典型RR中结合Mg²⁺的2个氨基酸，无法被磷酸化，因此属于非典型应答调控蛋白(atypical response regulator, ARR)^[88]。JadR1位于杰多霉素合成基因簇中第一个结构基因jadJ的上游，可特异性结合到jadJ启动子的上游激活jadJ的转录。JadR1同样结合自身启动子的上游区域，低浓度JadR1优先结合启动子较上游区域(-4–-60)；高浓度JadR1则覆盖整个启动子区域(-4–-112)，完全阻断RNA聚合酶的结合，实现对自身的负调控。此外，低浓度的JdB可与JadR1结合，诱导其构象变化，增强JadR1与jadJ启动子的结合能力，进一步激活转录；而当JdB浓度过高时，JadR1完全从jadJ启动子脱离，终止激活作用，形成负反馈调节^[88]。JadR1还受到JadR2 (TetR家族阻遏蛋白)和JadR* (TetR样阻遏蛋白)的协同抑制，JadR2和JadR*可直接结合jadR1的启动子，抑制其转录。双突变株ΔjadR*-R2中，jadR1的表达显著增加，导致杰多霉素产量大幅提升，表明两者协同抑制JadR1的表达^[89]。

4.4 OhkA (SCO1596)和OrrA (SCO3008)

孤儿组氨酸激酶OhkA是S. albidoflavus中次级代谢产物ACT、RED和CDA的负调控因子，同时也是气生菌丝形成和孢子形成的正调控因子。负责编码乙酰辅酶A羧化酶(acetyl-CoA carboxylase, ACCase)的accA2、accB和accE基因在ΔohkA突变株中的转录显著下调；ACCase可将乙酰辅酶A转化为丙二酸单酰辅酶A (malonyl-CoA)，而malonyl-CoA是ACT和RED合成的共同前体，因此突变株ΔohkA可提高ACT和RED生物合成的前体供应；在S. albidoflavus中敲除抑制基因ohkA或敲除ACT、CDA的生物合成基因簇均可显著提高RED的产量^[90]。缺失ohkA会显著降低气生菌丝形成所必需的chpABCDEFGH基因的转录，但会增加负责SapB形成和调控的ramS/C/R基因的转录；在S. avermitilis中敲除OhkA sav的表型与S. albidoflavus相似，气生菌丝变薄，孢子形成受阻且寡霉素A产量大幅增加，表明OhkA的调控机制在链霉菌属中是保守的；转录组分析显示多效性调控基因wblA和nsdA在ΔohkA sav突变株中的表达下调^[91]。OrrA是孤立的应答调控蛋白，已鉴定出OrrA是OhkA的同源RR。突变株ΔorrA与ΔohkA表型高度相似，生长早期较慢，生长后期呈粉红色，且ACT和RED的合成水平均高于野生型M145^[92]。wblA (负调控ACT，促进形态发育的全局性调控基因)和sco1375是OrrA的靶基因，OrrA能够结合其启动子，且在突变株ΔorrA中过表达sco1375或wblA可部分恢复野生型表型^[93]。过表达OrrA的菌株产生的气生菌丝少于野生菌株M145，且过量产生ACT^[94]。

4.5 PdtaS-p和PdtaR-p (SSDG_02492和SSDG_04087)

PdtaS-p/PdtaR-p是始旋链霉菌(S. pristinaespiralis)中ACT和RED生产的负调节因子以及分化过程的正调节因子；PdtaS-p和PdtaR-p在基因组中并不相邻，属于“孤儿”基因^[95]。体外磷酸转移实验(PdtaS-p可磷酸化PdtaR-p的D75位点)和表型分析证实PdtaS-p与PdtaR-p同源；突变株ΔpdtaS-p和ΔpdtaR-p表型相似，在MS培养基上表现出光秃表型，且普那霉素(pristinamycin, PRI)合成减少；在S. albidoflavus中，PdtaS-c和PdtaR-c分别与PdtaS-p和PdtaR-p同源，缺失pdtaS-c或pdtaR-c会导致形态分化受损和ACT产量增加，表明PdtaR-p/PdtaS-p介导的调控在链霉菌中可能是保守的^[96]。传统RR的效应结构域多为DNA结合域(HTH、OmpR等)，而PdtaR-p及其同源物的C端具有一个假定的ANTAR RNA结合结构域，可通过反终止作用在转录后水平调节基因表达，这是首次在链霉菌中报道功能明确的ANTAR调控因子，显著区别于传统TCS的调控机制。

4.6 SCO1135

TetR家族的孤立调控蛋白SCO1135是S. albidoflavus中的全局性调控因子，参与孢子形成和次级代谢产物的全局性调控。编码气生菌丝表面疏水性外鞘组分的chp基因簇中chpA、chpC和调控形态发育的基因whiH在突变株Δsco1135中表达下调约50%；RT-qPCR发现，在72 h时ACT生物合成基因簇中调控基因sco5085、结构基因sco5072和sco5086的转录水平较野生型上调13-20倍^[97]。在YBP固体培养基上，突变株Δsco1135气生菌丝的形成和产孢明显延迟于野生型M145，ACT产量为野生菌株的2-3倍^[98]。

4.7 SCO1979

孤立调控蛋白SCO1979是XRE家族的全局性调控因子，通过与actII-ORF4、redZ、cdaR等基因的启动子直接结合抑制其转录活性，负调控ACT、RED和CDA的生物合成，还可间接调控chp、rdl、ram等发育相关基因簇的表达，导致突变株Δsco1979气生菌丝分化延迟及孢子产量显著减少^[99]。此外，SCO1979是一种转录抑制因子，可以与自身启动子序列(-120–-35区域)相互作用，抑制sco1979的表达；且SCO1979在链霉菌属中高度保守，与S. venezuelae中的SVEN_6384 (84%一致性)、灰色链霉菌(S. griseus)中的SGR_1055 (81%一致性)及S. avermitilis中的SAV_6253 (90%一致性)的蛋白同源性较高，暗示其功能在进化中高度保守^[100]。

5 总结与展望

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链霉菌属因其复杂的形态分化和生产抗生素、免疫抑制剂和抗肿瘤药物等多种重要次级代谢产物的强大能力而闻名。这些生理过程受到复杂而严格的TCSs调控。截至目前，TCSs的功能及其调控机制主要是在模式菌株S. albidoflavus中完成的，而在非模式链霉菌中，许多TCS的具体功能和调控机制仍未被充分揭示。识别并揭示这些TCS对理解链霉菌的生理调控至关重要。

TCS几乎参与所有的生理生化过程，包括形态发育和分化、初级代谢和次级代谢等，以及各种应激反应。大多数TCS可以参与多种生化过程，其信号级联重叠，调控同一个靶基因，对同一过程具有不同的调控，这使得链霉菌全局调控水平的深入研究更加困难。不同TCS之间或TCS与其他调节蛋白家族之间可能存在相互作用，而这部分存在交叉调控的TCS (如PhoP/R、GlnR、MtrB/A)通常还控制着菌体的初级代谢。另外，组氨酸激酶可感知的信号分子种类繁多，具体何种信号分子可被识别也还有待研究。

大部分TCS可直接或间接地通过控制途径特异性调节因子或生物合成簇基因参与抗生素的生物合成，甚至一些应答调控蛋白如RedZ本身就是生物合成簇的一部分。不同TCS在调控不同链霉菌中次级代谢产物产生的作用是高度保守的。例如，DraK/R在S. albidoflavus中调控ACT和RED的产生，同时也在S. avermitilis中调控阿维菌素和寡霉素的产生。通过敲除抗生素生产的负调控因子，或者修饰预测的识别序列来调节目标基因的表达，可显著提高抗生素的生产能力。控制菌株初级代谢、形态发育和分化过程的TCS对于工业生产特定代谢产物同样重要，改良在液体培养中呈现颗粒状生长的链霉菌的形态特性，促进前体物质的合成，缩短形态分化和发酵周期，均有利于菌体在发酵罐中的生长和抗生素的合成。特定的TCS可以调控多个生物合成基因簇的表达，通过操纵这种TCS (例如AtcR/K)，重新布线调控通路，可以减少工程菌株改造的复杂性和步骤，显著提高抗生素的产量。另外，调节培养基组成、pH值、温度等形态学工程也有利于提高抗生素的产量。总的来说，链霉菌中不同TCS的功能和调控作用机制仍有待深入探索和揭示，研究TCS组成的调控网络有巨大的生物技术潜力。

基金

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国家自然科学基金(32272605)

参考文献

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2025年第65卷第8期

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doi: 10.13343/j.cnki.wsxb.20250042

接收时间：2025-01-15
首发时间：2026-02-06
出版时间：2025-08-04

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收稿日期：2025-01-15
录用日期：2025-03-20

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National Natural Science Foundation of China(32272605)

国家自然科学基金(32272605)

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^1.河北农业大学植物保护学院，河北省农作物病虫害生物防治技术创新中心，国家北方山区农业工程技术研究中心，河北保定

^2.中国农业科学院研究生院，北京

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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HK	Type	RR	Family	HK	Type	RR	Family
SCO0203	Classic	SCO0204	NarL	SCO0211	Classic	-	-
SCO0422	Classic	SCO0421	NarL	SCO0551	Classic	SCO0552	OmpR
SCO0588	Classic	-	-	SCO0599	Classic	-	-
SCO0946	Classic	-	-	SCO1071	Classic	SCO1070	NarL
SCO1137	Classic	SCO1136	IclR	SCO1160	Classic	-	-
SCO1217	Classic	-	-	-	-	SCO1220	LytTR
SCO1259	Classic	SCO1260	NarL	SCO1369	Classic	SCO1370	NarL
SCO1402	Classic	-	-	SCO1596	Classic	-	-
SCO1630	Classic	-	-	-	-	SCO1654	NarL
SCO1744	Classic	SCO1745	NarL	SCO1802	Classic	SCO1801	NarL
-	-	SCO2013	AmiR_NasR	SCO2121	Classic	SCO2120	NarL
SCO2142	Classic	SCO2143	OmpR	SCO2166	Classic	SCO2165	NarL
SCO2215	Classic	SCO2216	NarL	-	-	SCO2281	NarL
SCO2307	Classic	SCO2308	NarL	SCO2359	Classic	SCO2358	NarL
SCO2518	Classic	SCO2517	NarL	SCO2800	Classic	SCO2801	OmpR
SCO2879	Classic	-	-	-	-	SCO3008	NarL
SCO3012	Classic	SCO3013	OmpR	SCO3062	Classic	SCO3063	OmpR
SCO3119	Classic	-	-	-	-	SCO3134	NarL
-	-	SCO3144	NarL	SCO3225	Classic	SCO3226	NarL
SCO3284	Classic	-	-	SCO3359	Classic	SCO3358	OmpR
SCO3390	Classic	SCO3389	NarL	SCO3589	Classic	SCO3590	OmpR
SCO3654	Classic	SCO3653	NarL	SCO3740	Classic	SCO3741	OmpR
SCO3750	Classic	-	-	SCO3757	Classic	SCO3756	NarL
SCO3796	Classic	-	-	-	-	SCO3818	NarL
SCO3948	Classic	-	-	-	-	SCO4009	Unclassified
SCO4021	Classic	SCO4020	OmpR	SCO4073	Classic	SCO4072	NarL
SCO4120	Classic	-	-	SCO4124	Classic	SCO4123	NarL
SCO4155	Classic	SCO4156	OmpR	-	-	SCO4201	RsbU
SCO4229	Classic	SCO4230	OmpR	SCO4275	Classic	SCO4276	NarL
SCO4362	Classic	SCO4363	NarL	-	-	SCO4596	NarL
SCO4597	Classic	-	-	SCO4598	Classic	-	-
SCO4667	Classic	SCO4668	NarL		-	SCO4768	NarL
SCO4791	Classic	SCO4792	NarL	SCO4906	Classic	SCO4907	OmpR
-	-	SCO5006	Unclassified	SCO5131	Classic	SCO5132	NarL
SCO5239	Classic	-	-	SCO5282	Classic	SCO5283	OmpR
SCO5289	Classic	-	-	SCO5304	Classic	-	-
-	-	SCO5351	CheY	SCO5378	Classic	SCO5377	NarL
SCO5404	Classic	SCO5403	OmpR	SCO5435	Classic	SCO5434	IclR
SCO5454	Classic	SCO5455	NarL	SCO5460	Classic	-	-
SCO5540	Classic	-	-	SCO5544	Classic	-	-
-	-	SCO5567	Unclassified	SCO5683	Classic	SCO5684	NarL
SCO5748	Hybrid	-	-	-	-	SCO5749	Unclassified
SCO5779	Classic	SCO5778	OmpR	SCO5784	Classic	SCO5785	NarL
SCO5824	Classic	SCO5825	NarL	SCO5829	Classic	SCO5828	Unclassified
SCO5863	Classic	SCO5862	OmpR	SCO5871	Classic	SCO5872	OmpR
-	-	SCO5881	NarL	-	-	SCO6029	NarL
SCO6069	Classic	-	-	SCO6139	Classic	SCO6140	NarL
SCO6163	Classic	SCO6162	NarL	SCO6253	Classic	SCO6254	NarL
SCO6268	Classic	-	-	SCO6353	Classic	SCO6354	OmpR
SCO6362	Classic	SCO6363	NarL	-	-	SCO6364	OmpR
SCO6369	Classic	-	-	SCO6421	Classic	SCO6422	NarL
SCO6424	Classic	-	-	SCO6668	Classic	SCO6667	NarL
-	-	SCO6685	NarL	SCO6794	Classic	-	-
SCO6943	Classic	-	-	SCO7076	Classic	SCO7075	OmpR
SCO7089	Classic	SCO7088	NarL	SCO7231	Classic	SCO7230	OmpR
SCO7297	Classic	SCO7298	TrxB	SCO7327	Hybrid	-	-
SCO7422	Classic	-	-	SCO7463	Classic	-	-
SCO7534	Classic	SCO7533	OmpR	SCO7649	Classic	SCO7648	NarL
SCO7711	Classic	SCO7712	NarL	-	-	-	-

Type

Family

Type

Family

SCO0203

Classic

SCO0204

NarL

SCO0211

Classic

SCO0422

Classic

SCO0421

NarL

SCO0551

Classic

SCO0552

OmpR

SCO0588

Classic

SCO0599

Classic

SCO0946

Classic

SCO1071

Classic

SCO1070

NarL

SCO1137

Classic

SCO1136

IclR

SCO1160

Classic

SCO1217

Classic

SCO1220

LytTR

SCO1259

Classic

SCO1260

NarL

SCO1369

Classic

SCO1370

NarL

SCO1402

Classic

SCO1596

Classic

SCO1630

Classic

SCO1654

NarL

SCO1744

Classic

SCO1745

NarL

SCO1802

Classic

SCO1801

NarL

SCO2013

AmiR_NasR

SCO2121

Classic

SCO2120

NarL

SCO2142

Classic

SCO2143

OmpR

SCO2166

Classic

SCO2165

NarL

SCO2215

Classic

SCO2216

NarL

SCO2281

NarL

SCO2307

Classic

SCO2308

NarL

SCO2359

Classic

SCO2358

NarL

SCO2518

Classic

SCO2517

NarL

SCO2800

Classic

SCO2801

OmpR

SCO2879

Classic

SCO3008

NarL

SCO3012

Classic

SCO3013

OmpR

SCO3062

Classic

SCO3063

OmpR

SCO3119

Classic

SCO3134

NarL

SCO3144

NarL

SCO3225

Classic

SCO3226

NarL

SCO3284

Classic

SCO3359

Classic

SCO3358

OmpR

SCO3390

Classic

SCO3389

NarL

SCO3589

Classic

SCO3590

OmpR

SCO3654

Classic

SCO3653

NarL

SCO3740

Classic

SCO3741

OmpR

SCO3750

Classic

SCO3757

Classic

SCO3756

NarL

SCO3796

Classic

SCO3818

NarL

SCO3948

Classic

SCO4009

Unclassified

SCO4021

Classic

SCO4020

OmpR

SCO4073

Classic

SCO4072

NarL

SCO4120

Classic

SCO4124

Classic

SCO4123

NarL

SCO4155

Classic

SCO4156

OmpR

SCO4201

RsbU

SCO4229

Classic

SCO4230

OmpR

SCO4275

Classic

SCO4276

NarL

SCO4362

Classic

SCO4363

NarL

SCO4596

NarL

SCO4597

Classic

SCO4598

Classic

SCO4667

Classic

SCO4668

NarL

SCO4768

NarL

SCO4791

Classic

SCO4792

NarL

SCO4906

Classic

SCO4907

OmpR

SCO5006

Unclassified

SCO5131

Classic

SCO5132

NarL

SCO5239

Classic

SCO5282

Classic

SCO5283

OmpR

SCO5289

Classic

SCO5304

Classic

SCO5351

CheY

SCO5378

Classic

SCO5377

NarL

SCO5404

Classic

SCO5403

OmpR

SCO5435

Classic

SCO5434

IclR

SCO5454

Classic

SCO5455

NarL

SCO5460

Classic

SCO5540

Classic

SCO5544

Classic

SCO5567

Unclassified

SCO5683

Classic

SCO5684

NarL

SCO5748

Hybrid

SCO5749

Unclassified

SCO5779

Classic

SCO5778

OmpR

SCO5784

Classic

SCO5785

NarL

SCO5824

Classic

SCO5825

NarL

SCO5829

Classic

SCO5828

Unclassified

SCO5863

Classic

SCO5862

OmpR

SCO5871

Classic

SCO5872

OmpR

SCO5881

NarL

SCO6029

NarL

SCO6069

Classic

SCO6139

Classic

SCO6140

NarL

SCO6163

Classic

SCO6162

NarL

SCO6253

Classic

SCO6254

NarL

SCO6268

Classic

SCO6353

Classic

SCO6354

OmpR

SCO6362

Classic

SCO6363

NarL

SCO6364

OmpR

SCO6369

Classic

SCO6421

Classic

SCO6422

NarL

SCO6424

Classic

SCO6668

Classic

SCO6667

NarL

SCO6685

NarL

SCO6794

Classic

SCO6943

Classic

SCO7076

Classic

SCO7075

OmpR

SCO7089

Classic

SCO7088

NarL

SCO7231

Classic

SCO7230

OmpR

SCO7297

Classic

SCO7298

TrxB

SCO7327

Hybrid

SCO7422

Classic

SCO7463

Classic

SCO7534

Classic

SCO7533

OmpR

SCO7649

Classic

SCO7648

NarL

SCO7711

Classic

SCO7712

NarL

TCS名称 TCS name	编号 No.	功能 Function	调控机制 Regulatory mechanism	文献 References
AbrA1/A2	SCO1744/1745	Negatively regulates ACT, RED, CDA biosynthesis and morphological differentiation	Strains deficient in AbrA1/A2 serve as host bacteria with a significantly improved ability to produce the heterologous compound oviedomycin. Fe may be the activation signal for this system, and the self-regulation of AbrA1/A2 is dependent on the concentration of ferric ions	[51]
AbrB1/B2	SCO2165/2166	Negative regulation of ACT and RED biosynthesis and positive regulation of vancomycin resistance	Mechanisms not yet clear	[52]
AbrC1/C2/C3	SCO4598/4597/4596	Positive regulation of ACT, RED, and CDA biosynthesis and morphological differentiation	AbrC3 directly activates actII-ORF4 transcription and positively regulates ACT biosynthesis AbrC3 may indirectly regulate RED biosynthesis by affecting AfsS. The regulatory mechanism of CDA is unclear	[53-54]
CagR/S	-	Regulating the biosynthesis of clavulanic acid	CagR binds directly to the promoter regions of the key genes in the CA biosynthesis pathway, ceaS1, oat1, oat2, as well as claR. CagRS also extensively regulates genes involved in primary metabolism, particularly metabolic pathways related to the biosynthesis of the CA precursors glyceraldehyde-3-phosphate (G3P) and arginine	[55]
EcrA1/A2	SCO2518/2517	Located near the RED locus, it positively regulates the biosynthesis of RED	It regulates the biosynthesis of RED by affecting the transcription of redD and redZ	[56]
EcrE1/E2	SCO6421/6422	Located near the RED site and is regulating RED biosynthesis	Regulates RED biosynthesis by affecting redD and redZ transcription	[57]
OsaA/B	SCO5748/5749	Negatively regulates ACT and RED biosynthesis and is involved in morphological differentiation and osmotic pressure regulation	In R2YE containing 10.3% sucrose, deletion of OsaB resulted in impaired aerial mycelium formation, phenotypic baldness (no effect of deletion of OsaA), as well as a 3- to 5-fold increase in ACT and RED production	[58]
RapA1/A2	SCO5403/5404	Positive regulation of ACT and coelimycin biosynthesis	Deletion of RapA1/A2 decreased CpkI protein abundance and reduced the transcript levels of actII-ORF4 and kasO	[59]
-	SCO3134	May be involved in the regulation of carbon sources, secondary metabolites, and morphogenesis	Mechanisms not yet clear	[60]
-	SCO4020/4021	May be involved in the regulation of carbon sources, secondary metabolites, and morphogenesis	SCO4020 (RR) expression is up-regulated under glucose-containing culture conditions. Mechanisms not yet clear	[61]
-	SCO5351	Positively regulates ACT and CDA biosynthesis, aerial mycelium development and spore production	ActII-orf4 and cdaR expression are down-regulated in the Δsco5351 mutant	[62]

TCS名称

TCS name

编号

No.

功能

Function

调控机制

Regulatory mechanism

文献

References

AbrA1/A2

SCO1744/1745

Negatively regulates ACT, RED, CDA biosynthesis and morphological differentiation

Strains deficient in AbrA1/A2 serve as host bacteria with a significantly improved ability to produce the heterologous compound oviedomycin. Fe may be the activation signal for this system, and the self-regulation of AbrA1/A2 is dependent on the concentration of ferric ions

[51]

AbrB1/B2

SCO2165/2166

Negative regulation of ACT and RED biosynthesis and positive regulation of vancomycin resistance

Mechanisms not yet clear

[52]

AbrC1/C2/C3

SCO4598/4597/4596

Positive regulation of ACT, RED, and CDA biosynthesis and morphological differentiation

AbrC3 directly activates actII-ORF4 transcription and positively regulates ACT biosynthesis AbrC3 may indirectly regulate RED biosynthesis by affecting AfsS. The regulatory mechanism of CDA is unclear

[53-54]

CagR/S

Regulating the biosynthesis of clavulanic acid

CagR binds directly to the promoter regions of the key genes in the CA biosynthesis pathway, ceaS1, oat1, oat2, as well as claR. CagRS also extensively regulates genes involved in primary metabolism, particularly metabolic pathways related to the biosynthesis of the CA precursors glyceraldehyde-3-phosphate (G3P) and arginine

[55]

EcrA1/A2

SCO2518/2517

Located near the RED locus, it positively regulates the biosynthesis of RED

It regulates the biosynthesis of RED by affecting the transcription of redD and redZ

[56]

EcrE1/E2

SCO6421/6422

Located near the RED site and is regulating RED biosynthesis

Regulates RED biosynthesis by affecting redD and redZ transcription

[57]

OsaA/B

SCO5748/5749

Negatively regulates ACT and RED biosynthesis and is involved in morphological differentiation and osmotic pressure regulation

In R2YE containing 10.3% sucrose, deletion of OsaB resulted in impaired aerial mycelium formation, phenotypic baldness (no effect of deletion of OsaA), as well as a 3- to 5-fold increase in ACT and RED production

[58]

RapA1/A2

SCO5403/5404

Positive regulation of ACT and coelimycin biosynthesis

Deletion of RapA1/A2 decreased CpkI protein abundance and reduced the transcript levels of actII-ORF4 and kasO

[59]

SCO3134

May be involved in the regulation of carbon sources, secondary metabolites, and morphogenesis

Mechanisms not yet clear

[60]

SCO4020/4021

May be involved in the regulation of carbon sources, secondary metabolites, and morphogenesis

SCO4020 (RR) expression is up-regulated under glucose-containing culture conditions.

Mechanisms not yet clear

[61]

SCO5351

Positively regulates ACT and CDA biosynthesis, aerial mycelium development and spore production

ActII-orf4 and cdaR expression are down-regulated in the Δsco5351 mutant

[62]

No.	Plant disease	Pathogen	R&M
1	Wheat sharp eyespot	Rhizoctonia cerealis	2.05	7.44	6.18	27.17
2	Wheat scab	Fusarium graminearum	2.14	4.32	2.50	12.42
3	Apple and pear fruit ring rot	Botryosphaeria berengeriana	2.21	6.67	4.27	12.38
4	Wheat common rot	Bipolaris sorokiniana	2.49	19.87	1.62	3.59
5	Potato early blight	Alternaria soari	3.27	32.56	2.81	8.03
6	Apple and pear Valsa canker	Valsa ceratosperma	3.37	7.06	5.81	22.68
7	Pear black spot	Alternaria alternate	4.16	16.06	2.76	7.45
8	Potato mole	Rhizoctonia solani	4.24	26.87	0.50	5.20
9	Cotton Fusarium wilt	Fusarium oxysporum	4.43	14.27	4.61	14.44
10	Apple Alternaria blotch	Alternaria brassicae	4.51	14.88	3.22	12.62
11	Celery Septoria leaf spot	Septoria apicola	4.73	24.93	3.69	13.59
12	Tomato early blight	Alternaria solani	5.72	23.13	2.97	10.63
13	Cotton Verticillium wilt	Verticillium dahliae	5.80	22.01	12.45	32.44
14	Crucifers Alternaria leaf spot	Alternaria oleracea	5.95	16.60	3.46	12.54
15	Cotton pink smut	Cephalothecium roseum	6.79	16.11	2.25	6.31
16	Chrysanthemum root rot	Fusarium solani	6.89	54.45	3.04	23.35
17	Grape gray mold	Botrytis cinerea	7.09	22.48	2.29	14.91

No.

Plant disease

Pathogen

R&M

Natamycin

EC₅₀(µg/mL)

EC₉₀(µg/mL)

EC₅₀(µg/mL)

EC₉₀(µg/mL)

Wheat sharp eyespot

Rhizoctonia cerealis

2.05

7.44

6.18

27.17

Wheat scab

Fusarium graminearum

2.14

4.32

2.50

12.42

Apple and pear fruit ring rot

Botryosphaeria berengeriana

2.21

6.67

4.27

12.38

Wheat common rot

Bipolaris sorokiniana

2.49

19.87

1.62

3.59

Potato early blight

Alternaria soari

3.27

32.56

2.81

8.03

Apple and pear Valsa canker

Valsa ceratosperma

3.37

7.06

5.81

22.68

Pear black spot

Alternaria alternate

4.16

16.06

2.76

7.45

Potato mole

Rhizoctonia solani

4.24

26.87

0.50

5.20

Cotton Fusarium wilt

Fusarium oxysporum

4.43

14.27

4.61

14.44

Apple Alternaria blotch

Alternaria brassicae

4.51

14.88

3.22

12.62

Celery Septoria leaf spot

Septoria apicola

4.73

24.93

3.69

13.59

Tomato early blight

Alternaria solani

5.72

23.13

2.97

10.63

Cotton Verticillium wilt

Verticillium dahliae

5.80

22.01

12.45

32.44

Crucifers Alternaria leaf spot

Alternaria oleracea

5.95

16.60

3.46

12.54

Cotton pink smut

Cephalothecium roseum

6.79

16.11

2.25

6.31

Chrysanthemum root rot

Fusarium solani

6.89

54.45

3.04

23.35

Grape gray mold

Botrytis cinerea

7.09

22.48

2.29

14.91