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Article(id=1226136789795127618, tenantId=1146029695717560320, journalId=1192105938417971205, issueId=1226136782408954119, articleNumber=null, orderNo=null, doi=10.13343/j.cnki.wsxb.20250674, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1756828800000, receivedDateStr=2025-09-03, revisedDate=null, revisedDateStr=null, acceptedDate=1761580800000, acceptedDateStr=2025-10-28, onlineDate=1770263391207, onlineDateStr=2026-02-05, pubDate=1770134400000, pubDateStr=2026-02-04, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1770263391207, onlineIssueDateStr=2026-02-05, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1770263391207, creator=13701087609, updateTime=1770263391207, updator=13701087609, issue=Issue{id=1226136782408954119, tenantId=1146029695717560320, journalId=1192105938417971205, year='2026', volume='66', issue='2', pageStart='481', pageEnd='955', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1770263389446, creator=13701087609, updateTime=1770268138976, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1226156703490683529, tenantId=1146029695717560320, journalId=1192105938417971205, issueId=1226136782408954119, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1226156703490683530, tenantId=1146029695717560320, journalId=1192105938417971205, issueId=1226136782408954119, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=830, endPage=849, ext={EN=ArticleExt(id=1226136790239723868, articleId=1226136789795127618, tenantId=1146029695717560320, journalId=1192105938417971205, language=EN, title=Transcriptomics analysis of the mechanisms underlying citric acid/malic acid synthesis in Aspergillus niger, columnId=1192149543992045670, journalTitle=Acta Microbiologica Sinica, columnName=Research Article, runingTitle=null, highlight=null, articleAbstract=

[Objective] Citric acid is the main metabolite of Aspergillus niger at pH≤5.0, while l-malic acid becomes the main metabolite at pH 6.0. In this study, we employed transcriptomics to analyze the differences in the expression of key genes in metabolic pathways, aiming to explore the biosynthesis mechanisms of the two organic acids. [Methods] The cells at 48 h and 72 h of the fermentation processes for citric acid and l-malic acid production were selected for transcriptomics analysis. [Results] The transcriptome data of 72 h and 48 h were compared. GO enrichment analysis showed that the upregulated genes related to the synthesis of citric acid were concentrated in carbohydrate metabolism, while those related to the synthesis of l-malic acid were concentrated in ion transport process. The acid protease genes ANI_1_62014 (aspergillin II) and ANI_1_654124 (aspartic protease pepA) showed extremely high transcription levels during citric acid synthesis, while the key genes ANI_1_2494074 [3-oxoacyl-(acyl carrier protein) synthase] and ANI_1_2488074 (biosynthetic fatty acid synthase subunit β) essential for fatty acid chain synthesis showed extremely high transcription levels in the l-malic acid synthesis pathway. The transcription level of zinc cluster transcription factor [Zn(II)2Cys6 transcription factor] was higher in the synthesis process of l-malic acid. HacA, AP-1, and AtfA in the bZIP family showed higher transcriptional levels in response to environmental low pH stress during citric acid synthesis. Compared with l-malic acid synthesis, citric acid synthesis was accompanied by upregulated transcription levels of ANI_1_66114 (hexokinase), ANI_1_2950014 (citrate synthase), and ANI_1_478154 (citrate transporter) and a downregulated transcription level of ANI_1_3136024 (isocitrate dehydrogenase). Efficient glycolysis, citric acid synthesis, and citric acid transport capacity and low isocitrate dehydrogenase level were the key factors for citric acid production. In the process of l-malic acid synthesis, cytoplasmic ANI_1_440184 (pyruvate carboxylase), cytoplasmic ANI_1_12134 (malate dehydrogenase), ANI_1_914104 (isocitrate lyase), and ANI_1_2040144 (malate transporter) showed upregulated transcriptional levels. The cytoplasmic rTCA pathway and glyoxylic acid carboxylation pathway were thereby determined to be the main pathways for l-malic acid synthesis. [Conclusion] This study inferred the key differential metabolic pathways for the production of citric acid and l-malic acid by analyzing integrated transcriptomic data, and screened significant differentially expressed core genes, transcription factors, and potential transporters. These results provide important clues and a theoretical basis for elucidating the regulatory mechanisms of citric acid and l-malic acid synthesis.

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E-mail:
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【目的】 黑曲霉在pH≤5.0的条件下柠檬酸是主要代谢物，而在pH 6.0时l-苹果酸成为主要代谢物。通过转录组学分析代谢途径中关键基因的差异性，探究2种有机酸的生物合成机制。 【方法】 分别选取柠檬酸和l-苹果酸发酵过程48 h和72 h的菌体进行转录组学分析。 【结果】 转录组比较分析(72 h vs. 48 h)发现，GO富集分析结果显示合成柠檬酸的相关上调基因集中于碳水化合物代谢过程，而合成l-苹果酸的相关上调基因集中于离子转运过程。酸性蛋白水解酶ANI_1_62014 (曲霉菌素II)和ANI_1_654124 (天冬氨酸蛋白酶曲pepA)在柠檬酸合成过程中呈现极高的转录水平，而合成脂肪酸链的关键基因ANI_1_2494074 [3-氧酰基-(酰基载体蛋白)合酶]和ANI_1_2488074 (生物合成脂肪酸合酶亚基β)在l-苹果酸合成途径中呈现极高的转录水平；锌簇类转录因子[Zn(II)2 Cys6 transcription factor]在l-苹果酸合成过程中的转录水平更高；bZIP家族中的HacA、AP-1和AtfA在柠檬酸合成过程中呈现更高的转录水平，以应对环境低pH的抗逆性；与l-苹果酸发酵过程相比，柠檬酸发酵过程中ANI_1_66114 (己糖激酶)、ANI_1_2950014 (柠檬酸合酶)和ANI_1_478154 (柠檬酸转运蛋白)或ANI_1_3136024 (异柠檬酸脱氢酶)分别呈现较高或较低的转录水平。高效的糖酵解、柠檬酸合成和柠檬酸转运能力以及低异柠檬酸脱氢酶水平是柠檬酸大量生成的关键因素。在l-苹果酸发酵过程中，胞质ANI_1_440184 (丙酮酸羧化酶)、胞质ANI_1_12134 (苹果酸脱氢酶)、ANI_1_914104 (异柠檬酸裂解酶)和ANI_1_2040144 (苹果酸转运蛋白)呈现较高的转录水平，表明胞质rTCA途径和乙醛酸羧化途径是l-苹果酸合成的主要途径。 【结论】 本研究通过分析整合转录组数据，推测了生成柠檬酸和l-苹果酸的关键差异代谢通路，并筛选出显著差异表达的核心基因、转录因子及潜在转运蛋白。这些结果为解析柠檬酸与l-苹果酸合成的调控机制提供了重要线索和理论依据。

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作者贡献声明

蔺旭刚：实验操作、数据分析、撰写文章；苏佳：样品采集、实验操作；柴庆江：数据采集；刘贵玉：30 L发酵罐实验操作；相胜昌：30 L发酵罐数据收集；王德培：研究构思和设计；薛鲜丽：研究构思和设计，论文审阅和修改。

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Biotechnology Journal, 2024, 19(5): 2400014., articleTitle=Metabolic engineering of Aspergillus niger for accelerated malic acid biosynthesis by improving NADPH availability, refAbstract=null)], funds=[Fund(id=1226195563834684105, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1226136789795127618, awardId=2021YFC1808901, language=EN, fundingSource=the National Key Research and Development Program of China(2021YFC1808901), fundOrder=null, country=null), Fund(id=1226195563985679057, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1226136789795127618, awardId=2021YFC1808901, language=CN, fundingSource=国家重点研发计划(2021YFC1808901), fundOrder=null, country=null), Fund(id=1226195564115702488, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1226136789795127618, awardId=32400033, language=EN, fundingSource=the National Natural Science Foundation of China(32400033), fundOrder=null, country=null), Fund(id=1226195564233143006, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1226136789795127618, awardId=32400033, language=CN, fundingSource=国家自然科学基金(32400033), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1226195552719778038, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1226136789795127618, xref=1., ext=[AuthorCompanyExt(id=1226195552728166647, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1226136789795127618, companyId=1226195552719778038, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1.College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China), AuthorCompanyExt(id=1226195552736555256, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1226136789795127618, companyId=1226195552719778038, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1.天津科技大学 生物工程学院，天津)]), AuthorCompany(id=1226195552845607169, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1226136789795127618, xref=2., ext=[AuthorCompanyExt(id=1226195552858190082, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1226136789795127618, companyId=1226195552845607169, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2.RZBC Group Co. , Ltd. , Rizhao, Shandong, China), AuthorCompanyExt(id=1226195553097265428, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1226136789795127618, companyId=1226195552845607169, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2.山东日照金禾博源生化有限公司，山东 日照)]), AuthorCompany(id=1226195553197928732, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1226136789795127618, xref=3., ext=[AuthorCompanyExt(id=1226195553206317342, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1226136789795127618, companyId=1226195553197928732, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=3.Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin, China), AuthorCompanyExt(id=1226195553210511648, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1226136789795127618, companyId=1226195553197928732, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=3.工业发酵微生物教育部重点实验室，天津)])], figs=[ArticleFig(id=1226195560378577485, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1226136789795127618, language=EN, label=Figure 1, caption=Acid production by Aspergillus niger under different pH conditions. A: Schematic diagram of acid production in Aspergillus niger fermentation tank under different pH conditions; B: Fermentation to produce citric acid; C: Fermentation to produce l-malic acid., figureFileSmall=ebRVe3gUhlWX6AiP6j4+zQ==, figureFileBig=vn+8lQp2+Sa3gvnfz5Bpww==, tableContent=null), ArticleFig(id=1226195560508600917, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1226136789795127618, language=CN, label=图1, caption=黑曲霉在不同pH下产酸分析。A：不同pH条件下黑曲霉发酵罐产酸示意图；B：发酵生产柠檬酸；C：发酵生产l-苹果酸。, figureFileSmall=ebRVe3gUhlWX6AiP6j4+zQ==, figureFileBig=vn+8lQp2+Sa3gvnfz5Bpww==, tableContent=null), ArticleFig(id=1226195560638624348, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1226136789795127618, language=EN, label=Figure 2, caption=Screening of differentially expressed genes for the generation of citric acid and l-malic acid in MA-1. A: CA 72 h vs. CA 48 h volcano map; B: MA 72 h vs. MA 48 h volcano map; C: Scatter plot of GO enrichment analysis of CA 72 h vs. CA 48 h up-regulated gene; D: MA 72 h vs. MA 48 h up-regulated gene GO enrichment analysis scatter plot; E: Scatter plot of GO enrichment analysis of CA 72 h vs. CA 48 h down-regulated gene; F: MA 72 h vs. MA 48 h down-regulated gene GO enrichment analysis scatter plot., figureFileSmall=wYZ1MTEL/9hixXi6MyKw+w==, figureFileBig=M7X8IHQqv327juycG8EF3w==, tableContent=null), ArticleFig(id=1226195560789619301, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1226136789795127618, language=CN, label=图2, caption=MA-1生成柠檬酸和 l-苹果酸差异表达基因筛选。A：CA 72 h vs. CA 48 h火山图；B：MA 72 h vs. MA 48 h火山图；C：CA 72 h vs. CA 48 h上调基因GO富集分析散点图；D：MA 72 h vs. MA 48 h上调基因GO富集分析散点图；E：CA 72 h vs. CA 48 h下调基因GO富集分析散点图；F：MA 72 h vs. MA 48 h下调基因GO富集分析散点图。, figureFileSmall=wYZ1MTEL/9hixXi6MyKw+w==, figureFileBig=M7X8IHQqv327juycG8EF3w==, tableContent=null), ArticleFig(id=1226195560911254128, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1226136789795127618, language=EN, label=Figure 3, caption=Identification and functional enrichment analysis of differentially expressed genes. A: Venn diagram of CA and MA co-expression differential genes; B: Heatmap of 1 882 genes uniquely present in CA 72 h vs. MA 72 h compared with CA 48 h vs. MA 48 h; C: Up-regulated genes in CA vs. MA among 1 882 genes; D: Up-regulated genes in MA vs. CA among 1 882 genes., figureFileSmall=38z2bxZbFuPYIXN12VT15A==, figureFileBig=KQXSAcX6+14EtVNjBmTrEw==, tableContent=null), ArticleFig(id=1226195561049666173, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1226136789795127618, language=CN, label=图3, caption=差异基因的筛选与功能富集分析。A：CA及MA共表达差异基因韦恩图；B：CA 72 h vs. MA 72 h与CA 48 h vs. MA 48 h中单独存在的1 882个基因聚的类热图；C：1 882个基因中CA vs. MA上调基因；D：1 882个基因中MA vs. CA上调基因。, figureFileSmall=38z2bxZbFuPYIXN12VT15A==, figureFileBig=KQXSAcX6+14EtVNjBmTrEw==, tableContent=null), ArticleFig(id=1226195561171300994, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1226136789795127618, language=EN, label=Figure 4, caption=Transporter gene expression analysis. A: Upward and down-regulated map of citric acid 72 h vs. 48 h gene; B: Upward and down-regulated map of malic acid 72 h vs. 48 h gene; C: Upward and down-regulated map of citric acid 48 h vs. malic acid 48 h gene; D: Upward and down-regulated map of citric acid 72 h vs. malic acid 72 h gene. Red indicates an upward, and green indicates a downward., figureFileSmall=d7f4vPa5k6s+PBLkzxODXg==, figureFileBig=O1rI1Z/f1eV8xXmSQEq1Qg==, tableContent=null), ArticleFig(id=1226195561276158602, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1226136789795127618, language=CN, label=图4, caption=转运蛋白基因表达分析。A：柠檬酸72 h vs. 48 h基因上下调图；B：苹果酸72 h vs. 48 h基因上下调图；C：柠檬酸48 h vs.苹果酸48 h基因上下调图；D：柠檬酸72 h vs.苹果酸72 h基因上下调图。红色表示上调，绿色表示下调。, figureFileSmall=d7f4vPa5k6s+PBLkzxODXg==, figureFileBig=O1rI1Z/f1eV8xXmSQEq1Qg==, tableContent=null), ArticleFig(id=1226195561368433297, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1226136789795127618, language=EN, label=Figure 5, caption=Diagram of citric acid and l-malic acid metabolism pathways in Aspergillus niger., figureFileSmall=uoSQEAeonCpIs8k5mCZlFA==, figureFileBig=KSN6dWYT8PWRNhog02qsSA==, tableContent=null), ArticleFig(id=1226195561498456727, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1226136789795127618, language=CN, label=图5, caption=黑曲霉中柠檬酸及 l-苹果酸代谢通路图, figureFileSmall=uoSQEAeonCpIs8k5mCZlFA==, figureFileBig=KSN6dWYT8PWRNhog02qsSA==, tableContent=null), ArticleFig(id=1226195561624285853, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1226136789795127618, language=EN, label=Figure 6, caption=Relative expression levels of key genes. A: Expression levels of pyruvate carboxylase gene (pc) under citric acid and l-malic acid fermentation conditions; B: Expression levels of phosphofructokinase gene (pfk) under citric acid and l-malic acid fermentation conditions; C: Expression levels of hexokinase gene (hk) under citric acid and l-malic acid fermentation conditions., figureFileSmall=R4qHQHVuudO4uCEfPR2qIw==, figureFileBig=7ieuzMOXh1W+jn1oi0JovQ==, tableContent=null), ArticleFig(id=1226195561754309283, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1226136789795127618, language=CN, label=图6, caption=关键基因相对表达水平。A：丙酮酸羧化酶基因(pc)在柠檬酸和l-苹果酸发酵条件的表达水平；B：磷酸果糖激酶基因(pfk)在柠檬酸和l-苹果酸发酵条件的表达水平；C：己糖激酶基因(hk)在柠檬酸和l-苹果酸发酵条件的表达水平。, figureFileSmall=R4qHQHVuudO4uCEfPR2qIw==, figureFileBig=7ieuzMOXh1W+jn1oi0JovQ==, tableContent=null), ArticleFig(id=1226195561884332715, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1226136789795127618, language=EN, label=Table 1, caption=

Differentially expressed genes with high transcription levels

, figureFileSmall=null, figureFileBig=null, tableContent=
Gene IDEnzymeCA_48 hCA_72 hMA_48 hMA_72 h
Gene_ANI_1_62014Aspergillopepsin-2 heavy chain228 937.47249 619.9312.6627.80
Gene_ANI_1_654124Aspergillopepsin A-like aspartic endopeptidase86 825.0083 638.031 234.544 257.54
Gene_ANI_1_600841,3-beta-glucanosyltransferase gel373 748.5962 221.1439.94127.70
Gene_ANI_1_1216074Glutamate decarboxylase 167 498.1167 044.691 553.173 732.30
Gene_ANI_1_842034NACHT domain protein37 477.8365 571.05393.65536.57
Gene_ANI_1_24940743-oxoacyl-(acyl-carrier-protein) synthase413.01244.47187 963.84353 495.89
Gene_ANI_1_2488074Sterigmatocystin biosynthesis fatty acid synthase subunit beta111.4681.49102 257.86215 059.69
Gene_ANI_1_228094Thiazole biosynthetic enzyme8 059.7917 241.3994 236.72125 175.39
Gene_ANI_1_1450024Protein NMT12 070.242 766.8574 763.6386 823.48
Gene_ANI_1_1474074Citrate synthase/Citrate lyase62.2199.9232 971.2670 840.69
), ArticleFig(id=1226195562022744752, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1226136789795127618, language=CN, label=表1, caption=

高转录水平的差异表达基因

, figureFileSmall=null, figureFileBig=null, tableContent=
Gene IDEnzymeCA_48 hCA_72 hMA_48 hMA_72 h
Gene_ANI_1_62014Aspergillopepsin-2 heavy chain228 937.47249 619.9312.6627.80
Gene_ANI_1_654124Aspergillopepsin A-like aspartic endopeptidase86 825.0083 638.031 234.544 257.54
Gene_ANI_1_600841,3-beta-glucanosyltransferase gel373 748.5962 221.1439.94127.70
Gene_ANI_1_1216074Glutamate decarboxylase 167 498.1167 044.691 553.173 732.30
Gene_ANI_1_842034NACHT domain protein37 477.8365 571.05393.65536.57
Gene_ANI_1_24940743-oxoacyl-(acyl-carrier-protein) synthase413.01244.47187 963.84353 495.89
Gene_ANI_1_2488074Sterigmatocystin biosynthesis fatty acid synthase subunit beta111.4681.49102 257.86215 059.69
Gene_ANI_1_228094Thiazole biosynthetic enzyme8 059.7917 241.3994 236.72125 175.39
Gene_ANI_1_1450024Protein NMT12 070.242 766.8574 763.6386 823.48
Gene_ANI_1_1474074Citrate synthase/Citrate lyase62.2199.9232 971.2670 840.69
), ArticleFig(id=1226195562127602355, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1226136789795127618, language=EN, label=Table 2, caption=

Analysis of FPKM values of transcription factor-related genes

, figureFileSmall=null, figureFileBig=null, tableContent=
Gene IDEnzymeMA_48 hMA_72 hCA_48 hCA_72 h
ANI_1_970074C2H2 transcription factor (Rpn4)91 677.0041 274.72134 237.58137 449.00
ANI_1_1316094Mediator of RNA polymerase II transcription subunit 1239 302.8132 962.523 968.544 951.61
ANI_1_24014bZIP transcription factor HacA33 577.3224 761.5424 315.0035 481.06
ANI_1_1416094Zn(II)2Cys6 transcription factor24 636.3629 725.5912 760.1711 600.97
ANI_1_290144C2H2 transcription factor (Ace1)23 687.3120 181.6323 675.6122 748.90
ANI_1_1178184C6 transcription factor NosA17 919.9212 207.2319 796.0619 188.47
ANI_1_1026094bZIP transcription factor (AP-1)13 887.9110 572.807 696.888 660.47
ANI_1_730184C2H2 transcription factor (Seb1)13 314.0017 020.9214 261.0118 201.83
ANI_1_1080184Homeobox transcription factor (RfeB)11 830.9812 442.0414 062.2811 977.39
ANI_1_846074C2H2 transcription factor8 893.214 503.699 930.439 098.97
ANI_1_2590024C2H2 transcription factor (RfeC)8 559.977 647.937 040.215 571.53
ANI_1_654034HLH transcription factor7 843.806 471.805 973.984 623.70
ANI_1_562114Zn(II)2Cys6 transcription factor7 455.024 809.563 187.453 884.45
ANI_1_54104mRNA binding post-transcriptional regulator (Csx1)7 018.496 723.0913 788.3810 213.67
ANI_1_512064Transcription factor RfeG7 008.753 876.485 717.365 076.76
ANI_1_1970064Fungal specific transcription factor domain protein6 760.285 179.293 825.975 603.55
ANI_1_2310024Transcriptional regulator Medusa6 692.073 762.176 844.074 793.48
ANI_1_208074HLH transcription factor (GlcD gamma)6 580.995 061.885 302.628 902.03
ANI_1_1974074Jumonji family transcription factor6 575.156 132.962 881.582 467.07
ANI_1_26134Transcriptional repressor rco-16 167.865 759.126 800.016 668.76
ANI_1_2604024Transcription initiation factor IIB6 155.195 024.813 434.567 911.52
ANI_1_974024bZIP transcription factor (AtfA)6 082.115 762.214 255.405 859.66
ANI_1_3244014C6 transcription factor5 981.756 162.833 487.273 986.32
ANI_1_1318164Zn(II)2Cys6 transcription factor5 903.805 678.784 121.483 493.48
ANI_1_578144ccr4-Not transcription complex subunit (NOT1)5 868.726 643.796 809.517 328.46
), ArticleFig(id=1226195562278597306, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1226136789795127618, language=CN, label=表2, caption=

转录因子相关基因FPKM值分析

, figureFileSmall=null, figureFileBig=null, tableContent=
Gene IDEnzymeMA_48 hMA_72 hCA_48 hCA_72 h
ANI_1_970074C2H2 transcription factor (Rpn4)91 677.0041 274.72134 237.58137 449.00
ANI_1_1316094Mediator of RNA polymerase II transcription subunit 1239 302.8132 962.523 968.544 951.61
ANI_1_24014bZIP transcription factor HacA33 577.3224 761.5424 315.0035 481.06
ANI_1_1416094Zn(II)2Cys6 transcription factor24 636.3629 725.5912 760.1711 600.97
ANI_1_290144C2H2 transcription factor (Ace1)23 687.3120 181.6323 675.6122 748.90
ANI_1_1178184C6 transcription factor NosA17 919.9212 207.2319 796.0619 188.47
ANI_1_1026094bZIP transcription factor (AP-1)13 887.9110 572.807 696.888 660.47
ANI_1_730184C2H2 transcription factor (Seb1)13 314.0017 020.9214 261.0118 201.83
ANI_1_1080184Homeobox transcription factor (RfeB)11 830.9812 442.0414 062.2811 977.39
ANI_1_846074C2H2 transcription factor8 893.214 503.699 930.439 098.97
ANI_1_2590024C2H2 transcription factor (RfeC)8 559.977 647.937 040.215 571.53
ANI_1_654034HLH transcription factor7 843.806 471.805 973.984 623.70
ANI_1_562114Zn(II)2Cys6 transcription factor7 455.024 809.563 187.453 884.45
ANI_1_54104mRNA binding post-transcriptional regulator (Csx1)7 018.496 723.0913 788.3810 213.67
ANI_1_512064Transcription factor RfeG7 008.753 876.485 717.365 076.76
ANI_1_1970064Fungal specific transcription factor domain protein6 760.285 179.293 825.975 603.55
ANI_1_2310024Transcriptional regulator Medusa6 692.073 762.176 844.074 793.48
ANI_1_208074HLH transcription factor (GlcD gamma)6 580.995 061.885 302.628 902.03
ANI_1_1974074Jumonji family transcription factor6 575.156 132.962 881.582 467.07
ANI_1_26134Transcriptional repressor rco-16 167.865 759.126 800.016 668.76
ANI_1_2604024Transcription initiation factor IIB6 155.195 024.813 434.567 911.52
ANI_1_974024bZIP transcription factor (AtfA)6 082.115 762.214 255.405 859.66
ANI_1_3244014C6 transcription factor5 981.756 162.833 487.273 986.32
ANI_1_1318164Zn(II)2Cys6 transcription factor5 903.805 678.784 121.483 493.48
ANI_1_578144ccr4-Not transcription complex subunit (NOT1)5 868.726 643.796 809.517 328.46
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基于转录组学解析黑曲霉柠檬酸/苹果酸合成代谢机制
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蔺旭刚 1 , 苏佳 1 , 柴庆江 1 , 刘贵玉 2 , 相胜昌 2 , 王德培 1, 3 , 薛鲜丽 1, 3
微生物学报 | 研究报告 2026,66(2): 830-849
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微生物学报 | 研究报告 2026, 66(2): 830-849
基于转录组学解析黑曲霉柠檬酸/苹果酸合成代谢机制
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蔺旭刚1, 苏佳1, 柴庆江1, 刘贵玉2, 相胜昌2, 王德培1, 3, 薛鲜丽1, 3
作者信息
  • 1.天津科技大学 生物工程学院，天津
  • 2.山东日照金禾博源生化有限公司，山东 日照
  • 3.工业发酵微生物教育部重点实验室，天津
Transcriptomics analysis of the mechanisms underlying citric acid/malic acid synthesis in Aspergillus niger
Xugang LIN1, Jia SU1, Qingjiang CHAI1, Guiyu LIU2, Shengchang XIANG2, Depei WANG1, 3, Xianli XUE1, 3
Affiliations
  • 1.College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China
  • 2.RZBC Group Co. , Ltd. , Rizhao, Shandong, China
  • 3.Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin, China
出版时间: 2026-02-04 doi: 10.13343/j.cnki.wsxb.20250674
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摘要
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【目的】 黑曲霉在pH≤5.0的条件下柠檬酸是主要代谢物，而在pH 6.0时l-苹果酸成为主要代谢物。通过转录组学分析代谢途径中关键基因的差异性，探究2种有机酸的生物合成机制。 【方法】 分别选取柠檬酸和l-苹果酸发酵过程48 h和72 h的菌体进行转录组学分析。 【结果】 转录组比较分析(72 h vs. 48 h)发现，GO富集分析结果显示合成柠檬酸的相关上调基因集中于碳水化合物代谢过程，而合成l-苹果酸的相关上调基因集中于离子转运过程。酸性蛋白水解酶ANI_1_62014 (曲霉菌素II)和ANI_1_654124 (天冬氨酸蛋白酶曲pepA)在柠檬酸合成过程中呈现极高的转录水平，而合成脂肪酸链的关键基因ANI_1_2494074 [3-氧酰基-(酰基载体蛋白)合酶]和ANI_1_2488074 (生物合成脂肪酸合酶亚基β)在l-苹果酸合成途径中呈现极高的转录水平；锌簇类转录因子[Zn(II)2 Cys6 transcription factor]在l-苹果酸合成过程中的转录水平更高；bZIP家族中的HacA、AP-1和AtfA在柠檬酸合成过程中呈现更高的转录水平，以应对环境低pH的抗逆性；与l-苹果酸发酵过程相比，柠檬酸发酵过程中ANI_1_66114 (己糖激酶)、ANI_1_2950014 (柠檬酸合酶)和ANI_1_478154 (柠檬酸转运蛋白)或ANI_1_3136024 (异柠檬酸脱氢酶)分别呈现较高或较低的转录水平。高效的糖酵解、柠檬酸合成和柠檬酸转运能力以及低异柠檬酸脱氢酶水平是柠檬酸大量生成的关键因素。在l-苹果酸发酵过程中，胞质ANI_1_440184 (丙酮酸羧化酶)、胞质ANI_1_12134 (苹果酸脱氢酶)、ANI_1_914104 (异柠檬酸裂解酶)和ANI_1_2040144 (苹果酸转运蛋白)呈现较高的转录水平，表明胞质rTCA途径和乙醛酸羧化途径是l-苹果酸合成的主要途径。 【结论】 本研究通过分析整合转录组数据，推测了生成柠檬酸和l-苹果酸的关键差异代谢通路，并筛选出显著差异表达的核心基因、转录因子及潜在转运蛋白。这些结果为解析柠檬酸与l-苹果酸合成的调控机制提供了重要线索和理论依据。

黑曲霉  /  柠檬酸  /  l-苹果酸  /  转录组  /  差异基因

[Objective] Citric acid is the main metabolite of Aspergillus niger at pH≤5.0, while l-malic acid becomes the main metabolite at pH 6.0. In this study, we employed transcriptomics to analyze the differences in the expression of key genes in metabolic pathways, aiming to explore the biosynthesis mechanisms of the two organic acids. [Methods] The cells at 48 h and 72 h of the fermentation processes for citric acid and l-malic acid production were selected for transcriptomics analysis. [Results] The transcriptome data of 72 h and 48 h were compared. GO enrichment analysis showed that the upregulated genes related to the synthesis of citric acid were concentrated in carbohydrate metabolism, while those related to the synthesis of l-malic acid were concentrated in ion transport process. The acid protease genes ANI_1_62014 (aspergillin II) and ANI_1_654124 (aspartic protease pepA) showed extremely high transcription levels during citric acid synthesis, while the key genes ANI_1_2494074 [3-oxoacyl-(acyl carrier protein) synthase] and ANI_1_2488074 (biosynthetic fatty acid synthase subunit β) essential for fatty acid chain synthesis showed extremely high transcription levels in the l-malic acid synthesis pathway. The transcription level of zinc cluster transcription factor [Zn(II)2Cys6 transcription factor] was higher in the synthesis process of l-malic acid. HacA, AP-1, and AtfA in the bZIP family showed higher transcriptional levels in response to environmental low pH stress during citric acid synthesis. Compared with l-malic acid synthesis, citric acid synthesis was accompanied by upregulated transcription levels of ANI_1_66114 (hexokinase), ANI_1_2950014 (citrate synthase), and ANI_1_478154 (citrate transporter) and a downregulated transcription level of ANI_1_3136024 (isocitrate dehydrogenase). Efficient glycolysis, citric acid synthesis, and citric acid transport capacity and low isocitrate dehydrogenase level were the key factors for citric acid production. In the process of l-malic acid synthesis, cytoplasmic ANI_1_440184 (pyruvate carboxylase), cytoplasmic ANI_1_12134 (malate dehydrogenase), ANI_1_914104 (isocitrate lyase), and ANI_1_2040144 (malate transporter) showed upregulated transcriptional levels. The cytoplasmic rTCA pathway and glyoxylic acid carboxylation pathway were thereby determined to be the main pathways for l-malic acid synthesis. [Conclusion] This study inferred the key differential metabolic pathways for the production of citric acid and l-malic acid by analyzing integrated transcriptomic data, and screened significant differentially expressed core genes, transcription factors, and potential transporters. These results provide important clues and a theoretical basis for elucidating the regulatory mechanisms of citric acid and l-malic acid synthesis.

Aspergillus niger  /  citric acid  /  l-malic acid  /  transcriptome  /  differentially expressed genes
蔺旭刚, 苏佳, 柴庆江, 刘贵玉, 相胜昌, 王德培, 薛鲜丽. 基于转录组学解析黑曲霉柠檬酸/苹果酸合成代谢机制. 微生物学报, 2026 , 66 (2) : 830 -849 . DOI: 10.13343/j.cnki.wsxb.20250674
Xugang LIN, Jia SU, Qingjiang CHAI, Guiyu LIU, Shengchang XIANG, Depei WANG, Xianli XUE. Transcriptomics analysis of the mechanisms underlying citric acid/malic acid synthesis in Aspergillus niger[J]. Acta Microbiologica Sinica, 2026 , 66 (2) : 830 -849 . DOI: 10.13343/j.cnki.wsxb.20250674
正文
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有机酸是一类分子结构中含有羧基(-COOH)的酸性有机化合物，广泛应用于食品、医药、化工、农业等领域[1]。其中，柠檬酸和l-苹果酸作为重要的有机酸，在食品、饮料及医药领域的需求量逐年递增，中国是全球最大的柠檬酸生产国，产能占比达70%以上，而l-苹果酸的主要生产国为美国和日本[2]。在能量饮料应用方面，柠檬酸和l-苹果酸混合使用可优化风味，其复配需求在逐年上升[3]。随着环境问题日益严峻，生物发酵成为生产有机酸最理想的方法，其中工业生产柠檬酸和l-苹果酸所选用的菌株均为黑曲霉，但l-苹果酸的工业化进程较为困难，这限制了其大规模工业生产[4]。
黑曲霉(Aspergillus niger)是一种在自然界中广泛存在的半知菌亚门丝孢纲目曲霉属真菌，已被美国食品药品监督管理局认证为食品级安全菌种(generally recognized as safe)[5]，是工业发酵生产柠檬酸、苹果酸等有机酸的主要菌株[6]。黑曲霉菌株生长繁殖迅速，对胁迫条件(如低pH、高糖和高渗透压等)具有较高的耐受性，发酵周期短且不产生毒素。凭借其高遗传稳定性、高产酸水平、低成本等优势，黑曲霉被认为是生产有机酸(如琥珀酸、葡萄糖酸、乌头酸、衣康酸等)的最佳底盘细胞[7]。
随着基因工程技术、基因编辑技术、转录组及代谢组等技术的发展，工业黑曲霉产能的改良取得了较好成果。例如，Steiger等[8]通过使用tet-on诱导型系统过表达柠檬酸转运蛋白基因(cexA)，使柠檬酸分泌量显著增加，柠檬酸产量高达109 g/L；Xu等[9]敲除黑曲霉中的cexA基因以消除柠檬酸的积累，同时过表达葡萄糖转运蛋白基因(mstC)、己糖激酶基因(hxkA)、磷酸果糖激酶基因(pfkA)和丙酮酸激酶基因(pkiA)，发酵192 h后苹果酸滴度达到201.13 g/L；Yang等[10]在黑曲霉中过表达四碳二羧酸转运蛋白基因(dct1)，使l-苹果酸的产生量大幅增加；Liu等[11]通过在黑曲霉中重构胞质磷酸酮缩酶基因(PK)、乙酸激酶基因(ACK)和乙酰辅酶A合成酶基因(ACS)通路所得菌株的柠檬酸滴度和产量分别提高了96.4%。然而，部分产酸机制仍未阐明，这是限制工业化生产的主要原因之一。因此，解析黑曲霉产柠檬酸和l-苹果酸的机制是构建高效代谢通路和提高发酵产量的关键[12-13]。
在黑曲霉发酵生产有机酸的过程中发现，不同的pH条件会影响菌株生产的有机酸种类，如当pH≤5.0时，该菌株主要生产柠檬酸；而当pH为6.0时，则主要生产l-苹果酸。本研究通过转录组学对比2种发酵过程的差异基因，从基因表达层面探究pH值对这2种有机酸合成途径的调控机制，以期为优化黑曲霉发酵工艺及提高目标有机酸产量提供重要的理论依据。
1 材料与方法
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1.1 材料
1.1.1 菌株
本研究采用的黑曲霉菌株MA-1通过野生型黑曲霉菌株诱变获得，由中国普通微生物菌种保藏管理中心(CGMCC)保藏[14]。
1.1.2 主要试剂和仪器
葡萄糖、酵母提取物、胰蛋白胨、琼脂粉、(NH4)2SO4、KH2PO4、MgSO4、CuSO4、CaCl2，均为分析纯或生化试剂级别，国药集团化学试剂有限公司，Aminex® HPX-87H有机酸柱，Bio-Rad公司。
生化培养箱，江苏新春兰科学仪器有限公司；光学显微镜，北京普瑞赛司仪器有限公司。
1.1.3 培养基
PDA培养基(g/L)：土豆汁20.0 g/L，葡萄糖20.0，琼脂粉20.0[15]。
种子培养基(g/L)：葡萄糖60.0，(NH4)2SO4 5.0，KH2PO4 1.0，MgSO4 0.5，CuSO4 0.15，CaCl2 0.1；30 L发酵罐装液量20 L，115 ℃灭菌20 min。
发酵培养基(g/L)：葡萄糖180.0，(NH4)2SO4 5.0，KH2PO4 1.0，MgSO4 0.5，CuSO4 0.15，30 L发酵罐装液量20 L (含3 L种子液)，其中l-苹果酸发酵通过流加方式使用20% CaCO3调节pH至6.0。
1.2 柠檬酸发酵方法
将黑曲霉接种于PDA斜面培养基上，37 ℃培养6 d得到新鲜孢子。用无菌水洗涤获孢子，得孢子悬液，按2×105个孢子/mL接种于种子培养基中，搅拌速度为300 r/min，通气量为350 L/h，发酵24 h后取3 L种子液转接至发酵罐中，搅拌速度为400 r/min，发酵时间为72 h，温度控制在37 ℃，起始pH为5.0，发酵过程中不控制pH值。
1.3 苹果酸发酵方法
菌株培养条件、培养基、接种量及发酵条件同1.2节。发酵过程中需控制pH在6.0 (实际范围5.9-6.0)，通过流加20% CaCO3来控制发酵过程中的pH值。
1.4 柠檬酸及 l-苹果酸的测定
本研究采用高效液相色谱(HPLC)对发酵过程中的柠檬酸和l-苹果酸含量进行定量分析。使用Aminex® HPX-87H有机酸柱，柱温为60 ℃，流速为0.6 mL/min，检测波长为210 nm，流动相为5 mmol/L H2SO4溶液，l-苹果酸发酵液需使用2 mol/L HCl溶液按1:1进行酸化。
1.5 RNA样品制备与转录组测序分析
根据黑曲霉发酵过程中柠檬酸或l-苹果酸产酸速率呈现明显差异的时间点进行转录组分析。本研究选取发酵过程中48 h和72 h的发酵液，用200目筛进行过滤，用无菌无酶水洗涤并收集菌体，经液氮保存后送至北京诺禾致源科技股份有限公司进行RNA测序。采用Illumina平台SBS技术对cDNA文库进行测序，原始数据经质控后获得clean data，以FPKM值衡量基因表达水平。
1.6 RT-qPCR分析
收集在不同发酵条件下48 h和72 h的发酵液，使用200目筛收集发酵液中的菌体，用蒸馏水冲洗干净并挤干水分，然后进行液氮速冻与研磨，使用Fungal RNA Kit提取RNA，通过反转录获得黑曲霉cDNA[16]。对糖酵解途径及糖异生途径中的丙酮酸羧化酶基因(pc)、磷酸果糖激酶基因(pfk)和己糖激酶基因(hk)进行RT-qPCR分析，通过比较不同样本达到荧光阈值所需循环数(Ct值)，定量评估3种目标基因的转录水平差异，以18S rRNA基因为内参，采用2-ΔΔCt法计算基因相对表达量[17]。所有数据均来自3次生物学重复。
2 结果与分析
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2.1 黑曲霉发酵生产柠檬酸与 l-苹果酸分析
将黑曲霉MA-1按照1.2节和1.3节方法发酵后，转接至发酵罐，分别在24、48和72 h取样，测定其产酸量。如图1A所示，柠檬酸发酵起始pH为5.0，发酵至48 h和72 h时pH分别降至2.81和2.36。整个发酵过程中柠檬酸是主要产物，其48 h和72 h的产量分别达到154.8 g/L和185.5 g/L (图1B)；在该条件下，l-苹果酸的产量极低，仅为毫克级。当发酵过程中pH维持在6.0时，发酵液中以l-苹果酸为主，其48 h和72 h的产量分别达到16.98 g/L和39.35 g/L (图1C)；此条件下，柠檬酸含量为5.79 g/L和7.70 g/L。发酵结果表明2种发酵条件下菌株的代谢调控策略存在显著差异。在柠檬酸发酵过程中，产酸速率在24-48 h较快，而在l-苹果酸发酵中产酸高峰出现在48-72 h。为阐明pH值对这2种代谢通路的影响，对48 h与72 h的关键差异表达基因进行比较分析。
2.2 MA-1生成柠檬酸和 l-苹果酸差异基因分析
分别对MA-1生成柠檬酸及l-苹果酸发酵过程的关键时间节点48 h和72 h进行差异表达基因筛选。如图2A、2B所示，柠檬酸发酵过程中，72 h上调和下调的差异基因数目分别为250个和99个，其余10 285个基因无差异；l-苹果酸发酵过程中，72 h上调、下调和无差异的基因数目分别为123、110和10 632个。
对柠檬酸和l-苹果酸发酵过程中上调及下调的差异基因进行GO富集分析，其中柠檬酸发酵和l-苹果酸发酵过程中72 h vs. 48 h中72 h上调基因共有的功能主要集中于辅酶结合(coenzyme binding)、血红素结合(heme binding)、铁离子结合(iron ion binding)及氧化还原酶活性(oxidoreductase activity)，这些是黑曲霉生长发育的基本保障(图2C、2D)。二者的不同点在于，柠檬酸发酵过程部分差异基因集中于碳水化合物代谢过程(carbohydrate metabolic process)，l-苹果酸则集中于阳离子跨膜转运(cation transmembrane transport)等离子转运过程。
对于72 h下调的基因中柠檬酸和l-苹果酸发酵过程均涉及血红素结合(heme binding)、裂解酶活性(lyase activity)以及色氨酸、生物胺、吲哚化合物等代谢过程(图2E、2F)。在柠檬酸发酵过程中出现有机酸代谢过程(organic acid metabolic process)，其中ANI_1_248184 (谷氨酸脱氢酶基因gdhA)在CA 48 h和72 h时的FPKM值分别为3 737.84和1 017.68。谷氨酸脱氢酶在有机酸代谢中扮演核心角色，它通过调控α-酮戊二酸(α-KG)和谷氨酸(Glu)的相互转化，连接碳氮代谢，并影响三羧酸循环(TCA)和氨基酸合成，而gdhA在l-苹果酸发酵中MA 48 h和72 h时的FPKM值较高，分别为42 029.144和52 233.741。谷氨酸(Glu)转化为α-酮戊二酸(α-KG)时伴随NAD+/NADH的反应，NADH正是为l-苹果酸合成过程提供还原力，从而支持高效发酵[18]。
2.3 差异基因Venn分析
为探究柠檬酸和l-苹果酸发酵过程的异同，以组内和组间存在的差异基因绘制Venn图(图3A)。仅存在于CA 72 h vs. MA 72 h和CA 48 h vs. MA 48 h中的差异基因共有1 882个，对该1 882个基因进行聚类热图分析(图3B)，可以看出柠檬酸与l-苹果酸发酵过程存在显著差异，其中有849个基因在CA 48 h及CA 72 h中的转录水平均高于MA发酵过程，而另外的1 033个基因则在MA发酵过程中转录水平较高。为进一步探寻柠檬酸和l-苹果酸代谢途径中的差异，对上述2类基因进行KEGG富集分析(图3C、3D)。柠檬酸代谢过程中酪氨酸代谢和苯丙氨酸代谢途径的P值极为显著，二者均可通过合成乙酰乙酰CoA，进而生成乙酰CoA，从而参与柠檬酸合成。另外，在分析氨基酸核苷糖代谢和淀粉蔗糖代谢途径时发现ANI_1_1030104 (葡萄糖激酶)在柠檬酸发酵过程中呈现高转录水平；次级代谢途径中含有ANI_1_2950014 (柠檬酸合酶)；ABC转运蛋白过程包括ANI_1_690024 (ABC转运蛋白)和ANI_1_920084 (ABC多药转运蛋白)，它们使菌体能够在低pH环境中稳定生长。l-苹果酸发酵过程中氨基酸的生物合成途径存在显著差异，包括ANI_1_398134 (高异柠檬酸脱氢酶)、ANI_1_376134 (精氨酸琥珀酸合酶)、ANI_1_440184 (丙酮酸羧化酶)、ANI_1_440024 (3-异丙基苹果酸酯脱水酶)和ANI_1_3136024 (异柠檬酸脱氢酶)等，这些基因使l-苹果酸向下游代谢合成赖氨酸、精氨酸、缬氨酸及天冬氨酸等氨基酸。分析次级代谢和碳代谢途径发现，转录水平显著上调的基因有ANI_1_2706024 (琥珀酸脱氢酶)、ANI_1_204164 (6-磷酸果糖激酶)、ANI_1_12134 (苹果酸脱氢酶)、ANI_1_914104 (异柠檬酸裂解酶)和ANI_1_256144 (甘油醛-3-磷酸脱氢酶)等，它们均为l-苹果酸合成途径中的关键基因。
2.4 高转录水平基因的时序差异
柠檬酸和l-苹果酸发酵过程存在显著差异，通过对全部基因进行检索分析，分别以CA 48 h、CA 72 h、MA 48 h、MA 72 h为参考，对其中存在显著差异的基因进行筛选分析，筛选出差异较大的前10个基因，如表1所示。柠檬酸发酵过程中转录水平高的基因主要是耐酸性蛋白基因，如ANI_1_62014 (曲霉菌素II基因)、ANI_1_654124 (天冬氨酸蛋白酶曲基因pepA)、ANI_1_60084 (1,3-β葡萄糖苷转移酶基因)、ANI_1_1216074 (谷氨酸脱羧酶基因)和ANI_1_842034 (NACHT结构域蛋白基因)。发酵过程中柠檬酸的积累导致pH下降，该环境会诱导酸性蛋白水解酶的表达，通过分解体内外蛋白质以提供生长代谢过程中所必需的氨基酸，帮助菌体适应低pH环境。l-苹果酸发酵过程中ANI_1_1474074 (柠檬酸合酶/柠檬酸裂解酶基因)呈现高转录水平，通过rTCA途径将柠檬酸分解为草酰乙酸和乙酰CoA，乙酰CoA在高转录水平的ANI_1_2494074 [3-氧酰基-(酰基载体蛋白)合酶基因]和ANI_1_2488074 (生物合成脂肪酸合酶亚基β基因)的作用下合成脂肪酸链，同时可以消耗l-苹果酸生产过程中积累的NADPH，避免其过度积累导致的氧化还原失衡。另外，高转录水平的ANI_1_228094 (硫胺素合成酶基因)可以通过合成硫胺素间接激活丙酮酸脱氢酶，生成的乙酰CoA与乙醛酸循环途径中的乙醛酸合成l-苹果酸，为l-苹果酸高效生成提供更多途径。
2.5 转录因子分析
转录因子在菌株生长发育、合成代谢和环境适应性等方面发挥关键作用，分析柠檬酸和l-苹果酸发酵过程中差异性的转录调控因子对菌株基因工程改造具有重要意义。以l-苹果酸48 h为参考，对转录水平较高的前25个基因进行统计，如表2所示。其中，C2H2类转录因子Rpn4 (ANI_1_970074)、Ace1 (ANI_1_290144)、RfeC (ANI_1_2590024)、Seb1 (ANI_1_730184)在CA和l-MA发酵过程中的转录水平始终较高，在生物体基础的应激响应、金属解毒、发育调控等途径中发挥重要作用[19]；Zn(II)2Cys6锌簇家族的ANI_1_1416094、ANI_1_562114、ANI_1_1318164均在MA发酵过程中的转录水平高于CA，可能与l-MA发酵的特殊条件如pH或产物积累相关，从而参与特异性调控代谢或应激调控[20]；bZIP家族中的HacA (ANI_1_24014)、AP-1 (ANI_1_1026094)、AtfA (ANI_1_974024)在CA发酵过程中上调，而在l-MA过程中下调。这可能是由于CA发酵过程中面临pH低、缺氧、氧化应激等问题，因此该类转录因子可能在调控生物体的耐逆性方面发挥着重要作用[21]；RNA聚合酶II转录亚基12的介质ANI_1_1316094和mRNA结合转录后调节因子Csx1 (ANI_1_54104)分别在l-MA和CA发酵过程中存在显著差异，前者可结合RNA聚合酶II并控制II类基因的转录，后者为mRNA结合转录后调节因子[22]。
2.6 转运蛋白分析
生物体发酵生产有机酸需要建立专一且高效的转运蛋白体系。通过转录组分析对比柠檬酸和l-苹果酸发酵过程中转运蛋白存在的差异，对阐明二者代谢途径具有重要意义。对柠檬酸和l-苹果酸发酵过程中转运蛋白转录水平较高的差异基因进行分析，并绘制基因上下调柱状图，如图4所示。
这些基因多集中于糖转运蛋白、离子转运蛋白和氮/氨基酸相关转运蛋白，这类转运蛋白均与维持生物体基本生命活动相关。在l-苹果酸发酵过程中上调，而在柠檬酸发酵过程中下调的基因如图4A、4B所示。其中，ANI_1_280094为核苷酸-糖转运蛋白，UDP-葡萄糖是合成海藻糖(抗应激分子)的前体，而NADH是苹果酸合成的关键辅因子，可能通过影响抗氧化途径，间接维持苹果酸生产过程中所需的还原力。在柠檬酸发酵过程中上调，而在l-苹果酸发酵过程中下调的基因如图4C、4D所示，ANI_1_288154 (镁离子转运蛋白) 表现较为显著。此外，在分析过程中发现有3个基因在柠檬酸和l-苹果酸发酵过程中差异非常显著，包括ANI_1_2500074 (MFS多药转运蛋白)、ANI_1_840034 (寡肽转运蛋白)、ANI_1_888104 (糖转运蛋白)，它们的转录水平在l-苹果酸发酵过程中远远高于柠檬酸发酵过程。基因ANI_1_478154 (CexA)在柠檬酸发酵过程中的转录水平远远高于l-苹果酸发酵过程，该转运蛋白可以专一且高效地将柠檬酸转运出细胞外；而基因ANI_1_2040144 (dct1)在l-苹果酸发酵过程中的转录水平更高，该转运蛋白可以将l-苹果酸转运到胞外。过表达DCT系列基因显著提升了黑曲霉中l-苹果酸的产量，说明该系列基因在高表达状态下可有效增强细胞对l-苹果酸的转运能力[23]。
2.7 柠檬酸与 l-苹果酸主要合成途径及相关基因表达分析
柠檬酸合成代谢途径涉及糖酵解、三羧酸循环、柠檬酸合成与分泌；l-苹果酸合成代谢途径主要为糖酵解、三羧酸循环的回补途径、胞质丙酮酸羧化途径、乙醛酸循环途径以及l-苹果酸分泌。如图5所示，柠檬酸及l-苹果酸主要代谢通路，通过分析代谢通路上的基因可为菌株代谢途径改造以及发酵条件优化提供一定的理论基础。
在糖酵解途径中的关键基因己糖激酶基因(ANI_1_66114)在柠檬酸发酵过程中的转录水平是l-苹果酸发酵过程中的2倍，这可能是柠檬酸产量更高的原因之一。TCA循环中柠檬酸合酶基因(ANI_1_2950014)是柠檬酸合成的关键酶，在柠檬酸发酵过程中的转录水平远远高于l-苹果酸发酵过程。另外，异柠檬酸脱氢酶基因(ANI_1_3136024)在柠檬酸合成途径中的转录水平较低，表明TCA循环中柠檬酸下游途径被削弱，从而使柠檬酸得到大量积累，并且谷氨酸脱氢酶基因(ANI_1_2248184)可以将谷氨酸转化为α-酮戊二酸弥补TCA循环的缺失。作为柠檬酸专一性的细胞膜转运蛋白基因cexA (ANI_1_478154)，其转录水平随着柠檬酸的积累而增加且是苹果酸发酵过程中的26-33倍。在l-苹果酸发酵过程中，需要大量的NADH提供还原力，三磷酸甘油醛脱氢酶基因(ANI_1_256144)和谷氨酸脱氢酶基因(ANI_1_3136024)是提供还原力的关键酶，二者在l-苹果酸发酵过程中的转录水平均较高，分别是柠檬酸发酵过程的2.50-2.99倍和5.20-5.47倍。同时，丙酮酸羧化酶基因(ANI_1_440184)和苹果酸脱氢酶基因(ANI_1_12134)是胞质中合成l-苹果酸的关键基因，它们在l-苹果酸发酵过程中的高转录水平分别是柠檬酸发酵过程的2.67-2.77倍和2.26-2.58倍。在乙醛酸循环途径中异柠檬酸裂解酶基因(ANI_1_914104)也呈现较高的转录水平，是合成l-苹果酸的主要途径之一。对于苹果酸专一性的膜转运蛋白基因dct1 (ANI_1_2040144)，其在48 h时的转录水平最高，是柠檬酸48 h时的98倍，而在72 h时呈现大幅下降，这也可能是影响l-苹果酸产量的重要因素之一。
2.8 RT-qPCR分析糖酵解途径关键基因转录水平
按照1.6节所述方法对RT-qPCR结果进行分析(图6)。黑曲霉菌株在苹果酸pH发酵条件下丙酮酸羧化酶的表达水平是柠檬酸条件下的6.8-7.2倍，磷酸果糖激酶为2.7-3.3倍，己糖激酶则在柠檬酸pH发酵条件下更高，为苹果酸pH发酵条件下的3.1-6.2倍。分析结果与转录组分析结果基本保持一致。这种产量与关键基因的转录水平的一致性表明，2种发酵模式下存在不同的代谢调控策略，微生物通过调控不同基因的表达分别优化了柠檬酸和l-苹果酸发酵中的碳代谢流。
3 讨论与结论
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黑曲霉在不同pH条件下主要生产的有机酸不同。实验过程中发现，当pH≤5.0时主要生产柠檬酸，而pH 6.0时主要生产l-苹果酸。本研究通过对黑曲霉生产有机酸的关键时间节点(48 h和72 h)进行转录组学分析，对比2种代谢通路下的差异基因以揭示柠檬酸和l-苹果酸发酵的异同。首先分别对MA-1生成柠檬酸和l-苹果酸发酵过程中上调和下调的基因进行分析，同时在两者中上调或下调的基因可能参与生物体的基础生命活动，为生物体提供相对稳定的生长发育环境；另外，本研究重点分析两者中的差异基因，即该基因在一方中上调而在另一方中下调或在两者间的转录水平相差极大，通过差异基因分析目标代谢途径的强化或抑制、生物体在压力环境中的应对策略以及潜在的基因工程靶点，从而指导发酵工艺优化或菌株改造[24]。
通过火山图及GO富集分析发现，柠檬酸发酵过程中上调的基因数目明显高于下调基因，而l-苹果酸发酵过程中上、下调基因数目基本一致，这可能是由于在柠檬酸发酵过程中pH逐渐降低，菌体为了抵御低pH环境需要表达大量蛋白以维持自身的活性及生长；而l-苹果酸发酵过程中需要维持一个相对稳定的pH条件(5.9-6.0)，这使得l-苹果酸发酵过程中上调基因和下调基因数目基本稳定。
发酵过程中不同时间点转录水平最高的基因有助于对发酵阶段的划分或关键代谢的转换有清晰认知，也可对环境压力的响应有动态了解；柠檬酸发酵过程中转录水平高的差异基因集中于酸性蛋白水解酶，目的是使菌体适应低pH环境；而l-苹果酸发酵过程中则更多地合成脂肪酸，以维持生物体的氧化还原平衡[25-26]。
分析共表达差异基因可以看出，柠檬酸和l-苹果酸的发酵途径具有显著差异性。分析2条途径的差异基因有助于揭示黑曲霉在不同代谢状态下的调控策略或环境适应机制。共同上调的基因可能是高产菌株的通用靶点，共同下调的基因则可能是潜在敲除靶点[27]。
转录因子是调控基因表达的关键蛋白，分析2条代谢途径中的差异性转录因子可明确两者之间的差异[28]，为提高目标有机酸产量或优化培养条件作出贡献。锌指类转录因子、锌簇家族、bZIP家族相关基因分别在柠檬酸和l-苹果酸过程中起着不同作用，揭示了2种代谢过程对于抗逆性的差异。
专一且高效的转运蛋白可以精准调控物质进出细胞，增强发酵效率[29]。在柠檬酸和l-苹果酸过程中差异非常显著的3个转运蛋白表明l-苹果酸生产中需要强化转运系统以提升底物利用和产物外排的效率。基因ANI_1_280094参与代谢过程的氧化还原平衡在l-苹果酸中上调而在柠檬酸中下调，未来可考虑增强l-苹果酸发酵过程中的还原力，以达到提高l-苹果酸产量的目的[30]；cexA (ANI_1_478154)在柠檬酸发酵过程中转录水平很高，在l-苹果酸发酵过程中仍有少量表达，可通过敲除该基因减少l-苹果酸合成中副产物柠檬酸的积累；反之，可过表达柠檬酸转运蛋白基因cexA (ANI_1_478154)以提升柠檬酸的产量；也可通过提高柠檬酸合酶基因(ANI_1_2950014)的表达以实现柠檬酸源头供应量的增加。
柠檬酸生产过程中需要抑制TCA循环后续步骤，通过丙酮酸羧化途径确保草酰乙酸的供应，合成柠檬酸之后通过转运蛋白排出细胞；l-苹果酸发酵中仍需要TCA为其提供能量，并且与之相关的C4-二羧酸转运蛋白转录水平较低，或许可考虑过表达这类转运蛋白以提高苹果酸的输出能力。
从发酵结果上看，柠檬酸产量很高，说明其合成速率快，推测其上游代谢中己糖激酶基因(hk)的转录水平高，为柠檬酸的合成提供了充足保证；而苹果酸发酵过程中，维持细胞生长和跨膜运输需要较高的ATP，高表达的磷酸果糖激酶基因(pfk)是满足这种能量需求的最佳方式。
综上所述，本研究通过转录组学对柠檬酸和l-苹果酸发酵关键时间节点48 h和72 h存在的差异基因进行分析，确定了2条代谢通路的主要差异。通过分析差异基因、转录因子、转运蛋白及2条代谢途径中的关键差异基因，为优化黑曲霉发酵工艺、提高目标有机酸产量提供了重要的理论依据。
基金
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  • 国家重点研发计划(2021YFC1808901)
  • 国家自然科学基金(32400033)
文献
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参考文献 引证文献
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2026年第66卷第2期
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doi: 10.13343/j.cnki.wsxb.20250674
  • 接收时间：2025-09-03
  • 首发时间：2026-02-05
  • 出版时间：2026-02-04
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  • 收稿日期：2025-09-03
  • 录用日期：2025-10-28
基金
the National Key Research and Development Program of China(2021YFC1808901)
国家重点研发计划(2021YFC1808901)
the National Natural Science Foundation of China(32400033)
国家自然科学基金(32400033)
作者信息
    1.天津科技大学 生物工程学院，天津
    2.山东日照金禾博源生化有限公司，山东 日照
    3.工业发酵微生物教育部重点实验室，天津
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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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