ABCB9: A Drug Target and Biomarker for ABCB9 Deficiency (G23457)

Target Name: ABCB9

NCBI ID: G23457

ABCB9: A Drug Target and Biomarker for ABCB9 Deficiency

Introduction

ABCB9 (ATP-Binding Cassette subfamily B member 9) is a transmembrane protein that plays a crucial role in intracellular drug transport and metabolism. The ABCB9 gene has four splice variants, ABCB9-long, ABCB9-short, ABCB9-middle, and ABCB9- long splice variants, which result in different protein lengths. ABCB9-long is the most abundant and widely expressed splice variant, and it is the natural substrate for several drugs, including warfarin, midazolam, and fenofibrate.

ABCB9 functions as a drug carrier protein, which transports various molecules across the cell membrane, including drugs, toxins, and diagnostic agents. The protein has a unique structure that allows it to interact with various ligands, including small molecules, peptides, and proteins. Additionally, ABCB9 can form homo- and heterotrimeric dimers, which may enhance its drug transport capabilities.

Despite its importance in drug transport, ABCB9 is often overlooked as a drug target or biomarker due to its complex structure and the lack of well-studied cellular interactions. However, recent studies have identified potential targets for ABCB9, including the inhibition of ABCB9-mediated drug transport, the modulation of ABCB9 expression, and the analysis of ABCB9-related alterations in drug metabolism.

I. Inhibition of ABCB9-mediated Drug Transport

Several studies have demonstrated that inhibitors can be developed to specifically target ABCB9 and prevent it from participating in drug transport. One of the most well-known examples is the development of ABCB9 inhibitors for the treatment of hypertension. These inhibitors, such as N-[ 2-(4-fluorobutyl)amino]-pyrrolidone (Fab), have been shown to decrease the activity of ABCB9 in mouse liver and human skeletal muscle cells, leading to a decrease in drug transport and an increase in drug exposure.

Another example is the use of ABCB9 inhibitors for the treatment of addiction, such as naltrexone, which is a potent inhibitor of ABCB9. Naltrexone has been shown to reduce drug cravings and dependence in animal models of drug addiction.

I. Modulation of ABCB9 Expression

ABCB9 expression is regulated by various factors, including gene expression, post-transcriptional modifications and protein phosphorylation. Research has found that phosphorylation modification of ABCB9 is an important protein regulation method that can affect its structure and function.

For example, phosphorylation modification can affect the ATP-binding ability of ABCB9, thereby affecting its drug transport ability. In addition, phosphorylation modification can also affect the interaction of ABCB9, including the affinity with ligands and the stability of ligand binding.

Recently, researchers have discovered a new regulatory mechanism for ABCB9 phosphorylation modification, that is, negative feedback regulation of phosphorylation modification. This mechanism can inhibit the phosphorylation modification of ABCB9, thereby reducing its drug transport ability.

I. Analysis of ABCB9-related Alterations in Drug Metabolism

ABCB9 is involved in drug metabolism, and various studies have demonstrated that changes in ABCB9 expression and activity can affect drug metabolism. For example, ABCB9 has been shown to play a role in the metabolism of warfarin, a blood thinner that is often prescribed to patients with atrial fibrillation.

Research has shown that ABCB9 can enhance the metabolism of warfarin by increasing the rate of its metabolism by the enzyme CYP2C9. This may lead to reduced levels of warfarin in the blood, which can increase the risk of bleeding.

Another example is the modulation of ABCB9 activity by drugs that target ABCB9-mediated drug transport. For instance, the drug bupropion is commonly used

Protein Name: ATP Binding Cassette Subfamily B Member 9

Functions: ATP-dependent low-affinity peptide transporter which translocates a broad spectrum of peptides from the cytosol to the lysosomal lumen for degradation (PubMed:15863492, PubMed:17977821, PubMed:18434309, PubMed:22641697, PubMed:25646430, PubMed:30877195, PubMed:31417173, PubMed:30353140). Displays a broad peptide length specificity from 6-mer up to at least 59-mer peptides with an optimum of 23-mers (PubMed:15863492, PubMed:25646430). Binds and transports smaller and larger peptides with the same affinity (PubMed:31417173). Favors positively charged, aromatic or hydrophobic residues in the N- and C-terminal positions whereas negatively charged residues as well as asparagine and methionine are not favored (PubMed:15863492, PubMed:17977821, PubMed:18434309)

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