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J. Biol. Chem., Vol. 283, Issue 1, 518-528, January 4, 2008

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A Mammalian Type I Fatty Acid Synthase Acyl Carrier Protein Domain Does Not Sequester Acyl Chains^*

Eliza Plosko¹, Christopher J. Arthur, Simon E. Evans, Christopher Williams, John Crosby, Thomas J. Simpson, and Matthew P. Crump²

From the School of Chemistry, University of Bristol, Bristol BS8 1TS, United Kingdom

The synthases that produce fatty acids in mammals (FASs) are arranged as large multidomain polypeptides. The growing fatty acid chain is bound covalently during chain elongation and reduction to the acyl carrier protein (ACP) domain that is then able to access each catalytic site. In this work we report the high-resolution nuclear magnetic resonance (NMR) solution structure of the isolated rat fatty acid synthase apoACP domain. The final ensemble of NMR structures and backbone ¹⁵N relaxation studies show that apoACP adopts a single, well defined fold. On conversion to the holo form, several small chemical shift changes are observed on the ACP for residues surrounding the phosphopantetheine attachment site (as monitored by backbone ¹H-¹⁵N correlation experiments). However, there are negligible chemical shift changes when the holo form is modified to either the hexanoyl or palmitoyl forms. For further NMR analysis, a ¹³C,¹⁵N-labeled hexanoyl-ACP sample was prepared and full chemical shift assignments completed. Analysis of two-dimensional F₂-filtered and three-dimensional ¹³C-edited nuclear Overhauser effect spectroscopy experiments revealed no detectable NOEs to the acyl chain. These experiments demonstrate that unlike other FAS ACPs studied, this Type I ACP does not sequester a covalently linked acyl moiety, although transient interactions cannot be ruled out. This is an important mechanistic difference between the ACPs from Type I and Type II FASs and may be significant for the modulation and regulation of these important mega-synthases.

Received for publication, April 25, 2007 , and in revised form, October 23, 2007.

The atomic coordinates and structure factors (code 2png) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

The NMR chemical shifts have been deposited with BioMagResBank accession code 15449.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by a European Union FP6 Marie Curie Early Stage Research Training award.

² To whom correspondence should be addressed: Cantock's Close, Bristol, BS8 1TS, United Kingdom. Tel.: 44(0)117-3317163; Fax: 44(0)117-9298611; E-mail: matt.crump{at}bristol.ac.uk.

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