Six TM Alpha-
helices with one (NBD)
Figure 1two categories of ABC
Mechanism of Work:
It begins in the TMDs which recognize the
substrate by its sequence of recognition (part of the TMDs, it is not identified
yet). This recognition enhances the ATPase activity by which promotes the ATP
hydrolysis which ensure the require energy for substrate translocation.
Conformational change determines the open and
close states of the transporter and it’s result of substrate binding and ATP
ABCB1 and its Function:
ABCB1 (P-gp) is one of the ABC transporters, it
belongs to ABCB subfamily. It is found in all living organism on chromosome
7q21, that codes for 1280 amino acid which form ABCB1 protein. It localizes in different
plasma membrane compartments specially in organs that has barrier, elimination,
protective, and excretion functions.The most important role is to limit the
bioavailability of the drugs by efflux it out the cells of intestine, colon, and
liver. By applying that, it plays a master role in detoxification, it also has
a defense mechanism against Xenobiotic and metabolites. Another important role
of ABCB1, that is transporting hormone if it was expressed in the adrenal gland.
In immunological system and lymphocyte, it plays a role in viral resistance.
Finally, it is also important in lipid homeostasis.
It’s high capacity of transport and diverse
range of substrate recognition makes it able to transport abroad of substrates.
In addition, It prefers uncharged or positively charged hydrophobic compounds.
ABCB1 role in drug resistance:
ABCB1 (P-glycoprotein) works as a protective
structure of cells to keep them alive. On the other hand, it can be a cause of death.
It controls the bioavailability of drugs inside the cells and its toxicity.
P-gp reduces cellular drug exposure by pumping drug out the cells.
Drugs play two important roles in cancer
prevent proliferation (cytostatic effect).
kill the cancer cell (cytotoxic effect): It leads the cancer cells
to death by increase the DNA damage or give signals to other cells to kill the
cancer cell. Drugs accumulation is important to achieve this goal, so when the
cells use the P-gp pump, it will not be helpful.
Mutations may have influence on P-gp
expression, function, and disease risk. Some mutations can lead to loss of
function or gain of function that may cause drug resistance. For example, loss
of Bax (pro-apoptotic protein) associated with an increased drug resistance to
antimetabolites 5-flourouracil in colorectal cancer cell. Cells become
resistance to drugs by Increasing and decreasing the influx of the drug (defect
in P-gp expression), Increasing the number of target molecules within the cell,
Altering drug metabolism or DNA repair processes.
Interaction of drugs with the transporters leads
the cancer cells to use the P-gp pump as a resistance feedback against drugs, so
they are trying to develop anticancer drug which not interact with any of the
Full transporter half
ABCB1 transporter fall in two categories:full
transporter and half transport. However, ABCG2 includes only half transporter
while ABCC1 includes only full transporter.
The general structure of ABC protein consists
of four domains, two of them are transmembrane domains (TMDs), and the other
two are nucleotide binding domains (NBD). The domains can represent either full
transporter or half transporter. TMDs form like a pore structure across the
membrane and they are responsible for spanning the membrane to efflux the
substrates out.They depend on the inner domain (NBD) by which the energy will
be derived.TMDs are more variable and composed of 12 TM Alpha-helices proteins
(6 per domain), each six subunits of TMDs are attached to one NBD. NBDs located
in the cytoplasmic face, considered as a place of ATP binding to power the
Structure of ABCB1:
There are seven subfamilies of ABC transporters,
they were grouped based on the similarity in the gene structure, order of the
domains, and sequence homology in the nucleotide binding domains (NBD) and transmembrane
domains (TMD). ABC transporters can function as importers or exporters. Each
member of ABC transporters performs a different function. Physiological
expression and role of the transporter will determine the substrate which can
export out the cell.
ATP-binding cassette (ABC) transporter is one
of the most understanding transporters in living organism. ABC transporters
form a large family which contain 48 members of membrane protein which are
responsible for transporting a verity of compounds across the cell membrane. ABC
transporters are active transporter, they depend on ATP hydrolysis. They are found
in all forms of living organism (both simple and complex organisms). They work
as a protective structure of the cells from an endogenous biometabolites and
toxic compounds. If the role of protection has been defected, it will prevent
uptake or clearance of the substances in a way that can cause some diseases.