Metabolic function and hinting at therapeutic prospective in combatingCorrespondence to Joseph A. P/Q-type calcium channel Antagonist list Mindell: [email protected] Abbreviations employed in this paper: DASS, divalent anion:Na+ symporter; MM(PEG)12, methyl-PEG12-maleimide.The Rockefeller University Press 30.00 J. Gen. Physiol. Vol. 143 No. six 74559 jgp.org/cgi/doi/10.1085/jgp.metabolic illness, obesity, and diabetes (Birkenfeld et al., 2011). Members of your SLC13 loved ones are 50 identical to each and every other and display distinct functional properties. NaCT is mostly a citrate transporter but also can transport C4-dicarboxylates for instance succinate, fumarate, and malate (Inoue et al., 2002b). NaDC1 and NaDC3 are C4-dicarboxylate transporters with a low and high affinity, respectively, but additionally retain the capability to transport citrate (Pajor, 1995; Pajor and Sun, 1996, 2000; Kekuda et al., 1999; Oshiro and Pajor, 2005). Two other SLC13 members (NaS1 [SLC13A1] and NaS2 [SLC13A4]) transport, among other compounds, divalent anions sulfate and selenate (Busch et al., 1994; Markovich et al., 2005). Despite differences in substrate affinity and specificity, all five SLC13 members couple the electrogenic transport of their respective substrates for the transport of multiple Na+ ions. The SLC13 transporters belong to a larger group of related transporters known as the divalent anion:Na+ symporter (DASS) household (Transporter Classification Database no. two.A.47) (Saier et al., 2006). Knockdown of a geneThis post is distributed below the terms of an Attribution oncommercial hare AlikeNo Mirror Web pages license for the very first six months right after the publication date (see http://www .rupress.org/terms). Soon after six months it really is available under a Creative Commons License (Attribution oncommercial hare Alike 3.0 Unported license, as described at http:// creativecommons.org/licenses/by-nc-sa/3.0/).encoding a DASS family members member (I am not dead but [INDY]) inside the fruit fly Drosophila melanogaster leads to lowered fat storage and, interestingly, an extended lifespan phenotype, mimicking the effects of caloric restriction (Rogina et al., 2000). In contrast to its human counterparts, citrate and C4-dicarboxylate transport by the fly homologue, DrINDY, is apparently electroneutral and cation independent (Knauf et al., 2002). Various bacterial DASS family members (30 identical to human SLC13 family members) have also been studied, revealing functional characteristics sometimes equivalent but in some cases divergent compared with all the human homologues. Nonetheless, the similarities are sufficient to suggest a comparable architecture and shared fundamental mode of action (Hall and Pajor, 2007; Youn et al., 2008; Strickler et al., 2009; Pajor et al., 2013). Recently, our understanding of the transport mechanism of this family members took a substantial step MMP-9 Activator Compound forward together with the publication of a high resolution x-ray crystal structure of VcINDY, a SLC13 homologue from Vibrio cholerae (Mancusso et al., 2012) (Fig. 1, A and B). VcINDY is 2633 identical to SLC13 members of the family in amino acid sequence and, like other DASS members of the family, couples a Na+ gradient to the transport of succinate, a C4-dicarboxylate, in cell-based assays (Mancusso et al., 2012). In these assays, transport of succinate is inhibited by the presence of other C4-dicarboxylates, malate and fumarate, suggesting that they may also serve as substrates. Alternatively, citrate and glutamate only mildly inhibit succinate transport, whereas sulfate has no effect (Mancusso et al., 2012).
