Int J Biochem Mol Biol 2012;3(3):250-272
Review Article
Insights to the evolution of Nucleobase-Ascorbate Transporters (NAT/NCS2 family) from
the Cys-scanning analysis of xanthine permease XanQ
Stathis Frillingos
Laboratory of Biological Chemistry, University of Ioannina Medical School, 45110 Ioannina Greece
Received June 5, 2012; Accepted July 2, 2012; Epub September 25, 2012; Published September 30, 2012
Abstract: The nucleobase-ascorbate transporter or nucleobase-cation symporter-2 (NAT/NCS2) family is one of the five known families of
transporters that use nucleobases as their principal substrates and the only one that is evolutionarily conserved and widespread in all major
taxa of organisms. The family is a typical paradigm of a group of related transporters for which conservation in sequence and overall structure
correlates with high functional variations between homologs. Strikingly, the human homologs fail to recognize nucleobases or related cytotoxic
compounds. This fact allows important biomedical perspectives for translation of structure-function knowledge on this family to the rational
design of targeted antimicrobial purine-related drugs. To date, very few homologs have been characterized experimentally in detail and only
two, the xanthine permease XanQ and the uric acid/xanthine permease UapA, have been studied extensively with site-directed mutagenesis.
Recently, the high-resolution structure of a related homolog, the uracil permease UraA, has been solved for the first time with crystallography.
In this review, I summarize current knowledge and emphasize how the systematic Cys-scanning mutagenesis of XanQ, in conjunction with
existing biochemical and genetic evidence for UapA and the x-ray structure of UraA, allow insight on the structure-function and evolutionary
relationships of this important group of transporters. The review is organized in three parts referring to (I) the theory of use of Cys-scanning
approaches in the study of membrane transporter families, (II) the state of the art with experimental knowledge and current research on the
NAT/NCS2 family, (III) the perspectives derived from the Cys-scanning analysis of XanQ. (IJBMB1206001).
Keywords: Nucleobase uptake, xanthine permease, Cys-scanning analysis, evolution, specificity, binding site
Address all correspondence to:
Dr. Stathis Frillingos
Laboratory of Biological Chemistry
University of Ioannina Medical School
45110 Ioannina, Greece.
Tel: 30 26510 07559; Fax: 30 2651007814
E-mail: efriligo@cc.uoi.gr
Review Article
Insights to the evolution of Nucleobase-Ascorbate Transporters (NAT/NCS2 family) from
the Cys-scanning analysis of xanthine permease XanQ
Stathis Frillingos
Laboratory of Biological Chemistry, University of Ioannina Medical School, 45110 Ioannina Greece
Received June 5, 2012; Accepted July 2, 2012; Epub September 25, 2012; Published September 30, 2012
Abstract: The nucleobase-ascorbate transporter or nucleobase-cation symporter-2 (NAT/NCS2) family is one of the five known families of
transporters that use nucleobases as their principal substrates and the only one that is evolutionarily conserved and widespread in all major
taxa of organisms. The family is a typical paradigm of a group of related transporters for which conservation in sequence and overall structure
correlates with high functional variations between homologs. Strikingly, the human homologs fail to recognize nucleobases or related cytotoxic
compounds. This fact allows important biomedical perspectives for translation of structure-function knowledge on this family to the rational
design of targeted antimicrobial purine-related drugs. To date, very few homologs have been characterized experimentally in detail and only
two, the xanthine permease XanQ and the uric acid/xanthine permease UapA, have been studied extensively with site-directed mutagenesis.
Recently, the high-resolution structure of a related homolog, the uracil permease UraA, has been solved for the first time with crystallography.
In this review, I summarize current knowledge and emphasize how the systematic Cys-scanning mutagenesis of XanQ, in conjunction with
existing biochemical and genetic evidence for UapA and the x-ray structure of UraA, allow insight on the structure-function and evolutionary
relationships of this important group of transporters. The review is organized in three parts referring to (I) the theory of use of Cys-scanning
approaches in the study of membrane transporter families, (II) the state of the art with experimental knowledge and current research on the
NAT/NCS2 family, (III) the perspectives derived from the Cys-scanning analysis of XanQ. (IJBMB1206001).
Keywords: Nucleobase uptake, xanthine permease, Cys-scanning analysis, evolution, specificity, binding site
Address all correspondence to:
Dr. Stathis Frillingos
Laboratory of Biological Chemistry
University of Ioannina Medical School
45110 Ioannina, Greece.
Tel: 30 26510 07559; Fax: 30 2651007814
E-mail: efriligo@cc.uoi.gr
 |  |  |  |  |  |  |