title: Functional specialization in nucleotide sugar transporters occurred through differentiation of the gene cluster EamA (DUF6) before the radiation of Viridiplantae.
abstract: BACKGROUND
  The drug/metabolite transporter superfamily comprises a diversity of protein domain families with multiple functions including transport of nucleotide sugars. Drug/metabolite transporter domains are contained in both solute carrier families 30, 35 and 39 proteins as well as in acyl-malonyl condensing enzyme proteins. In this paper, we present an evolutionary analysis of nucleotide sugar transporters in relation to the entire superfamily of drug/metabolite transporters that considers crucial intra-protein duplication events that have shaped the transporters. We use a method that combines the strengths of hidden Markov models and maximum likelihood to find relationships between drug/metabolite transporter families, and branches within families.
  
  
  RESULTS
  We present evidence that the triose-phosphate transporters, domain unknown function 914, uracil-diphosphate glucose-N-acetylglucosamine, and nucleotide sugar transporter families have evolved from a domain duplication event before the radiation of Viridiplantae in the EamA family (previously called domain unknown function 6). We identify previously unknown branches in the solute carrier 30, 35 and 39 protein families that emerged simultaneously as key physiological developments after the radiation of Viridiplantae, including the "35C/E" branch of EamA, which formed in the lineage of T. adhaerens (Animalia). We identify a second cluster of DMTs, called the domain unknown function 1632 cluster, which has non-cytosolic N- and C-termini, and thus appears to have been formed from a different domain duplication event. We identify a previously uncharacterized motif, G-X(6)-G, which is overrepresented in the fifth transmembrane helix of C-terminal domains. We present evidence that the family called fatty acid elongases are homologous to transporters, not enzymes as had previously been thought.
  
  
  CONCLUSIONS
  The nucleotide sugar transporters families were formed through differentiation of the gene cluster EamA (domain unknown function 6) before Viridiplantae, showing for the first time the significance of EamA.
authors.affiliation: Department of Neuroscience, Functional Pharmacology, Uppsala University, BMC, Box 593, 751 24, Uppsala, Sweden. ake.vastermark@neuro.uu.se
authors.forename: Åke
authors.initials: Å
authors.lastname: Västermark
authors.forename: Markus Sällman
authors.initials: MS
authors.lastname: Almén
authors.forename: Martin W
authors.initials: MW
authors.lastname: Simmen
authors.forename: Robert
authors.initials: R
authors.lastname: Fredriksson
authors.forename: Helgi B
authors.initials: HB
authors.lastname: Schiöth
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D001692:Biological Transport; D050260:Carbohydrate Metabolism; D027682:Cation Transport Proteins / Q000235:genetics; D016384:Consensus Sequence; D019143:Evolution, Molecular; D006801:Humans; D026901:Membrane Transport Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005810:Multigene Family; D009711:Nucleotides / Q000378:metabolism; D010802:Phylogeny; D010940:Plant Proteins / Q000235:genetics*; D017434:Protein Structure, Tertiary; D057948:Viridiplantae / Q000235:genetics* / Q000378:metabolism
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D027682:Cation Transport Proteins; D026901:Membrane Transport Proteins; D009711:Nucleotides; D010940:Plant Proteins