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Expression and Functional Characterization of the Human Plasma Membrane Citrate Transporter and the Vibrio cholerae Dicarboxylate Transporter
Başlık:
Expression and Functional Characterization of the Human Plasma Membrane Citrate Transporter and the Vibrio cholerae Dicarboxylate Transporter
Yazar:
Stark, Steven, author.
ISBN:
9780438079748
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (116 pages)
Genel Not:
Source: Masters Abstracts International, Volume: 57-06M(E).
Advisors: Ronald Kaplan; Marc Glucksman Committee members: Marc Glucksman; Ronald Kaplan; Min Lu.
Özet:
The human Plasma Membrane Citrate Transporter (PMCT) is the protein that drives the sodium-dependent, active transport of citrate from the extracellular space inwardly across the plasma membrane into the cytoplasm. The transporter is most abundantly expressed in liver cells as well as in the salivary glands, brain, and testis to lesser extents. Classified as SLC13A5 (solute carrier family 13 member 5), the PMCT transports various dicarboxylates and tricarboxylates, with citrate having the highest affinity and being the predominant substrate.
Citrate plays a crucial role in many biochemical pathways including the synthesis of fatty acids, phospholipids, triacylglycerols, and cholesterol. Inhibition of citrate transport has been shown, in lower eurkaryotic orthologs, to cause weight loss and a subsequent increase in life-span, which therefore makes the PMCT a promising target for pharmacological modulation in human diseases such as type 2 diabetes and morbid obesity. Furthermore, based on fuel requirements, the PMCT has been targeted for chemotherapeutic intervention in liver tumors.
Expressing the human ortholog, a key first step for functional studies, has proven to be most challenging, even while utilizing a variety of protein expression systems. Recently, we have succeeded in expressing functional PMCT in Human Embryonic Kidney 293T cells (HEK293T). We developed a specific citrate transport assay that allows us to conduct a detailed functional analysis of this transporter. In the present investigations the kinetics and substrate specificity of the expressed PMCT have been characterized and studies have been initiated to identify inhibitors of this metabolically critical transport protein. The ultimate goal of this project is to identify high-affinity PMCT inhibitors that will serve as potential lead compounds for future drug development.
This thesis also explores a plasma membrane transporter that belongs to the divalent anion/Na+ symporter (DASS) family, of which the SLC13 transporter family is a member. The DASS family of transporters is responsible for moving Kreb's cycle intermediates or sulphate across the cell membrane utilizing a Na+ gradient that is present in the cell. VcINDY (I'm Not Dead Yet), a Na+-driven succinate co-transporter from Vibrio cholerae, is the only known bacterial DASS transporter with a high-resolution structure and is relevant to drug development targeting human DASS transport proteins.
Notlar:
School code: 1489
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(694495.1) | 694495-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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