米曲霉异源表达天然产物研究进展

doi:10.12211/2096-8280.2022-007

合成生物学 ›› 2022, Vol. 3 ›› Issue (6): 1126-1149.DOI: 10.12211/2096-8280.2022-007

米曲霉异源表达天然产物研究进展

董佳钰¹, 李敏¹, 肖宗华¹, 胡明¹, 松田侑大², 汪伟光¹

^1.云南民族大学，国家民委民族药内生菌天然产物合成生物学重点实验室，教育部国家民委民族药资源化学重点实验室，云南，昆明 650031
^2.香港城市大学化学系，香港 999077

收稿日期:2022-01-22 修回日期:2022-02-16 出版日期:2022-12-31 发布日期:2023-01-17
通讯作者: 松田侑大,汪伟光
作者简介:董佳钰（1997—），女，硕士研究生。研究方向为真菌来源天然产物生物合成。E-mail：785661452@qq.com
松田侑大（1988—），男，助理教授，博士生导师。研究方向为天然产物生物合成和合成生物学。E-mail：ymatsuda@cityu.edu.hk
汪伟光（1984—），男，研究员，硕士生导师。研究方向为天然药物化学。E-mail：wwg@live.cn
基金资助:
国家自然科学基金(31960095);云南省应用基础项目(202101AS070022)

Recent advances in heterologous production of natural products using Aspergillus oryzae

Jiayu DONG¹, Min LI¹, Zonghua XIAO¹, Ming HU¹, Yudai MATSUDA², Weiguang WANG¹

^1.Key Laboratory of Natural Products Synthetic Biology of Ethnic Medicinal Endophytes，State Ethnic Affairs Commission，and Key Laboratory of Chemistry in Ethnic Medicinal Resources，State Ethnic Affairs Commission and Ministry of Education，Yunnan Minzu University，Kunming 650031，Yunnan，China
^2.Department of Chemistry，City University of Hong Kong，Kowloon，Hong Kong SAR 999077，China

Received:2022-01-22 Revised:2022-02-16 Online:2022-12-31 Published:2023-01-17
Contact: Yudai MATSUDA, Weiguang WANG

摘要/Abstract

摘要：

天然产物是创新药物和生物农药研发的重要源泉。阐明天然产物生物合成关键基因的功能、解析其生物合成通路和酶催化机制对于促进功能天然产物的应用和开发至关重要。异源表达是研究天然产物生物合成和合成生物学的重要手段之一。近年来，米曲霉异源宿主得到了广泛的应用。通过基因工程技术，将目的天然产物生物合成基因和基因簇在米曲霉中异源表达，不仅能够有效地激活沉默的生物合成基因和基因簇，挖掘全新活性天然产物，而且可以快速高效地鉴定天然产物生物合成基因功能，解析和重构其生物合成途径。米曲霉异源表达宿主已经成为天然产物合成生物学研究的强有力工具。本文对米曲霉遗传转化系统在天然产物研究中的应用进行了系统综述。首先，概述了异源表达的应用和意义，介绍了米曲霉遗传转化系统的发展过程、应用基础和优势以及遗传转化方法的实践和优化。其次，根据不同天然产物的结构类型和与之相对应的合成酶特点，着重介绍了该体系表达各类天然产物的成功案例。最后，对米曲霉异源表达宿主在天然产物化学领域的研究和应用前景进行了总结和展望。随着基因编辑、定向进化、合成生物学、生物信息学技术以及人工智能技术的发展和应用，米曲霉异源表达宿主的发展和完善将会极大地促进更多天然产物化学研究技术的发展和革新，以期为天然产物合成生物学的研究和创新药物研发提供借鉴。

关键词: 米曲霉, 异源表达, 天然产物, 生物合成, 合成生物学

Abstract:

Organic molecules produced by living organisms, generally termed as natural products, are rich sources of pharmaceutical drugs and biopesticides, and fungi are one of the most prolific producers of medicinally important natural products, as represented by penicillins, lovastatin, and cyclosporins. Heterologous expression is a commonly used approach to study the function of biosynthetic genes of natural products, and a number of heterologous hosts have been developed and utilized over the last decades. The filamentous fungus Aspergillus oryzae has long been utilized for the production of fermented food and drinks in East Asia, and intensive genetic and molecular biological studies on the fungus have allowed for its genetic engineering in an efficient manner. Importantly, A. oryzae is known to possess a relatively clean metabolic background with a low level of secondary metabolite production, providing an attractive feature as a heterologous host. Furthermore, unlike prokaryotic and yeast hosts, most coding sequences of fungal biosynthetic proteins can be directly introduced into A. oryzae in their intact form without removing introns, which simplifies the transformation procedures. Collectively, A. oryzae is a robust platform for heterologous production of natural products, which not only facilitates the elucidation of the biosynthetic pathway of a given natural product but also allows the activation of silent or cryptic biosynthetic gene clusters. Thus, the A. oryzae host has been widely utilized for biosynthetic studies, genome mining, and synthetic biology of fungal natural products. It should be noted that more than ten biosynthetic genes can readily be introduced into the fungus, indicating that the majority of fungal biosynthetic gene clusters can be easily transferred to the A. oryzae host. This review first provides the general transformation procedure of A. oryzae and the molecular biological tools available for the fungus. Next, recent successful applications of this fungal host for the heterologous production of natural products are summarized. With the recent rapid advance in molecular biology, such as the development of genome editing tools, we believe that the heterologous expression of biosynthetic genes in A. oryzae will be performed in a much faster and more versatile manner in the near future, which would ultimately lead to the discovery of useful natural products for drug leads and other applications.

Key words: Aspergillus oryzae, heterologous expression, natural products, biosynthesis, synthetic biology

中图分类号:

Q816

董佳钰, 李敏, 肖宗华, 胡明, 松田侑大, 汪伟光. 米曲霉异源表达天然产物研究进展[J]. 合成生物学, 2022, 3(6): 1126-1149.

Jiayu DONG, Min LI, Zonghua XIAO, Ming HU, Yudai MATSUDA, Weiguang WANG. Recent advances in heterologous production of natural products using Aspergillus oryzae[J]. Synthetic Biology Journal, 2022, 3(6): 1126-1149.

图/表 15

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化合物名称和编号	基因来源	表达宿主	参考文献
YWA1 (1)	Aspergillus fumigatus	A. oryzae M-2-3	[39]
2	Phoma sp. C2932	A. oryzae M-2-3	[40]
3,5-dihydroxybenzoic acid (3)	Aspergillus oryzae RIB40	A. oryzae M-2-3	[41]
4	Nectria haematococca mpVI 77-13-4	A. oryzae NSAR1	[42]
anhydromevalonolactone (5)	Xylaria sp. BCC 1067	A. oryzae U1638	[43-44]
betaenone B (6)	Phoma betae Fr.	A. oryzae NSAR1	[45]
2-acetyl-7-methyl-3,6,8-trihydroxynaphthalene (7)	Talaromyces stipitatus ATCC 10500	A. oryzae M-2-3	[46]
8	unidentified fungus ATCC 74256	A. oryzae NSAR1	[47]
citrinin (9)	Monascus ruber M7	A. oryzae NSAR1	[48]
10和11	Arthrinium sp. NF2194	A. oryzae NSAR1	[49]
dalmanol A (12) acetodalmanol A (13)	Daldinia eschscholzii	A. oryzae NSAR1	[50]
(-)-orthosporin (14) (-)-6-hydroxymellein (15)	Menisporopsis theobromae BCC 4162	A. oryzae NSAR1	[51]
benzopyran (16) flaviolin (17)	Cladosporium fulvum	A. oryzae M-2-3	[52]
alternariol (18) alternariol monomethyl ether (19)	Alternaria alternata ATCC 66981	A. oryzae NSAR1	[53]
soppiline C (20)	Penicillium soppi Okera-1	A. oryzae NSAR1	[54]
orsellinic acid (21)	Fusarium sp. NBRC100844	A. oryzae NSAR1	[55]
22-24	Aspergillus terreus	A. oryzae ∆snfA∆SCAP	[56]
strobilurin A (25)	Strobilurus tenacellus	A. oryzae NSAR1	[31]
zopfiellin (26)	Zopfiella curvata No. 37-3	A. oryzae NSAR1	[57]
shimalactone A (27)、shimalactone B (28)	Emericella variecolor GF10	A. oryzae M-2-3	[58]
spirosorbicillinol B (29)	Trichoderma reesei QM6a	A. oryzae NSAR1	[59]
gregatin A (30)	Penicillium sp. sh18	A. oryzae NSAR1	[60]
sporothriolide (31)	Hypomontagnella monticulosa MUCL 54604	A. oryzae NSAR1	[61]
32	Emericella variecolor NBRC 32302	A. oryzae NSAR1	[62]
secalonic acid D (33)	Aspergillus aculeatus CBS 172.66	A. oryzae NSAR1	[33]
TKL (34)	Saccharopolyspora erythraea	A. oryzae NSAR1	[63]

化合物名称和编号	基因来源	表达宿主	参考文献
YWA1 (1)	Aspergillus fumigatus	A. oryzae M-2-3	[39]
2	Phoma sp. C2932	A. oryzae M-2-3	[40]
3,5-dihydroxybenzoic acid (3)	Aspergillus oryzae RIB40	A. oryzae M-2-3	[41]
4	Nectria haematococca mpVI 77-13-4	A. oryzae NSAR1	[42]
anhydromevalonolactone (5)	Xylaria sp. BCC 1067	A. oryzae U1638	[43-44]
betaenone B (6)	Phoma betae Fr.	A. oryzae NSAR1	[45]
2-acetyl-7-methyl-3,6,8-trihydroxynaphthalene (7)	Talaromyces stipitatus ATCC 10500	A. oryzae M-2-3	[46]
8	unidentified fungus ATCC 74256	A. oryzae NSAR1	[47]
citrinin (9)	Monascus ruber M7	A. oryzae NSAR1	[48]
10和11	Arthrinium sp. NF2194	A. oryzae NSAR1	[49]
dalmanol A (12) acetodalmanol A (13)	Daldinia eschscholzii	A. oryzae NSAR1	[50]
(-)-orthosporin (14) (-)-6-hydroxymellein (15)	Menisporopsis theobromae BCC 4162	A. oryzae NSAR1	[51]
benzopyran (16) flaviolin (17)	Cladosporium fulvum	A. oryzae M-2-3	[52]
alternariol (18) alternariol monomethyl ether (19)	Alternaria alternata ATCC 66981	A. oryzae NSAR1	[53]
soppiline C (20)	Penicillium soppi Okera-1	A. oryzae NSAR1	[54]
orsellinic acid (21)	Fusarium sp. NBRC100844	A. oryzae NSAR1	[55]
22-24	Aspergillus terreus	A. oryzae ∆snfA∆SCAP	[56]
strobilurin A (25)	Strobilurus tenacellus	A. oryzae NSAR1	[31]
zopfiellin (26)	Zopfiella curvata No. 37-3	A. oryzae NSAR1	[57]
shimalactone A (27)、shimalactone B (28)	Emericella variecolor GF10	A. oryzae M-2-3	[58]
spirosorbicillinol B (29)	Trichoderma reesei QM6a	A. oryzae NSAR1	[59]
gregatin A (30)	Penicillium sp. sh18	A. oryzae NSAR1	[60]
sporothriolide (31)	Hypomontagnella monticulosa MUCL 54604	A. oryzae NSAR1	[61]
32	Emericella variecolor NBRC 32302	A. oryzae NSAR1	[62]
secalonic acid D (33)	Aspergillus aculeatus CBS 172.66	A. oryzae NSAR1	[33]
TKL (34)	Saccharopolyspora erythraea	A. oryzae NSAR1	[63]

化合物分类	化合物名称和编号	基因来源	表达宿主	参考文献
非核糖体多肽	cycloaspeptide A (35) cycloaspeptide E (36)	Penicillium soppii CBS 869.70	A. oryzae NSAR1	[66]
非核糖体多肽	KK-1 (37)	Curvularia clavata	A. oryzae CNT	[67]
核糖体多肽	ustiloxin B (38)	Aspergillus flavus CA14	A. oryzae NSAR1	[69]
核糖体多肽	asperipin-2a (39)	Aspergillus flavus CA14	A. oryzae NSAR1	[70]
聚酮和非核糖体多肽杂合化合物	cAATrp (40)	Aspergillus flavus NRRL 3357	A. oryzae M-2-3	[73]
	pretenellin A (41)、pretenellin B (42) tenellin (43)	Beauveria bassiana 110.25	A. oryzae M-2-3	[74]
	pretenellin A (41) desmethyl-pretenellin A (44)	Beauveria bassiana 992.05	A. oryzae M-2-3	[75]
	45	Aspergillus clavatus NRRL1	A. oryzae NSAR1	[76]
	aspyridone A (46)	Aspergillus nidulans SB4.1	A. oryzae M-2-3	[77]
	47	Magnaporthe oryzae	A. oryzae M-2-3	[78]
	didymellamide B (48)	Alternaria solani A-17	A. oryzae NSAR1	[79]
	tolypyridone C (49)、tolypyridone D (50)	Tolypocladium sp. 49Y	A. oryzae NSAR1	[80]

化合物分类	化合物名称和编号	基因来源	表达宿主	参考文献
非核糖体多肽	cycloaspeptide A (35) cycloaspeptide E (36)	Penicillium soppii CBS 869.70	A. oryzae NSAR1	[66]
非核糖体多肽	KK-1 (37)	Curvularia clavata	A. oryzae CNT	[67]
核糖体多肽	ustiloxin B (38)	Aspergillus flavus CA14	A. oryzae NSAR1	[69]
核糖体多肽	asperipin-2a (39)	Aspergillus flavus CA14	A. oryzae NSAR1	[70]
聚酮和非核糖体多肽杂合化合物	cAATrp (40)	Aspergillus flavus NRRL 3357	A. oryzae M-2-3	[73]
	pretenellin A (41)、pretenellin B (42) tenellin (43)	Beauveria bassiana 110.25	A. oryzae M-2-3	[74]
	pretenellin A (41) desmethyl-pretenellin A (44)	Beauveria bassiana 992.05	A. oryzae M-2-3	[75]
	45	Aspergillus clavatus NRRL1	A. oryzae NSAR1	[76]
	aspyridone A (46)	Aspergillus nidulans SB4.1	A. oryzae M-2-3	[77]
	47	Magnaporthe oryzae	A. oryzae M-2-3	[78]
	didymellamide B (48)	Alternaria solani A-17	A. oryzae NSAR1	[79]
	tolypyridone C (49)、tolypyridone D (50)	Tolypocladium sp. 49Y	A. oryzae NSAR1	[80]

结构分类	化合物名称和编号	基因来源	表达宿主	参考文献
倍半萜	abscisic acid (51)	Botrytis cinerea SAS56	A. oryzae NSAR1	[92]
	trichobrasilenol (52)	T. atroviride FKI-3849	A. oryzae NSAR1	[93]
	aculene D (53)、asperaculane C(54)、asperaculane D(55)、asperaculane E(56)、asperaculane F(57)、asperaculane G (58)	A. aculeatus ATCC16872	A. oryzae NSAR1	[94]
	brasilane A (59)、brasilane D (60) brasilane E (61)	Annulohypoxylon truncatum CBS 140778	A. oryzae NSAR1	[95]
二萜	aphidicolin (62)	Phoma betae PS-13	A. oryzae NSAR1	[97]
	variediene (63)	Emericella variecolor NBRC 32302	A. oryzae NSAR1	[98]
	pleuromutilin (64)	Clitopilus passeckerianus ATCC 34646	A. oryzae NSAR1	[34]
		Clitopillus pseudo-pinsitus ATCC20527	A. oryzae NSAR1	[29]
		Clitopilus passeckerianus ATCC 34646	A. oryzae NSAR1	[99]
	(+)-copalol (65)	Penicillium verruculosum TPU1311和Penicillium fellutanum ATCC 48694	A. oryzae NSAR1	[100]
	66	Penicillium chrysogenum MT-12	A. oryzae NSAR1	[101]
	brassicicene Ⅰ (67)	Pseudocercospora fijiensis 10CR-1-24	A. oryzae NSAR1	[102]
	erinacine Q (68)	Hericium erinaceus yamabushitake Y2	A. oryzae NSPlD1	[30]
	myrothec-15(17)-en-7-ol (69)	Myrothecium graminearum ZLW0801-19	A. oryzae NSAR1	[103]
二倍半萜	ophiobolin F (70)	Aspergillus clavatus NRRL1	A. oryzae NSAR1	[106]
	ophiobolin F (70)	Aspergillus calidoustus CBS121601	A. oryzae NSAR1	[107]
	stellata-2,6,19-triene (71)	Emericella variecolor NBRC32302	A. oryzae NSAR1	[108]
	astellifadiene (72)	Emericella variecolor NBRC32302	A. oryzae NSAR1	[109]
	quiannulatene (73) quiannulatic acid (74)	Emericella variecolor NBRC32302	A. oryzae NSAR1	[110]
	Bm1 (75)、 Bm3 (76)	Bipolaris maydis ATCC48331	A. oryzae NSAR1	[111]
	Pb1 (77)	Phoma betae PS-13	A. oryzae NSAR1	[111]
	(-)-terpestacin (78)	Bipolaris maydis C5	A. oryzae NSAR1	[112]
	betaestacin Ⅱ (79)	Phoma betae PS-13	A. oryzae NSAR1	[113]
	asperterpenoid A (80)	Talaromyces wortmannii ATCC 26942	A. oryzae NSAR1	[114]
	asperterpenol A(81)、 asperterpenol B (82)	Aspergillus calidoustus CBS121601	A. oryzae NSAR1	[115]
	aspergiltriene A (83) aspergildiene A(84)、aspergildiene B(85)、aspergildiene C(86)、aspergildiene D (87)	Aspergillus ustus 094102	A. oryzae NSAR1	[116]
	fusoxypene A(88)、fusoxypene B(89)、fusoxypene C (90) (-)-astellatene (91)	Fusarium oxysporum FO14005	A. oryzae NSAR1	[117]
	preaspterpenacid I (92)	Aspergillus terreus NIH 2624	A. oryzae NSAR1	[117]
三萜和甾体	helvolic acid (93)	Aspergillus fumigatus Af293	A. oryzae NSAR1	[119]
	94	Nodulisporium sp. (no. 65-17-2-1)	A. oryzae NSAR1	[120]
	fusidic acid (95)	Acremonium fusidioides ATCC 14700	A. oryzae NSAR1	[121]
	96	Thanatephorus cucumeris NBRC 6298	A. oryzae NSAR1	[122]
	cephalosporin P₁ (97)	Acremonium chrysogenum ATCC 11550	A. oryzae NSAR1	[123]

米曲霉异源表达天然产物研究进展

Recent advances in heterologous production of natural products using Aspergillus oryzae

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化合物分类	化合物名称和编号	基因来源	表达宿主	参考文献
Ⅰ型萜烯环化酶（聚酮杂萜）	xenovulene A (98)	Acremonium strictum IMI 501407	A. oryzae NSAR1	[125]
Ⅰ型萜烯环化酶（聚酮杂萜）	xenovulene B (99)	Acremonium strictum IMI 501407	A. oryzae NSAR1	[126]
Ⅱ型萜烯环化酶 (聚酮杂萜)	deacetyl-pyripyropene E (100)	Aspergillus fumigatus FO-1289	A. oryzae M-2-3	[127]
	11-deacetyl-pyripyropene O (101) deacetyl-pyripyropene A (102)	Penicillium coprobium PF1169	A. oryzae HL-1105	[128]
	pyripyropene A (103)	Penicillium coprobium PF1169	A. oryzae HL-1105	[129]
	andrastin A (104)	Penicillium chrysogenum NBRC 32030	A. oryzae NSAR1	[130]
	preaustinoid A3 (105)	Aspergillus nidulans FGSC A4	A. oryzae NSAR1	[131]
	anditomin (106)	Emericella variecolor NBRC 32302	A. oryzae NSAR1	[26]
	terretonin (107)	Aspergillus terreus NIH 2624	A. oryzae NSAR1	[132]
	citreohybridonol (108)	Emericella variecolor NBRC 32302	A. oryzae NSAR1	[133]
	berkeleydione (109)	Penicillium brasilianum NBRC 6234	A. oryzae NSAR1	[134]
	novofumigatonin (110)	Aspergillus novofumigatus IBT 16806	A. oryzae NSAR1	[135]
	chrodrimanin B (111)	Penicillium verruculosum TPU1311	A. oryzae NSAR1	[136]
	chevalone E (112) sartorypyrone D (113)	Aspergillus versicolor 0312 Aspergillus felis 0260	A. oryzae NSAR1	[137-138]
	114	Fusarium graminearum PH-1	A. oryzae NSAR1	[139]
	andiconin B (115) andiconin D (116)	Aspergillus sp. TJ23	A. oryzae NSAR1	[140]
	funiculolide A、funiculolide B、 funiculolide C、funiculolide D (117～120)	Aspergillus funiculosus CBS 116.56	A. oryzae NSAR1	[141]
	setosusin (121)	Aspergillus duricaulis CBS 481.65	A. oryzae NSAR1	[35]
Ⅱ型萜烯环化酶 (吲哚类杂萜）	paxilline (122)	Penicillium paxilli	A. oryzae NSAR1	[142]
	aflatrem (123) β-aflatrem (124)	Aspergillus flavus NBRC 4295	A. oryzae NSAR1	[28]
	penitrem A (125)	Penicillium simplicissimum AK-40	A. oryzae NSAR1	[143]
	shearinine D (126)	Penicillium janthinellum PN2408	A. oryzae NSAR1	[144]
	sespendole (127)	Pseudobotrytis terrestris FKA-25	A. oryzae NSAR1	[145]
	lolitrem B (128)	Epichloë festucae var. loll	A. oryzae NSPlD1	[146]
其他类型杂萜	LL-Z1272β (129)	Stachybotrys bisbyi PYH05-7	A. oryzae NSAR1	[147]
	daurichromenic acid (130)	Rhododendron dauricum	A. oryzae NSAR1	[148]
	5-chlorodaurichromenic acid (131)	Fusarium sp. NBRC100844	A. oryzae NSAR1	[148]
	ilicicolin A、 ilicicolin B (132和133)	Acremonium egyptiacum F-1392	A. oryzae NSAR1	[149]
	biscognienyne B (134)	Biscogniauxia sp. (71-10-1-1)	A. oryzae NSAR1	[150]

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