Crits-Christoph Alexander, Bhattacharya Nicholas, Olm Matthew R, Song Yun S, Banfield Jillian F
Department of Plant and Microbial Biology, University of California, Berkeley, California 94720, USA.
Innovative Genomics Institute, Berkeley, California 94720, USA.
Genome Res. 2021 Feb;31(2):239-250. doi: 10.1101/gr.268169.120. Epub 2020 Dec 23.
Biosynthetic gene clusters (BGCs) are operonic sets of microbial genes that synthesize specialized metabolites with diverse functions, including siderophores and antibiotics, which often require export to the extracellular environment. For this reason, genes for transport across cellular membranes are essential for the production of specialized metabolites and are often genomically colocalized with BGCs. Here, we conducted a comprehensive computational analysis of transporters associated with characterized BGCs. In addition to known exporters, in BGCs we found many importer-specific transmembrane domains that co-occur with substrate binding proteins possibly for uptake of siderophores or metabolic precursors. Machine learning models using transporter gene frequencies were predictive of known siderophore activity, molecular weights, and a measure of lipophilicity (log ) for corresponding BGC-synthesized metabolites. Transporter genes associated with BGCs were often equally or more predictive of metabolite features than biosynthetic genes. Given the importance of siderophores as pathogenicity factors, we used transporters specific for siderophore BGCs to identify both known and uncharacterized siderophore-like BGCs in genomes from metagenomes from the infant and adult gut microbiome. We find that 23% of microbial genomes from premature infant guts have siderophore-like BGCs, but only 3% of those assembled from adult gut microbiomes do. Although siderophore-like BGCs from the infant gut are predominantly associated with Enterobacteriaceae and , siderophore-like BGCs can be identified from taxa in the adult gut microbiome that have rarely been recognized for siderophore production. Taken together, these results show that consideration of BGC-associated transporter genes can inform predictions of specialized metabolite structure and function.
生物合成基因簇（BGCs）是微生物基因的操纵子集合，可合成具有多种功能的特殊代谢产物，包括铁载体和抗生素，这些产物通常需要输出到细胞外环境。因此，跨细胞膜运输的基因对于特殊代谢产物的产生至关重要，并且在基因组上通常与BGCs共定位。在这里，我们对与已鉴定的BGCs相关的转运蛋白进行了全面的计算分析。除了已知的输出蛋白外，在BGCs中我们还发现了许多与底物结合蛋白共同出现的进口特异性跨膜结构域，可能用于摄取铁载体或代谢前体。使用转运蛋白基因频率的机器学习模型可预测已知铁载体活性、分子量以及相应BGC合成代谢产物的亲脂性度量（log）。与BGCs相关的转运蛋白基因通常比生物合成基因更能预测代谢产物特征。鉴于铁载体作为致病因素的重要性，我们使用铁载体BGCs特异性的转运蛋白来鉴定来自婴儿和成人肠道微生物组宏基因组的基因组中已知和未鉴定的类铁载体BGCs。我们发现，早产婴儿肠道中23%的微生物基因组具有类铁载体BGCs，但从成人肠道微生物组组装的基因组中只有3%具有。虽然婴儿肠道中的类铁载体BGCs主要与肠杆菌科和有关，但也可以从成人肠道微生物组中很少被认为能产生铁载体的分类群中鉴定出类铁载体BGCs。综上所述，这些结果表明，考虑与BGC相关的转运蛋白基因可以为特殊代谢产物的结构和功能预测提供信息。
