**4.7. Class II family members**

With GLUT5 being identified in 1990 and established as a fructose transporter initial transport studies for GLUT7 and 9 indicated that those transporters might also transport fructose. A specific feature for class II transporters is that cytochalasin B as a classical GLUT inhibitor does not block glucose transport. Furthermore, all isoforms do not show an affinity for 2-DG and galactose. Unique for GLUT9 and GLUT11 is the alternative splicing /promoter usage, where either two or three different mRNA's are transcribed, respectively. In case of GLUT9 this leads to two proteins that only differ in their N-terminal region.

between fructose and non-fructose transporting GLUT isoforms identified a motif in GLUT7 that potentially confers its ability to transport fructose. Mutational analysis of those residues in GLUT7 identified isoleucine 314 as an important determinant for fructose affinity. The finding of a specific residue within the extracellular vestibule of helix 7 that drives substrate specificity was extended to GLUT2, 5, 9 and 11 and proposed as a common NXI/V consensus

Mammalian Sugar Transporters http://dx.doi.org/10.5772/58325 27

Human GLUT9 cDNA was isolated by PCR amplification from a human kidney cDNA library on the basis of sequence information from ESTs and from its genomic sequence. GLUT9 mRNA is detected almost exclusively in the kidney and liver and at low levels in the small intestine, placenta, lung and leucocytes. GLUT9 is localized to the insulin-secreting β-cells of human and mouse islets, where downregulation of the protein by siRNA in rat and mouse insulinoma cells leads to a reduced glucose-stimulated insulin secretion. In humans as well as in mice alternative splicing/or promoter usage results in two proteins, GLUT9a and GLUT9b, which only differ in their N-terminal region. While human and mouse GLUT9b are mainly expressed in the kidney, placenta and liver, GLUT9a shows a broader tissue distribution. The different N-termini of human GLUT9a and b determine basolateral versus apical sorting in polarized cells *in vitro*, respectively. In mouse kidney, GLUT9 is localized to apical as well as basolateral membranes of distal convoluted tubules. Initial characterization of GLUT9 determined a rather low affinity for 2-DG. However, a high affinity transport has been reported for glucose and fructose with Km values of 0.6 mM and 0.4 mM, respectively. More recently, GLUT9 has been identified as a high-affinity uric acid transporter with a Km of 0.9 mM and 0.6 mM for the human and mouse protein, respectively. Although transport of glucose and fructose has not been observed by some investigators, GLUT9 is thought to exchange glucose or fructose for urate. The classical inhibitor cytochalasin B does not block GLUT9 function. GLUT9 has been established to represent a major regulator of urate homeostasis in dogs, mice, and men.

*In humans GLUT9 is involved in renal uric acid reabsorption-mutations in the GLUT9 gene have*

Various genome wide association studies uncovered polymorphisms in *SLC2A9* as being one of the most significantly associated genes that can be linked to gout and increased serum uric acid concentrations. Although the identified SNPs are located in intronic regions of the gene, evidence exists that increased RNA expression for GLUT9 positively correlates with increased serum uric acid concentrations. In contrast, exonic mutations in GLUT9 suggested that loss of GLUT9 function is associated with hypouricemia. Two distinct heterozygous missense mutations (R380W and R198C in GLUT9a) were described in three patients with hypouricemia. The two mutations were shown to result in loss of function when uric acid transport was studied in *Xenopus laevis* oocyes. A genome-wide homozygosity screen linked hereditary hypouricemia to two homozygous SLC2A9 mutations that lead to a missense mutation (L75R) or a 36-kb deletion. The homozygous loss-of-function mutations of GLUT9 caused a total defect

motif among isoforms capable of transporting fructose.

**4.10. GLUT9** *(SLC2A9)*

*4.10.1. GLUT9 physiology*

*consequences on plasma uric acid levels*
