Molecular Biochemistry II

Fatty Acid Synthesis

Reading:

Textbook Reading: Voet & Voet, Biochemistry, 3rd Edition, p. 930-938, 940-942

Some recent articles (optional reading): 
S. Kersten (2001) "Mechanisms of nutritional and hormonal regulation of lipogenesis," EMBO reports 21: 282-286.
J. G. Wallis, J. L. Watts & J. Browse (2002) "Polyunsaturated fatty acid synthesis: What will they think of next?" Trends in Biochem. Sci. 27: 467-473.
E. Duplus & C. Forest (2002) "Is there a single mechanism for fatty acid regulation of gene transcription?" Biochem. Pharm. 64: 893-901.
M. R. Munday (2002) "Regulation of mammalian acetyl-CoA carboxylase," Biochem. Soc. Trans. 30: 1059-1064.
D. G. Hardie & D. A. Pan (2002) "Regulation of fatty acid synthesis and oxidation by the AMP-activated protein kinase," Biochem. Soc. Trans. 30: 1064-1070.
S. Smith, A. Witkowski, & A. K. Joshi (2003) "Structural and functional organization of the animal fatty acid synthase," Progr. in Lipid Res. 42: 289-317.
M. C. Barber, N. T. Price & M. T. Travers (2005) "Structure and regulation of acetyl-CoA carboxylase genes of metazoa," Biochim. Biophys. Acta 1733: 1-28.
S. W. White, J. Zheng, Y.-M. Zhang & C. O. Rock (2005) "The structural biology of type II fatty acid biosynthesis," Annu. Rev. Biochem. 74: 791-831.
F. J. Asturias, J. Z. Chadick, I. K. Cheung, H. Stark, A. Witkowski, A. K. Joshi & S. Smith (2005) "Structure and molecular organization of mammalian fatty acid synthase," Nature Struct. Molec. Biol. 12: 225-232.
T. Maier, S. Jenni & N. Ban (2006) "Architecture of mammalian fatty acid synthase at 4.5 resolution," Science 311: 1258-1262.
A. Jakobsson, R. Westerberg & A. Jacobsson (2006) "Fatty acid elongases in mammals: Their regulation and roles in metabolism," Progr. In Lipid Res. 45: 237-249.
M. J. Wolfgang & M. D. Lane (2006) "The role of hypothalamic malonyl-CoA in energy homeostatis," J. Biol. Chem. 281: 37265-37269.
Y.-M. Zhang, S. W. White & C. O. Rock (2006) "Inhibiting bacterial fatty acid synthesis," J. Biol. Chem. 281: 17541-17544.
T. Maier, M. Leibundgut & N. Ban (2008) "The crystal structure of a mammalian fatty acid synthase," Science 321: 1315-1322.

Potential Test Questions:

1. What enzyme catalyzes the committed step of fatty acid synthesis? Write out the 2-step reaction catalyzed by this enzyme, providing names of reactants, intermediates, and products only. Summarize the ways in which this enzyme is regulated, including by allosteric effectors and by phosphorylation. Explain the value to the cell or organism of these regulatory effects. What kinases are responsible for the regulation by phosphorylation? What physical change accompanies activation of the enzyme?

2.a. Diagram the structure of active site thioester intermediates of the mammalian Fatty Acid Synthase, following the initial transacylase reactions.
Then draw the products of the reaction catalyzed by Condensing Enzyme (reaction 3). 
b. Diagram or describe in words the subsequent reduction and dehydration steps.
c. What might be the significance of the long flexible chain of the phosphopantetheine group of the acyl carrier protein domain (ACP) of Fatty Acid Synthase?

Balance sheet for Fatty Acid Synthase:


1a. How many acetyl-CoA used for initial priming of the enzyme? ________
b. How many acetyl-CoA used for synthesis of each malonate? __________
c. How many malonate used (how many reaction cycles) per synthesis of one 16-C palminate? ________
d. Total acetyl-CoA used for priming and for syntheisis of malonate, a + b(c): ________
2a. How many ~P bonds of ATP used for synthesis of each malonate? __________
b. Total ~P bonds of ATP used for synthesis of one 16-C palmitate, 2a(1c): ________
3a. How many NADPH used per reaction cycle? __________
b. Total NADPH used per synthesis of one 16-C palmitate, 3a(1c): _________
4. Write a balanced equation for synthesis of palmitate from acetyl-CoA, listing net inputs and outputs:

 

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Lecture Notes on
Fatty Acid Synthesis

Interactive Quiz on  
    Fatty Acid Synthesis  

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