The SLC37 Family of Sugar-Phosphate/Phosphate Exchangers

Abstract

The SLC37 family members are endoplasmic reticulum (ER)-associated sugar-phosphate/phosphate (Pi) exchangers. Three of the four members, SLC37A1, SLC37A2, and SLC37A4, function as Pi-linked glucose-6-phosphate (G6P) antiporters catalyzing G6P:Pi and Pi:Pi exchanges. The activity of SLC37A3 is unknown. SLC37A4, better known as the G6P transporter (G6PT), has been extensively characterized, functionally and structurally, and is the best characterized family member. G6PT contains 10 transmembrane helices with both N and C termini facing the cytoplasm. The primary in vivo function of the G6PT protein is to translocate G6P from the cytoplasm into the ER lumen where it couples with either the liver/kidney/intestine-restricted glucose-6-phosphatase-α (G6Pase-α or G6PC) or the ubiquitously expressed G6Pase-β (or G6PC3) to hydrolyze G6P to glucose and Pi. The G6PT/G6Pase-α complex maintains interprandial glucose homeostasis, and the G6PT/G6Pase-β complex maintains neutro-phil energy homeostasis and functionality. G6PT is highly selective for G6P and is competitively inhibited by cholorogenic acid and its derivatives. Neither SLC37A1 nor SLC37A2 can couple functionally with G6Pase-α or G6Pase-β, and the antiporter activities of SLC37A1 or SLC37A2 are not inhibited by cholorogenic acid. Deficiencies in G6PT cause glycogen storage disease type Ib (GSD-Ib), a metabolic and immune disorder. To date, 91 separate SLC37A4 mutations, including 39 missense mutations, have been identified in GSD-Ib patients. Characterization of missense mutations has yielded valuable information on functionally important residues in the G6PT protein. The biological roles of the other SLC37 proteins remain to be determined and deficiencies have not yet been correlated to diseases.

Type I glycogen storage diseases: disorders of the glucose‐6‐phosphatase/glucose‐6‐phosphate transporter complexes

“…GSD-Ib is not restricted to any one racial or ethnic group, although prevalent mutations in the SLC37A4 gene have been described in several groups (Chou et al , 2010Chou and Mansfield 2014). Notably, not all patients diagnosed with GSD-Ib, based on their metabolic phenotype and genetic analysis, seem to develop neutropenia (Chou et al 2010).…”

“…The human G6PT protein is encoded by the single copy SLC37A4 gene that was initially reported, based on sequence homology, as a member of the solute carrier family 37 (SLC37) (Chen et al 2008;Chou and Mansfield 2014). The SLC37A4 gene is composed of nine exons (Hiraiwa et al 1999) located on chromosome 11q23 and produces two alternatively spliced transcripts, that encode the primary, ubiquitously expressed G6PT (Gerin et al 1997) and the brain/heart/muscle-specific variant G6PT (Lin et al 2000).…”

“…These include 39 missense, 11 nonsense, 22 insertion/deletion, and 19 splicing mutations. Of these, 31 missense and two codondeletion mutations have been confirmed as pathogenic using site-directed mutagenesis and transient expression assays, resulting in the abolishment, or greatly reduced microsomal G6P uptake activity Chou and Mansfield 2014). As with the G6PC mutations there does not appear to be a strict genotype-phenotype relationship.…”

“…Whether this is a true lack of penetrance, which might suggest there are important modifier gene activities, or not, remains to be determined. To date, 92 separate mutations have been identified in the SLC37A4 gene of GSD-Ib and non-GSD-Ia patients (Chou et al 2010;Chou and Mansfield 2014). These include 39 missense, 11 nonsense, 22 insertion/deletion, and 19 splicing mutations.…”

Crystal structures reveal a new and novel FoxO1 binding site within the human glucose-6-phosphatase catalytic subunit 1 gene promoter

“…The catalytic subunit of G6Pase is encoded by one of three genes, G6PC1 , G6PC2 and G6PC3 whereas the antiporter that catalyzes transport of glucose-6-phosphate and inorganic phosphate is encoded by the SLC37A4 gene (Chou and Mansfield, 2014; Hutton and O’Brien, 2009). Hepatic gluconeogenesis is regulated in part by transcription mechanisms with both G6PC1 and SLC37A4 being targets for hormone- and nutrition-dependent modulation of expression (Mihaylova et al, 2011; Oh et al, 2013a).…”