ATP Binding Cassette Transporters, also known as ABC transporters are one of largest superfamily of proteins that utilize ATP energy for moving substrate across biological membrane [1]. Various inorganic as well as organic molecules such as proteins, metal ions are carried across membranes by these ABC transporters [2][3]. ABC transporters have magnificent role in regulating the metabolism of lipids, maintain the homeostasis of cholesterol [4]. Literature survey indicates that ABC transporters are classified as exporters, importers, extruders on the basis catalyzed substrate translocation, by their direction [5]. The transporters present in the human functions by secreting from cells cytotoxic compounds. The P Glycoprotein, MRP1 and BCRP have large presence in kidney, liver and guts. They decrease the bioavailability of administered drugs. BCRP and P-Glycoprotein also performs as a barrier due to their expression in brain and placenta [6] [7]. Till now, total of 49 types of ABC transporters are found in humans, which also includes a pseudogene. These types are again divided in the seven subfamilies which is differentiated on the basis of various aspects like structure of gene, the sequence of amino acid and domain organization [8]. The basic structure of ABC Transporters consists of 4 domains, in which two are transmembrane domains and the remaining two are Nucleotide-binding domains, also regarded as full transporters [9]. Half transporters consist of genes with only one transmembrane as well as nucleotide binding unit, which with dimerization linked with other half transporters. The dimer formed can be homo as well as hetero [5, 10, 11].

Due to extensive expression of ABC Transporters in drug-resistance tumors, they implicated as tumor cell protecting agents. These agents reduce pharmacological action by modifying concentration of drug [12]. Additionally, ABC transporters have been noted to cause Multi-Drug Resistance in human cells and are evident in failure of anticancer therapies, serious public health concern [9,13] Evidences indicated approximately 21 ABC transporters are found in association of monogenic disorders [14] Such as Cystic fibrosis, Dublin-Johnson syndrome, MDR tumors and hypoglycemia in children [15].

Researchers indicated the role of Cystic Fibrosis Transmembrane Conductance Regulator, ABC Transporter (ABCC7) which is targeted by drug. Approved drug is used for treatment of cystic fibrosis [8,14]. The compounds that targets CFTR helps improving the pulmonary function by maintaining chloride transport [10].

Structure of ABC Transporters

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Various reports conducted that ABC Transporters possess two domains; transmembrane domains are responsible for translocation across pathway and Nucleotide Binding domains hydrolyzes the ATP. These TMDs and NBDs works as single polypeptide chains in ABC importers. In addition, NBD have further subdomains such as RecA-like and helical subdomain. [1] The TMD consist 6 to 10 alpha-helix for 12 to 20 segments, according to the class of transporters [16]. The TMDs and NBDs possess intracytosolic loop domains, which function to coordinate the binding as well as hydrolysis of ATPs by transferring signals [17].

Roles of ABC Transporters in diseases:

In Monogenic diseases: As of today, 21 ABC transporters have been found in various monogenic diseases.

ABC Transporters and their association with various diseases:

1. Cardiometabolic diseases:

2. Neurological Disease

3. Liver Diseases

4. Rheumatoid disease

5. Ophthalmological disease

Table 1 and 2 is obtained from latest research article where the role or even presence of ABC Transporters in various diseases has been cited. [59].

Therapeutic Implications of ABC Transporters in major disorders –

1. Alzheimer’s disease – AD is neurodegenerative disease in which there is extensive loss of neurons and hyper phosphorylation of tau proteins, also there is accumulation of amyloid plaques [18,19].

By relevance, the Transporters found in AD are – ABCA7, ABCA1, ABCB1, ABCG2, ABCA2, ABCC1, ABCG1, ABCG4, ABCA5.

1. ABCA7 – The association of AD with this transporter is proposed on observations that increase in SNPs increases AD risk. SNP rs3764650 is variant for sporadic AD [20]. According to the research, ABCA7 alters processing of AβPP and inhibits Aβ production in cells [21,22].
2. ABCA1 – After ABCA7, the ABCA1 has the largest association with sporadic Alzheimer’s disease. The gene is present close to chromosome 9q, several loci present there is predicted to have influence on AD [23].
3. ABCB1 – There is modest linkage between ABCB1 SNPs (rs1045642 and rs2032582) which has maybe associated with sporadic AD [24,25]. The ABCB1 SNP rs2032582 can increase Alzheimer’s risk in gender specific and allele dependent manner [24].
4. ABCG2 – A study about genetic association shows the linkage of ABCG2 SNP rs2231142 with more likely to develop sporadic AD [26]. Various studies have also shown the directly interaction of ABCG2 with Aβ [27].
5. ABCA2 – The relationship of ABCA2 and AD is shown after two studies identified a genetic variant of ABCA2 – SNP rs908832 which shows higher susceptibility of both sporadic and non-sporadic AD [28,29].
6. ABCC1 – Some reports suggested the protective role of ABCC1 in AD. In study, researchers found that deficiency of ABCC1 in mice caused higher levels of Aβ40 and Aβ42. The increased level of proteins results in rise of amyloid plaque burden. Upon treatment with ABCC1 agonist, the negative effects due to ABCC1 deficiency were decreased [30].
7. ABCG1 – The studies regarding role of ABCG1 is limited. Some reports suggested that AD pathogenesis is prevented by ABCG1 [31]. Another study showed increased ABCG1 levels didn’t affect Aβ protein, Aβ precursor protein [32]. Further research is necessary to understanding the exact relationship of ABCG1 with AD.
8. ABCG4 – ABCG4 has some protective activities against AD, by mimicking the action of other transporters. Similar to ABCG1, ABCG4 also decrease the amount of Aβ in cell culture models [31].
9. ABCA5 – According to recent study, there was notable increase in ABCA5 in hippocampus part of brain in AD patients. ABCA5 lowered both Aβ40 and Aβ42, without any change in AβPP mRNA [33].

Notably, extensive research is indeed required to fully understand the role of ABC Transporters in AD. But previous studies have shown critical role in protecting CNS from damaging effects of Aβ protein.

ABC Transporter in cardiovascular diseases:

1. Atherosclerosis: Atherosclerosis is condition in which plaques form up on inner wall of arteries. It is heavily influenced by hypertension, diabetes, smoking etc.
2. ABCA1 – ABCA1 is most prominent transporter in influencing atherosclerosis. Because of its role in formation of HDL [34].
3. ABCG1 – The ABCG1 had been reported in increasing the level of advanced lesions. This role is linked via inducing the necrotic core of Atherosclerosis plaque [35].
4. ABCC6 – Relationship of ABCC6 with cardiovascular diseases is not much defined [36]. However, there is role of ABCC6 in abnormal calcification of specific tissues. Calcification is linked with atherosclerosis [37,38].
5. ABCG5/ABCG8 – These transporters are linked with promoting excretion of sterols. The mutations in these transporters are responsible for sitosterolemia. The early onset of Atherosclerosis is also linked with reduced biliary excretion of dietary sterols [39].

Type 2 Diabetes Mellitus:

1. ABCA1 – Abnormal functioning of this transporter in b -cells of pancreas leads to buildup of cholesterol and decrease in HDL-C. This decreases the amount of insulin secretion, inevitably causing the Diabetes [40].
2. ABCG1 – Without ABCG1, the insulin granules formation is not up to mark. Further, the deficiency leads to inhibit insulin secretion [41].

ABC Transporters in Rheumatoid Diseases:

1. Gout: Gout is an inflammatory disease which affects the joints. The main cause of gout is increased levels of uric acid.
2. ABCG2: Common variants of ABCG2 (Q126X and Q141K) are linked strongly with gout [42]. Also, age of onset of gout is associated with these variants [43].

Pharmacotherapeutic Potential of ABC Transporters: Till now the Cystic Fibrosis is the only disease that has been treated by the ABC Transporters.

Cystic Fibrosis -: Cystic fibrosis is inherited monogenic disorder which has been linked with ABC Transporters. This recessive disease can be diagnosed by raised concentrations of sweat chloride and mutations in ABCC7 gene, also known as CFTR [44]. The mutations occur in CFTR gene is classified into 6 various classification based on defects which is happening in production process [45,46]. The seriousness of Cystic Fibrosis is completely dependent on mutations type, genes and presence of alleles [47].

CFTR Protein – Main functions of CFTR gene are transportation of bicarbonate and chloride across sweat glands, GIT, pancreas, airways [48]. Abnormal CFTR causes dehydration in airways which leads to thick mucopulurent secretions, inflammation and lung damage [49].

Types of mutations in CFTR Gene:

1. Class 1 mutation – The mutations caused by defects in the protein production. In class 1 mutation, there is premature termination of mRNA. Examples are G542X, W1282X, R553X.
2. Class 2 mutations – Class 2 mutations are caused due to protein processing defects. The mutations alter post-translational process of CFTR Protein.
3. Class 3 mutations – The defective regulation causes the class 3 mutations. Despite ATP levels being adequate, class 3 mutations diminish the channel activity.
4. Class 4 mutations – Arises due to defect in conduction process. The CFTR Protein is transported to the cell surface as usual, but channel opening time and ion flow rate is decreased comparing to normal CFTR Protein. Class 4 mutations commonly occurs in Caucasian population that induces CFTR Protein amino acid substitution (R117H) [50].
5. Class 5 mutations – This class is not major one. Class 5 mutations caused due to decreased level of functional CFTR Protein. Alternations in mRNA stability and alternation of mature CFTR Protein are examples of class 5 mutations [46,51].
6. Class 6 mutations – Class 6 mutations caused by decreased CFTR stability. Instability of substantial plasma membrane occurs in these mutations [46].

As of 2021, a total of 2107 have been recorded in Cystic Fibrosis Mutation Database (www.genet.sickkids.on.ca/StatisticsPage.html)

Therapies for Cystic Fibrosis:

CFTR modulators: CFTR modulators are class of molecules that helps in Cystic Fibrosis by helping restoring the function of defective CFTR Protein after binding with them [52].

Ivacaftor: Ivacaftor was the first CFTR modulator that has been in market from 2012. It comes under CFTR potentiator. As of 2023, Ivacaftor is now approved for patients older than 1 month and older. Ivacaftor up-regulate the frequency of CFTR channel opening after binding with CFTR protein in plasma membrane [53,54] It is sold under the commercial name of Kalydeco, developed by Vertex Pharmaceuticals.

Tezacaftor: CFTR corrector which was developed with Lumacaftor to target F508del mutations. The combination with Ivacaftor and Tezacaftor was approved in 2018 [55,56].

Lumacaftor: Lumacaftor is CFTR corrector which is developed after promising results of ivacaftor. The mechanism is not completely known, but according to some researchers Lumacaftor helps in repairing the aberrant assembly of protein [57]. The combination of Ivacaftor and Lumacaftor was approved in 2015 under brand name Orkambi.

Elexacaftor: A next generation CFTR corrector which at cell surface elevates the mature CFTR protein. Elexacaftor is given in combination with Tezacaftor and Ivacaftor for F508del mutations (58). It was given approval for patients aged 12 years and older under the name Kaftrio-Kalydeco.

Role of ABC transporters in human body and diseases has been huge. But despite various research and publications, we are still not able to reach the threshold potential in understanding ABC transporters. Although the drug has been developed against cystic fibrosis targeting the ABCC7 protein, the future possibilities of ABC transporters in clinical research are huge. Association of multiple ABC transporters in various mental disorders makes them promising prospect in future medical advancements. This field of research is still in process and evolving to target ABC transporters directly for therapeutic purposes.

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