Meta-Biol

• Pathways

Two gene families are responsible for glucose transport in humans. SLC2 (encoding GLUTs) and SLC5 (encoding SGLTs) families mediate glucose absorption in the small intestine, glucose reabsorption in the kidney, glucose uptake by the brain across the blood-brain barrier and glucose release by all cells in the body. Glucose is taken up from interstitial fluid by a passive, facilitative transport driven by the diffusion gradient of glucose (and other sugars) across the plasma membrane. This process is mediated by a family of Na+-independent, facilitative glucose transporters (GLUTs) encoded by the SLC2A gene family (Zhao & Keating 2007; Wood & Trayhurn 2003). There are 14 members belonging to this family (GLUT1-12, 14 and HMIT (H+/myo-inositol symporter)). The GLUT family can be subdivided into three subclasses (I-III) based on sequence similarity and characteristic sequence motifs (Joost & Thorens 2001).

Hexoses, notably fructose, glucose, and galactose, generated in the lumen of the small intestine by breakdown of dietary carbohydrate are taken up by enterocytes lining the microvilli of the small intestine and released from them into the blood. Uptake into enterocytes is mediated by two transporters localized on the lumenal surfaces of the cells, SGLT1 (glucose and galactose, together with sodium ions) and GLUT5 (fructose). GLUT2, localized on the basolateral surfaces of enterocytes, mediates the release of these hexoses into the blood (Wright et al. 2004). GLUT2 may also play a role in hexose uptake from the gut lumen into enterocytes when the lumenal content of monosaccharides is very high (Kellet & Brot-Laroche 2005) and GLUT5 mediates fructose uptake from the blood into cells of the body, notably hepatocytes.

Cells take up glucose by facilitated diffusion, via glucose transporters (GLUTs) associated with the plasma membrane, a reversible reaction. Four tissue-specific GLUT isoforms are known. Glucose in the cytosol is phosphorylated by tissue-specific kinases to yield glucose 6-phosphate, which cannot cross the plasma membrane because of its negative charge. In the liver, this reaction is catalyzed by glucokinase which has a low affinity for glucose (Km about 10 mM) but is not inhibited by glucose 6-phosphate. In other tissues, this reaction is catalyzed by isoforms of hexokinase. Hexokinases are feedback-inhibited by glucose 6-phosphate and have a high affinity for glucose (Km about 0.1 mM). Liver cells can thus accumulate large amounts of glucose 6-phosphate but only when blood glucose concentrations are high, while most other tissues can take up glucose even when blood glucose concentrations are low but cannot accumulate much intracellular glucose 6-phosphate. These differences are consistent with the view that that the liver functions to buffer blood glucose concentrations, while most other tissues take up glucose to meet immediate metabolic needs.

Glucose 6-phosphatase, expressed in liver and kidney, allows glucose 6-phosphate generated by gluconeogenesis (both tissues) and glycogen breakdown (liver) to leave the cell. The absence of glucose 6-phosphatase from other tissues makes glucose uptake by these tissues essentially irreversible, consistent with the view that cells in these tissues take up glucose for local metabolic use.

Class II facilitative transporters consist of GLUT5, 7, 9 and 11 (Zhao & Keating 2007, Wood & Trayhurn 2003).

Proteins with transporting functions can be roughly classified into 3 categories: ATP-powered pumps, ion channels, and transporters. Pumps utilize the energy released by ATP hydrolysis to power the movement of the substrates across the membrane, against their electrochemical gradient. Channels at the open state can transfer the substrates (ions or water) down their electrochemical gradient, at an extremely high efficiency (up to 108 s-1). Transporters facilitate the movement of a specific substrate either against or following their concentration gradient, at a lower speed (about 102 -104 s-1); as generally believed, conformational change of the transporter protein is involved in the transfer process.

According to the Human Genome Organization (HUGO) Gene Nomenclature Committee, all human transporters can be grouped into the solute-carrier (SLC) superfamily (http://www.genenames.org/genefamilies/SLC). Currently, there are 55 SLC families in the superfamily, with a total of at least 362 putatively functional protein-coding genes (Hediger et al. 2004, He et al. 2009; http://www.bioparadigms.org/slc/intro.htm). At least 20-25% amino-acid sequence identity is shared by members belonging to the same SLC family. No homology is shared between different SLC families. While the HUGO nomenclature system by definition only includes human genes, the nomenclature system has been informally extended to include rodent species through the use of lower cases letters (e.g., Slc1a1 denotes the rodent ortholog of the human SLC1A1 gene). And it's worthwhile to mention that pumps, channels and aquaporins are not included in SLC superfamily.

To date, nine SLC gene families (SLC4, SLC5, SLC8, SLC9, SLC12, SLC20, SLC24, SLC26 and SLC34) comprise the group that exclusively transports inorganic cations and anions across membranes. A further eight SLC gene families (SLC1, SLC6, SLC7, SLC16, SLC25, SLC36, SLC38 and SLC43) are involved in the transport of amino acids and oligopeptides (He et al. 2009). Two gene families are responsible for glucose transport in humans. SLC2 (encoding GLUTs) and SLC5 (encoding SGLTs) families mediate glucose absorption in the small intestine, glucose reabsorption in the kidney, glucose uptake by the brain across the blood-brain barrier and glucose release by all cells in the body (Wood & Trayhurn 2003).

SLC transporters are able to transport bile salts, organic acids, metal ions and amine compounds. Myo-Inositol is a precursor to phosphatidylinositols (PtdIns) and to the inositol phosphates (IP), which serve as second messengers and also act as key regulators of many cell functions (Schneider 2015). Mono-, di- and tri-carboxylate transporters mediate the transport of these acids across cellular membranes (Pajor 2006, Morris & Felmlee 2008). Essential metals are transported by metal-transporting proteins, which also control their efflux to avoid toxic build-up (Bressler et al. 2007). The SLC6 gene family encodes proteins that mediate neurotransmitter uptake in the central nervous system (CSN) and peripheral nervous system (PNS), thus terminating a synaptic signal (Chen et al. 2004). Urea transport is particularly important in the process of urinary concentration and for rapid urea equilibrium in non-renal tissues (Olives et al. 1994). Choline uptake is the rate-limiting step in the synthesis of the neurotransmitter acetylcholine. SLC genes SLC5A7 and the SLC44 family encode choline transporters (Traiffort et al. 2005). The SLC22 gene family of solute carriers function as organic cation transporters (OCTs), cation/zwitterion transporters (OCTNs) and organic anion transporters (OATs). They play important roles in drug absorption and excretion. Substrates include xenobiotics, drugs, and endogenous amine compounds (Koepsell & Endou 2004).

The human SLC5A6 encodes the Na+-dependent multivitamin transporter SMVT (Prasad et al. 1999). SMVT co-transports biotin (vitamin B7), D-Pantothoate (vitamin B5) and lipoic acid into cells with Na+ ions electrogenically. Four SLC gene families encode transporters that play key roles in nucleoside and nucleobase uptake for salvage pathways of nucleotide synthesis, and in the cellular uptake of nucleoside analogues used in the treatment of cancers and viral diseases (He et al. 2009). The human gene SLC33A1 encodes acetyl-CoA transporter AT1 (Kanamori et al. 1997). Acetyl-CoA is transported to the lumen of the Golgi apparatus, where it serves as the substrate of acetyltransferases that O-acetylates sialyl residues of gangliosides and glycoproteins. Nucleotide sugars are used as sugar donors by glycosyltransferases to create the sugar chains for glycoconjugates such as glycoproteins, polysaccharides and glycolipids. The human solute carrier family SLC35 encode nucleotide sugar transporters (NSTs), localised on Golgi and ER membranes, which can mediate the antiport of nucleotide sugars in exchange for the corresponding nucleoside monophosphates (eg. UMP for UDP-sugars) (Handford et al. 2006). Long chain fatty acids (LCFAs) can be used for energy sources and steroid hormone synthesis and regulate many cellular processes such as inflammation, blood pressure, the clotting process, blood lipid levels and the immune response. The SLC27A family encode fatty acid transporter proteins (FATPs) (Anderson & Stahl 2013). The SLC gene family members SLCO1 SLCO2 and SLCO3 encode organic anion transporting polypeptides (OATPs). OATPs are membrane transport proteins that mediate the sodium-independent transport of a wide range of amphipathic organic compounds including bile salts, steroid conjugates, thyroid hormones, anionic oligopeptides and numerous drugs (Hagenbuch & Meier 2004).

By definition cells have a critical separation between inner (cytoplasmic) and outer (extracellular) compartments. This separation provides for protection, gradient assembly, and environmental control but at the same time isolates the interior compartments of the cell from energy resources, oxygen, and raw materials. Cells have evolved a myriad of mechanisms to regulate, and enable transportation of small molecules ascross plasma membranes and between cellular organelle compartments within cells.