Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd DE GRUYTER Journal of Integrative Bioinformatics. 2019; 20190016 O. Vasieva 1,2 / I. Goryanin 3,4,5 Is there a Function for a Sex Pheromone Precursor? A Predicted Link between Bacterial Redox Metabolism and Propagation of Antibiotic Resistance 1 University of Liverpool, Crown street, Liverpool, UK, E-mail: ovasieva@ingenets.com 2 Ingenet ltd, 3d floor, 207 Regent street, London, UK, E-mail: ovasieva@ingenets.com 3 University of Edinburgh, Edinburgh, UK, E-mail: goryanin@oist.jp. https://orcid.org/0000-0002-8293-774X. 4 Okinawa Institute Science and Technology, Okinawa, Japan, E-mail: goryanin@oist.jp. https://orcid.org/0000-0002-8293-774X. 5 Tianjin Institute of Industrial Biotechnology, Tianjin, China, E-mail: goryanin@oist.jp. https://orcid.org/0000-0002-8293-774X. Abstract: Functional coupling and comparative genomics analysis have been applied to study functional associations of orthologs of enterococcal cAD1 sex pheromone (P13268) known to be responsible for bioflm formation, con- jugative plasmid transfer and spreading of bacterial antibiotics resistance. cAD1 peptide pheromone is released from the membrane lipoprotein with the peptide precursor encoded by a gene cad (tr|C2JQE7). Our analysis of genomic neighbourhood of cad and motifs of the encoded polypeptide and its orthologs suggests a close func- tional association between cAD1 and ApbE protein (Q82Z24), a FMN insertion and traficking facilitator. The cad and apbE orthologs were coupled in the genomes and ApbE-specifc motifs for FMN covalent attachment were identifed in cad-encoded protein sequence and its orthologs. These fndings suggest a potential role of FMN-based reductase function of the cAD1 lipoprotein precursor in its processing and release of the active sex pheromone peptide. They may lead to a new approach in prevention of antibiotic resistance spread via tar- geting sex pheromone processing chaperones or by suppression of the FMN availability and covalent binding. This methods can be also applied to a controlled evolution of bacterial pathogenicity in microbial fuel cells, as the fndings suggest the crosstalk between bacterial pathogenicity and bacterial electro-activity. Keywords: ApbE, cAD1, Enterococcus, redox metabolism, SEED DOI: 10.1515/jib-2019-0016 Received: March 9, 2019; Revised: May 24, 2019; Accepted: June 7, 2019 1 Introduction Recently developed insights in microbial redox metabolism [1], [2], [3] and emerged biotechnology of microbial fuel cells (MFC) [4] provided new data enabling to link cell redox processes and electron transfer to functions involved in virulence and bacterial pathogenicity, previously considered as largely autonomous. Suppression of pathogenic traits, observed in MFC under an applied electric potential [5], [6] in some groups of bacteria, is the fact that leaves more questions than answers. Functional links between bacterial redox metabolism and factors triggering bioflm formation and conjugational processes are coming to the focus of the research, and this in silico study establishes one of the potential connections. Functional coupling of genes in bacterial genomes was demonstrated on multiple examples and is used to predict protein functions and new pathway connections [7], [8] A number of tool has been developed to sup- port this analytical approach [7] and are at the moment among the most cited in the area of bacterial genomics. We have applied this method to infer functional connections of cAD1 sex pheromone (P13268) [9] produced by Enterococcus. As other known bacterial sex pheromones, cAD1 is secreted by plasmid-free cells to be recog- nised by plasmid-baring cells and initiate cell clumping, conjugation and the virulence pAD1 plasmid transfer [10], [11], [12]. This processes are tightly associated with bioflm formation and a number of other pathogenic determinants and are triggered by stressors, especially in a form of free radicals [13], [14], [15]. O. Vasieva, I. Goryanin are the corresponding authors. © 2019, O. Vasieva and I. Goryanin, published by Walter de Gruyter GmbH, Berlin/Boston. This work is licensed under the Creative Commons Attribution 4.0 Public License. 1