Transporter Superfamilies In The Human Genome

SLC TRANSPORTERS The SLC superfamily includes 43 families and contains -300 human genes. Many of these genes are associated with genetic diseases (Table 2-2). SLC transporters transport diverse ionic and nonionic endogenous compounds and xenobiotics, acting either as facilitated transporters or as secondary active symporters or antiporters.

ABC SUPERFAMILY The ABC superfamily consists of 49 genes, each containing one or two conserved ABC regions. The ABC region—the core catalytic domain of ATP hydrolysis—contains Walker A and B sequences and an ABC transporter-specific signature C sequence. The ABC regions of these proteins bind and hydrolyze ATP, and the proteins use the energy for uphill transport of their substrates across the membrane. Although some ABC superfamily transporters contain only a single ABC motif, they form homodimers (BCRP/ABCG2) or heterodimers (ABCG5 and ABCG8) that exhibit a transport function. ABC transporters in prokaryotes are involved in the import of essential compounds that cannot be obtained by passive diffusion (e.g., sugars, vitamins, and metals). Most ABC genes in eukaryotes transport compounds from the cytoplasm to the outside or into an intra-cellular compartment (e.g., endoplasmic reticulum, mitochondria, and peroxisomes).

ABC transporters are divided into seven groups based on their sequence homology (Table 2-3). They are essential for many cellular processes, and mutations in at least 13 of the genes cause or contribute to human genetic disorders.

In addition to conferring multidrug resistance, an important pharmacological aspect of these transporters is xenobiotic export from healthy tissues. In particular, MDR1/ABCB1, MRP2/ ABCC2, and BCRP/ABCG2 have been shown to be involved in overall drug disposition.

Properties of ABC Transporters Related to Drug Action

The tissue distribution of drug-related ABC transporters is summarized in Table 2-4, together with information about typical substrates.

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