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The chemistry and biology of secramine

Record Type:	Electronic resources : Monograph/item
Title/Author:	The chemistry and biology of secramine
Author:	Pelish, Henry Efrem.
Description:	187 p.
Notes:	Adviser: Matthew D. Shair.
Notes:	Source: Dissertation Abstracts International, Volume: 65-05, Section: B, page: 2423.
Contained By:	Dissertation Abstracts International65-05B.
Subject:	Chemistry, Organic.
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3131951
ISBN:	0496791915

The chemistry and biology of secramine
Pelish, Henry Efrem.

The chemistry and biology of secramine [electronic resource] - 187 p.

Adviser: Matthew D. Shair.

Thesis (Ph.D.)--Harvard University, 2004.

As a portable, tunable, and cell-permeable probe, secramine was used to test whether Cdc42 was required for cholera toxin-induced chloride transport in intestinal crypt epithelial cells, a pathway responsible for life-threatening secretory diarrhea. Cholera toxin activity requires retrograde transport through the secretory pathway and CAMP-dependent ion flux through membrane transporters and channels. Secramine inhibited cholera toxin-induced chloride transport and acted by selectively disrupting barium-sensitive basolateral membrane K+ channel conductance. Furthermore, secramine inhibited cAMP-dependent Cdc42 activation and rounding of Y1 cells. These experiments revealed a pathway whereby RhoGTPases modulate cAMP-dependent basolateral K+ channel activity and cellular morphological changes. The synthesis, discovery, and use of secramine demonstrate the efficacy of a chemical genetics approach to defining biological function.

ISBN: 0496791915Subjects--Topical Terms:

193634
Chemistry, Organic.

The chemistry and biology of secramine
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245 1 4 $a The chemistry and biology of secramine $h [electronic resource]
300 $a 187 p.
500 $a Adviser: Matthew D. Shair.
500 $a Source: Dissertation Abstracts International, Volume: 65-05, Section: B, page: 2423.
502 $a Thesis (Ph.D.)--Harvard University, 2004.
520 # $a As a portable, tunable, and cell-permeable probe, secramine was used to test whether Cdc42 was required for cholera toxin-induced chloride transport in intestinal crypt epithelial cells, a pathway responsible for life-threatening secretory diarrhea. Cholera toxin activity requires retrograde transport through the secretory pathway and CAMP-dependent ion flux through membrane transporters and channels. Secramine inhibited cholera toxin-induced chloride transport and acted by selectively disrupting barium-sensitive basolateral membrane K+ channel conductance. Furthermore, secramine inhibited cAMP-dependent Cdc42 activation and rounding of Y1 cells. These experiments revealed a pathway whereby RhoGTPases modulate cAMP-dependent basolateral K+ channel activity and cellular morphological changes. The synthesis, discovery, and use of secramine demonstrate the efficacy of a chemical genetics approach to defining biological function.
520 # $a Chemical genetics is the systematic discovery and use of small molecules to perturb and thereby gain insight into biological function. Inspired by the fundamental contributions that natural products have made to chemistry, biology, and medicine, presented here is the solid phase biomimetic diversity-oriented synthesis and screening of a library of &sim;2,500 galanthamine-like small molecules. The library synthesis highlights the utility of complexity-generating reactions and introduces split-parallel synthesis, as an alternative to split-pool and parallel synthesis, for the rapid construction of thousands of small molecules without the need for chemical encoding. In an image-based phenotypic screen, a member of the library, named secramine, inhibited Golgi apparatus to plasma membrane exocytosis.
520 # $a Secramine inhibits protein export from the trans-Golgi network to the basolateral plasma membrane and seemingly acts by perturbing Cdc42- and Rac1-dependent signaling pathways. Cdc42 and Rac1 are members of the Rho family of small GTPases (RhoGTPases) and are active when bound to GTP and associated with membranes. Secramine prevents their membrane association, possibly by stabilizing the interaction between Cdc42 and RhoGDI, a protein that shuttles Cdc42 between the cytosol and intracellular membranes. By synthesis and testing of secramine analogs, structure-activity corroborated the link between Cdc42 function and protein trafficking.
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773 0 # $g 65-05B. $t Dissertation Abstracts International
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790 1 0 $a Shair, Matthew D., $e advisor
791 $a Ph.D.
792 $a 2004
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