Abstract
Nucleobase transporters are important for supplying the cell with purines and/or pyrimidines, for controlling the intracellular pool of nucleotides, and for obtaining exogenous nitrogen/carbon sources for metabolism. Nucleobase transporters are also evaluated as potential targets for antimicrobial therapies, since several pathogenic microorganisms rely on purine/pyrimidine salvage from their hosts. The majority of known nucleobase transporters belong to the evolutionarily conserved and ubiquitous nucleobase-ascorbate transporter/nucleobase-cation symporter-2 (NAT/NCS2) protein family. Based on a large-scale phylogenetic analysis that we performed on thousands of prokaryotic proteomes, we developed a webserver that can detect and distinguish this family of transporters from other homologous families that recognize different substrates. We can further categorize these transporters to certain evolutionary groups with distinct substrate preferences. The webserver scans whole proteomes and graphically displays which proteins are identified as NAT/NCS2, to which evolutionary groups and subgroups they belong to, and which conserved motifs they have. For key subgroups and motifs, the server displays annotated information from published crystal-structures and mutational studies pointing to key functional amino acids that may help experts assess the transport capability of the target sequences. The server is 100% accurate in detecting NAT/NCS2 family members. We also used the server to analyze 9,109 prokaryotic proteomes and identified Clostridia, Bacilli, β- and γ-Proteobacteria, Actinobacteria, and Fusobacteria as the taxa with the largest number of NAT/NCS2 transporters per proteome. An analysis of 120 representative eukaryotic proteomes also demonstrates the server's capability of correctly analyzing this major lineage, with plants emerging as the group with the highest number of NAT/NCS2 members per proteome.
Highlights
The nucleobase-ascorbate transporter (NAT)/nucleobase-cation symporter-2 (NCS2) (Nucleobase-Ascorbate Transporter / Nucleobase-Cation Symporter-2)protein family encompasses ion-gradient driven transporters of key metabolites or anti-19 metabolite analogs with diverse substrate preferences, ranging from purine or pyrimidine permeases in various organisms to Na+-dependent vitamin C transporters in human and other mammals [1,2,3,4,5,6]
The NAT/NCS2 transporters consist of 14 transmembrane segments (TMs) divided in two inverted repeats (7+7) and arranged spatially into a core domain
The NAT/NCS2 family is organized in two major subfamilies
Summary
The NAT/NCS2 (Nucleobase-Ascorbate Transporter / Nucleobase-Cation Symporter-2)protein family encompasses ion-gradient driven transporters of key metabolites or anti-19 metabolite analogs with diverse substrate preferences, ranging from purine or pyrimidine permeases in various organisms to Na+-dependent vitamin C transporters in human and other mammals [1,2,3,4,5,6]. Their additional function as providers of nitrogen/carbon source may affect energy production, replication and protein synthesis through the salvage pathways for nucleotide synthesis [7,8,9] In addition to their important direct role on the central metabolism of the cell, these and other nucleobase transporters have attracted interest as potential targets of purine/pyrimidine-based antimicrobials that could either be selectively routed into target cells to act as anti-metabolites or selectively inhibit an essential nucleobase transporter of the target cell [10,11,12,13,14]. The proteins probably function as homodimers and may use an elevator-
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