深入了解NAT基因家族为微生物二次代谢服务的基因组和功能差异-动脉网

Insights into the genomic and functional divergence of NAT gene family to serve microbial secondary metabolism

Nature 等信源发布 2024-06-28 16:38

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AbstractMicrobial NAT enzymes, which employ acyl-CoA to acylate aromatic amines and hydrazines, have been well-studied for their role in xenobiotic metabolism. Some homologues have also been linked to secondary metabolism, but this function of NAT enzymes is not as well-known. For this comparative study, we surveyed sequenced microbial genomes to update the list of formally annotated NAT genes, adding over 4000 new sequences (mainly bacterial, but also archaeal, fungal and protist) and portraying a broad but not universal distribution of NATs in the microbiocosmos.

摘要利用酰基辅酶A酰化芳香胺和肼的微生物NAT酶因其在异生素代谢中的作用而得到了很好的研究。一些同源物也与次级代谢有关，但NAT酶的这种功能尚不为人所知。对于这项比较研究，我们调查了测序的微生物基因组，以更新正式注释的NAT基因列表，添加了4000多个新序列（主要是细菌，但也有古细菌，真菌和原生生物），并描绘了NAT在微生物中的广泛但不普遍的分布。

Localization of NAT sequences within microbial gene clusters was not a rare finding, and this association was evident across all main types of biosynthetic gene clusters (BGCs) implicated in secondary metabolism. Interrogation of the MIBiG database for experimentally characterized clusters with NAT genes further supports that secondary metabolism must be a major function for microbial NAT enzymes and should not be overlooked by researchers in the field.

NAT序列在微生物基因簇内的定位并不罕见，这种关联在涉及次级代谢的所有主要类型的生物合成基因簇（BGC）中都很明显。。

We also show that NAT sequences can be associated with bacterial plasmids potentially involved in horizontal gene transfer. Combined, our computational predictions and MIBiG literature findings reveal the extraordinary functional diversification of microbial NAT genes, prompting further research into their role in predicted BGCs with as yet uncharacterized function..

我们还表明，NAT序列可能与可能参与水平基因转移的细菌质粒相关。结合起来，我们的计算预测和MIBiG文献发现揭示了微生物NAT基因的非凡功能多样化，促使人们进一步研究它们在具有尚未表征功能的预测BGC中的作用。。

IntroductionIn the course of evolutionary time, microorganisms have developed immense metabolic potential and adaptability, and their capabilities have attracted scientific interest for useful biotechnological applications. Through xenobiotic metabolism, bacteria and fungi can detoxify, degrade or biotransform exogenous compounds of natural or synthetic origin, surviving and even thriving in adverse chemical environments that would be toxic to more complex organisms1.

引言在进化过程中，微生物具有巨大的代谢潜力和适应性，其能力吸引了有用的生物技术应用的科学兴趣。通过异生素代谢，细菌和真菌可以解毒，降解或生物转化天然或合成来源的外源化合物，在对更复杂的生物有毒的不利化学环境中生存甚至繁衍1。

Microbial xenobiotic metabolism involves a plethora of enzyme activities, and arylamine N-acetyltransferase (NAT, E.C. 2.3.1.5) is one of them2. Microbial NAT enzymes catalyze the N-acetylation of aromatic amines, leading to detoxification of many harmful by-products of industrial activity and farming (e.g.

微生物异生素代谢涉及过多的酶活性，芳胺N-乙酰转移酶（NAT，E.C.2.3.1.5）是其中之一。微生物NAT酶催化芳香胺的N-乙酰化，导致工业活动和农业的许多有害副产物的解毒（例如。

pharmaceuticals, dyes, pesticides, etc.)3,4,5,6,7,8. However, they can also bioactivate procarcinogenic N-hydroxyarylamines via O-acetylation (E.C. 2.3.1.118), an activity exploited by Ames and colleagues in the popular Salmonella mutagenicity test9. The study of Salmonella NAT was indeed groundbreaking, in that it additionally revealed the basic structure and catalytic mechanism of the enzyme family, which employs a cysteine-histidine-aspartate (Cys-His-Asp) protease-like catalytic triad to transfer an acetyl group from donor acetyl coenzyme A (CoA) to the amino group of the acceptor aromatic amine10,11.An unexpected discovery was reported for the (AMYMS)NAT3 (alias symbol RifF, GenBank ID: AFO74156.1) homologue of the actinobacterium Amycolatopsis mediterranei str.

药物，染料，农药等）3,4,5,6,7,8。然而，它们也可以通过O-乙酰化（E.C.2.3.1.118）对致癌的N-羟基芳胺进行生物活化，这是Ames及其同事在流行的沙门氏菌致突变性试验中利用的一种活性9。沙门氏菌NAT的研究确实是开创性的，因为它还揭示了酶家族的基本结构和催化机制，该酶家族使用半胱氨酸组氨酸天冬氨酸（Cys-His-Asp）蛋白酶样催化三联体将乙酰基从供体乙酰辅酶a（CoA）转移到受体芳香胺的氨基10,11。据报道，（AMYMS）NAT3（别名符号RifF，GenBank ID:AFO74156.1）同源物的意外发现了放线菌Amycolatopsis mediterranei str。

S699, implicating NAT not only in xenobiotic, but also in secondary metabolism. That particular homologue, which acts as an amide synthase, is encoded by a gene located at the end of the core biosynthetic gene cluster (BGC) driving producti.

S699，不仅涉及异生素，还涉及次级代谢。作为酰胺合酶的特定同源物由位于驱动产物I的核心生物合成基因簇（BGC）末端的基因编码。

Data availability

数据可用性

All data generated or analysed during this study are included in this published article (and its Supplementary Information files).

本研究期间生成或分析的所有数据均包含在本文（及其补充信息文件）中。

Abbreviations3,4-AHBA:

缩写3,4-AHBA：

3-Amino-4-hydroxybenzoic acid

3-氨基-4-羟基苯甲酸

3,5-AHBA:

3.5 AHBA：

3-Amino-5-hydroxybenzoic acid

3-氨基-5-羟基苯甲酸

antiSMASH:

抗SMASH：

Secondary metabolite analysis shell software

次生代谢物分析shell软件

BGC:

BGC：

Biosynthetic gene cluster

生物合成基因簇

CoA:

辅酶A：

Coenzyme A

辅酶A

EFI-EST:

EFI-EST：

EFI-enzyme similarity tool

EFI酶相似性工具

HGT:

HGT：

Horizontal gene transfer

水平基因转移

MIBiG:

MIBiG：

Minimum information about a biosynthetic gene cluster

关于生物合成基因簇的最小信息

NRPS:

NRPS：

Non-ribosomal peptide synthase

非核糖体肽合酶

ORF:

开放阅读框：

Open reading frame

打开阅读框

PKS:

PKS：

Polyketide synthase

聚酮合酶

SSN:

SSN：

Sequence similarity network

序列相似性网络

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Download referencesAcknowledgementsThe research project was partly supported by the Hellenic Foundation for Research and Innovation (H.F.R.I.) under the “2nd Call for H.F.R.I. Research Projects to support Faculty Members & Researchers” (Project Number: 3712), providing funding to work performed by D.B., D.T., S.Z.

下载参考文献致谢该研究项目得到了希腊研究与创新基金会（H.F.R.I.）在“第二次呼吁H.F.R.I.研究项目支持教师和研究人员”（项目编号：3712）下的部分支持，为D.B.，D.T.，S.Z.的工作提供资金。

and S.B. For her part of work, E.K. was recipient of a Ph.D. scholarship (2016-2019) co-financed by Greece and the European Union (European Social Fund-ESF) through Operational Program “Human Resources Development, Education and Lifelong Learning” in the context of project “Strengthening Human Resources Research Potential via Doctorate Research” (MIS-5000432), implemented by the State Scholarships Foundation (ΙΚΥ).

而S.B.在她的部分工作中，E.K.获得了由希腊和欧盟（欧洲社会基金ESF）共同资助的博士奖学金（2016-2019），该奖学金是通过国家奖学金基金会（National Scholarss Foundation）（MIS-5000432）实施的“人力资源开发、教育和终身学习”运营计划获得的。

We thank former students Marina Avramidou, Athina Eleftheraki, Christina Vagena-Pantoula, Maria-Giusy Papavergi, Charalampos Ioannidis and Vasiliki Garefalaki for assistance.Author informationAuthors and AffiliationsDepartment of Molecular Biology and Genetics, Democritus University of Thrace, 68100, Alexandroupolis, GreeceSotiria Boukouvala, Evanthia Kontomina, Ioannis Olbasalis, Dionysios Patriarcheas, Dimosthenis Tzimotoudis, Konstantina Arvaniti, Aggelos Manolias, Maria-Aggeliki Tsatiri, Dimitra Basdani & Sokratis ZekkasAuthorsSotiria BoukouvalaView author publicationsYou can also search for this author in.

我们感谢前学生Marina Avramidou、Athina Eleftheraki、Christina Vagena Pantoula、Maria Giusy Papavergi、Charalampos Ioannidis和Vasiliki Garefalaki的帮助。。

PubMed Google ScholarEvanthia KontominaView author publicationsYou can also search for this author in

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PubMed Google ScholarContributionsS.B. conceptualized the study, supervised the team and wrote the manuscript with help from E.K. and other co-authors. E.K., I.O., D.P., D.T., K.A., A.M., M.A.T., D.B. and S.Z. implemented various aspects of the research with equal contributions, and they are featured in the chronological order of their participation in the project.

PubMed谷歌学术贡献。B、在E.K.和其他合著者的帮助下，对研究进行了概念化，监督了团队并撰写了手稿。E、 K.，I.O.，D.P.，D.T.，K.A.，A.M.，M.A.T.，D.B.和S.Z.以相同的贡献实施了研究的各个方面，并且按照他们参与项目的时间顺序排列。

All authors reviewed the manuscript.Corresponding authorCorrespondence to.

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Reprints and permissionsAbout this articleCite this articleBoukouvala, S., Kontomina, E., Olbasalis, I. et al. Insights into the genomic and functional divergence of NAT gene family to serve microbial secondary metabolism.

转载和许可本文引用本文Boukouvala，S.，Kontomina，E.，Olbasalis，I。等人对NAT基因家族的基因组和功能差异的见解，以服务于微生物次级代谢。

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