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UNCOVERING THE MOLECULAR BASIS FOR FATTY ACID SYNTHASE PRODUCT SPECIFICITY: STRUCTURAL AND KINETIC EVALUATION OF THIOESTERASE I AND THIOESTERASE II

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abstract
Fatty acid synthase (FASN) is a multifunctional homodimeric enzyme solely responsible for the synthesis long chain fatty acids (LCFAs) de novo. Fatty acids, and their lipid derivatives, are critical components of all cellular biological processes, including energy storage and utilization, membrane maintenance and expansion, post-translational modification of proteins, and intracellular signalling. FASN primarily generates palmitate (C16) and to a lesser extent stearate (C18), and this strict product distribution is dictated by the acyl chain-length selectivity of the endogenous thioesterase (TE1) domain. With the exception of lactating breast, liver and adipose tissues, FASN expression is essentially absent in normal cells since these cells obtain lipids from the diet. In lactating breast, the product distribution of FASN is modulated by a monofunctional type II thioesterase, called thioesterase II (TE2), to favor the medium chain fatty acids (MCFAs) laurate (C12) and myristate (C14). The TE2 interaction with FASN and its ability to outcompete TE1 for the acyl substrate tethered to the acyl carrier protein (ACP) domain is quite remarkable, yet the mechanisms of binding and catalysis are poorly understood. Moreover, there are additional implications for understanding TE1 and TE2 mechanisms of catalysis as it relates to chemotherapeutic research targeting FASN. It is widely accepted that increased lipogenesis of LCFAs via FASN is a hallmark of neoplastic transformation. Therefore, FASN has been firmly established as a target for pharmaceutical intervention in several cancers, including lung, colon, prostate, ovarian and breast. Current drug discovery strategies have succeeded in killing cancer cells in vitro and in vivo via targeting FASN through inhibition of the endogenous thioesterase (TE1) domain. The success of TE1-targeted FASN inhibition warrants a more comprehensive understanding of the interplay between TE1 and TE2 and their relationship to FASN product distribution. Aberrant TE2 expression and activity on TE1-inactivated FASN could rescue fatty acid biosynthesis, thus negating current drug development strategies.
subject
acyl-ACP
Acyl Carrier Protein
Fatty Acid Synthase
Lipid
Thioesterase
contributor
Ritchie, Melissa Kay (author)
Lowther, William T (committee chair)
Kridel, Steve (committee member)
Hollis, Thomas (committee member)
Poole, Leslie (committee member)
Lyles, Douglas (committee member)
date
2014-01-15T09:35:28Z (accessioned)
2016-01-15T09:30:11Z (available)
2013 (issued)
degree
Biochemistry and Molecular Biology (discipline)
embargo
2016-01-15 (terms)
identifier
http://hdl.handle.net/10339/39121 (uri)
language
en (iso)
publisher
Wake Forest University
title
UNCOVERING THE MOLECULAR BASIS FOR FATTY ACID SYNTHASE PRODUCT SPECIFICITY: STRUCTURAL AND KINETIC EVALUATION OF THIOESTERASE I AND THIOESTERASE II
type
Dissertation

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