Share on Facebook Share on Twitter Email
Answers.com

Fatty acid synthase

 
Wikipedia: Fatty acid synthase
Home > Library > Miscellaneous > Wikipedia
FAS revised model with positions of polypeptides, three catalytic domains and their corresponding reactions, visualization by Kosi Gramatikoff.

Fatty acid synthase (FAS) is enzymatic system composed of 272 kDa multifunctional polypeptide, in which substrates are handed from one functional domain to the next[1][2][3][4][5].

Contents

Metabolic function

Fatty acids are aliphatic acids fundamental to energy production and storage, cellular structure and as intermediates in the biosynthesis of hormones and other biologically important molecules. They are synthesized by a series of decarboxylative Claisen condensation reactions from acetyl-CoA and malonyl-CoA (see fatty acid synthesis). Following each round of elongation the beta keto group is reduced to the fully saturated carbon chain by the sequential action of a ketoreductase (KR), dehydratase (DH), and enol reductase (ER). The growing fatty acid chain is carried between these active sites while attached covalently to the phophopantetheine prosthetic group of an acyl carrier protein (ACP), and is released by the action of a thioesterase (TE) (see positions of the polypeptides in the 3D models on the right) While this 3D model resembles the monomer structure published by Smith and Asturias groups in 2005 these positions are incorrect according to a crystal structure of the FAS dimer published by Ban's group in 2006 and refined to higher resolution and published in 2008).

Classes

There are two principal classes of fatty acid synthases.

  • Type I systems utilise a single large, multifunctional polypeptide and are common to both mammals and fungi (although the structural arrangement of fungal and mammalian synthases differ). A Type I fatty acid synthase system is also found in the CMN group of bacteria (corynebacteria, mycobacteria, and nocardia). In these bacteria, the FAS I system produces palmititic acid, and cooperates with the FAS II system to produce a greater diversity of lipid products.[6]
  • Type II is found in archaeabacterial and eubacterial, and is characterized by the use of discrete, monofunctional enzymes for fatty acid synthesis. Inhibitors of this pathway (FASII) are being investigated as possible antibiotics.[7]

The mechanism of FAS I and FAS II elongation and reduction is the same, as the domains of the FAS II enzymes are largely homologous to their domain counterparts in FAS I multienzyme polypeptides. However, the differences in the organization of the enzymes - integrated in FAS I, discrete in FAS II - gives rise to many important biochemical differences.[8]

The evolutionary history of fatty acid synthases are very much intertwined with that of polyketide synthases (PKS). Polyketide synthases use a similar mechanism and homologous domains to produce secondary metabolite lipids. Furthermore, polyketide synthases also exhibit a Type I and Type II organization. FAS I in animals is thought to have arisen through modification of PKS I in fungi, whereas FAS I in fungi and the CMN group of bacteria seem to have arisen separately through the fusion of FAS II genes.[9]

Structure

FAS 'head-to-tail' model with positions of polypeptides, three catalytic domains and their corresponding reactions, visualization by Kosi Gramatikoff.

Mammalian FAS consists of two identical multifunctional polypeptides, in which three catalytic domains in the N-terminal section (-ketoacyl synthase (KS), malonyl/acetyltransferase (MAT), and dehydrase (DH)), are separated by a core region of 600 residues from four C-terminal domains (enoyl reductase (ER), -ketoacyl reductase (KR), acyl carrier protein (ACP) and thioesterase (TE))[10][11].

The conventional model for organization of FAS (see the 'head-to-tail' model on the right) is largely based on the observations that the bifunctional reagent 1,3-dibromopropanone (DBP) is able to crosslink the active site cysteine thiol of the KS domain in one FAS monomer with the phosphopantetheine prosthetic group of the ACP domain in the other monomer[12][13]. Complementation analysis of FAS dimers carrying different mutations on each monomer has established that the KS and MAT domains can cooperate with the ACP of either monomer[14][15] and a reinvestigation of the DBP crosslinking experiments revealed that the KS active site Cys161 thiol could be crosslinked to the ACP 4'-phosphopantetheine thiol of either monomer[16]. In addition, it has been recently reported that a heterodimeric FAS containing only one competent monomer is capable of palmitate synthesis[17].

The above observations seemed incompatible with the classical 'head-to-tail' model for FAS organization, and an alternative model has been proposed, predicting that the KS and MAT domains of both monomers lie closer to the center of the FAS dimer, where they can access the ACP of either subunit [18](see figure on the top right).

Recently, the elucidation of the low resolution X-ray crystallography structure of both human (homodimer)[19] and yeast FAS (heterododecamer) [20] has provided key structural and mechanistic insights into this important enzyme.

Regulation

Metabolism and homeostasis of fatty acid synthase is transcriptionally regulated by Upstream Stimulatory Factor (USFs) and sterol regulatory element binding protein-1c (SREBP-1c) in response to feeding/insulin in living animals[21][22]. Although liver X receptor (LXRs) modulate the expression of sterol regulatory element binding protein-1c (SREBP-1c) in feeding, regulation of FAS by SREBP-1c is USFs dependent.[23].[24][25][26]

Clinical significance

It has been investigated as a possible oncogene.[27] FAS is up-regulated in breast cancers and as well as being an indicator of poor prognosis may also be worthwhile as a chemotherapeutic target.[28][29]

See also

References

  1. ^ Alberts, A.W., Strauss, A.W., Hennessy, S. & Vagelos, P.R. Regulation of synthesis of hepatic fatty acid synthetase: binding of fatty acid synthetase antibodies to polysomes. Proc. Natl. Acad. Sci. USA 72, 3956−3960
  2. ^ Stoops, J.K. et al. Presence of two polypeptide chains comprising fatty acid synthetase. Proc. Natl. Acad. Sci. USA 72, 1940−1944 (1975)
  3. ^ Smith, S., Agradi, E., Libertini, L. & Dileepan, K.N. Specific release of the thioesterase component of the fatty acid synthetase multienzyme complex by limited trypsinization. Proc. Natl. Acad. Sci. USA 73, 1184−1188 (1976)
  4. ^ Wakil, S.J. Fatty acid synthase, a proficient multifunctional enzyme. Biochemistry 28, 4523−4530 (1989)
  5. ^ Smith, S., Witkowski, A. & Joshi, A.K. Structural and functional organization of the animal fatty acid synthase. Prog. Lipid Res. 42, 289−317
  6. ^ Jenke-Kodama, H., A. Sandmann, R. Muller, and E. Dittmann. 2005. Evolutionary implications of bacterial polyketide synthases. Molecular Biology and Evolution 22:2027-2039.
  7. ^ http://www.nature.com/scibx/journal/v2/n11/full/scibx.2009.430.html
  8. ^ Price, N. C., and L. Stevens. 1999, Fundamentals of enzymology: The cell and molecular biology of catalytic proteins. New York, Oxford University Press.
  9. ^ Jenke-Kodama, H., A. Sandmann, R. Muller, and E. Dittmann. 2005. Evolutionary implications of bacterial polyketide synthases. Molecular Biology and Evolution 22:2027-2039
  10. ^ Chirala, S.S., Jayakumar, A., Gu, Z.W. & Wakil, S.J. Human fatty acid synthase: role of interdomain in the formation of catalytically active synthase dimer. Proc. Natl. Acad. Sci. USA 98, 3104−3108 (2001)
  11. ^ Smith, S. The animal fatty acid synthase: one gene, one polypeptide, seven enzymes. FASEB J. 8, 1248−1259 (1994)
  12. ^ Stoops, J.K. & Wakil, S.J. Animal fatty acid synthetase. A novel arrangement of the -ketoacyl synthetase sites comprising domains of the two subunits. J. Biol. Chem. 256, 5128−5133 (1981)
  13. ^ Stoops, J.K. & Wakil, S.J. Animal fatty acid synthetase. Identification of the residues comprising the novel arrangement of the -ketoacyl synthetase site and their role in its cold inactivation. J. Biol. Chem. 257, 3230−3235
  14. ^ Joshi, A.K., Rangan, V.S. & Smith, S. Differential affinity labeling of the two subunits of the homodimeric animal fatty acid synthase allows isolation of heterodimers consisting of subunits that have been independently modified. J. Biol. Chem. 273, 4937−4943 (1998)
  15. ^ Rangan, V.S., Joshi, A.K. & Smith, S. Mapping the functional topology of the animal fatty acid synthase by mutant complementation in vitro. Biochemistry 40, 10792−10799 (2001)
  16. ^ Witkowski, A. et al. Dibromopropanone cross-linking of the phosphopantetheine and active-site cysteine thiols of the animal fatty acid synthase can occur both inter- and intrasubunit. Reevaluation of the side-by-side, antiparallel subunit model. J. Biol. Chem. 274, 11557−11563 (1999)
  17. ^ Joshi, A.K., Rangan, V.S., Witkowski, A. & Smith, S. Engineering of an active animal fatty acid synthase dimer with only one competent subunit. Chem. Biol. 10, 169−173 (2003)
  18. ^ Asturias FJ et al., Structure and molecular organization of mammalian fatty acid synthase. Nature Structural & Molecular Biology 12, 225 - 232 (2005) PMID 15711565
  19. ^ Ban N et al. (2008) Science 321:1315
  20. ^ Xiong Y, Steitz TA et al. (2007) Cell 129:319
  21. ^ Paulauskis JD, Sul HS.Hormonal regulation of mouse fatty acid synthase gene transcription in liver.J Biol Chem. 1989 Jan 5;264(1):574-7.
  22. ^ Latasa MJ, Griffin MJ, Moon YS, Kang C, Sul HS. Occupancy and function of the -150 sterol regulatory element and -65 E-box in nutritional regulation of the fatty acid synthase gene in living animals.Mol Cell Biol. 2003 Aug;23(16):5896-907.
  23. ^ Latasa MJ, Griffin MJ, Moon YS, Kang C, Sul HS. Occupancy and function of the -150 sterol regulatory element and -65 E-box in nutritional regulation of the fatty acid synthase gene in living animals.Mol Cell Biol. 2003 Aug;23(16):5896-907.
  24. ^ Griffin MJ, Wong RH, Pandya N, Sul HS. Direct interaction between USF and SREBP-1c mediates synergistic activation of the fatty-acid synthase promoter. J Biol Chem. 2007 Feb 23;282(8):5453-67. Epub 2006 Dec 31.
  25. ^ Yoshikawa T, Shimano H, Amemiya-Kudo M, Yahagi N, Hasty AH, Matsuzaka T, Okazaki H, Tamura Y, Iizuka Y, Ohashi K, Osuga J, Harada K, Gotoda T, Kimura S, Ishibashi S, Yamada N. Identification of liver X receptor-retinoid X receptor as an activator of the sterol regulatory element-binding protein 1c gene promoter. Mol Cell Biol. 2001 May;21(9):2991-3000. PMID 11287605
  26. ^ Repa JJ, Liang G, Ou J, Bashmakov Y, Lobaccaro JM, Shimomura I, Shan B, Brown MS, Goldstein JL, Mangelsdorf DJ. Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta. Genes Dev. 2000 Nov 15;14(22):2819-30. PMID 11090130
  27. ^ Baron A, Migita T, Tang D, Loda M (2004). "Fatty acid synthase: a metabolic oncogene in prostate cancer?". J Cell Biochem 91 (1): 47–53. doi:10.1002/jcb.10708. PMID 14689581. 
  28. ^ Hunt DA. Lane HM. Zygmont ME. Dervan PA. Hennigar RA. MRNA stability and overexpression of fatty acid synthase in human breast cancer cell lines. [Journal Article] Anticancer Research. 27(1A):27-34, 2007 Jan-Feb. UI: 17352212
  29. ^ Gansler TS. Hardman W 3rd. Hunt DA. Schaffel S. Hennigar RA. Increased expression of fatty acid synthase (OA-519) in ovarian neoplasms predicts shorter survival. [Journal Article] Human Pathology. 28(6):686-92, 1997 Jun. UI: 9191002

External links

Stub icon This article about metabolism is a stub. You can help Wikipedia by expanding it.
v • d • e
Enzymes: multienzyme complexes
Photosynthesis
Dehydrogenase
Other
v • d • e
Metabolism: lipid metabolism · triglyceride and fatty acid enzymes
Synthesis
Malonyl-CoA synthesis
Fatty acid synthesis/
Fatty acid synthase
Fatty acid desaturases
Triacyl glycerol
Degradation
General
Other

This entry is from Wikipedia, the leading user-contributed encyclopedia. It may not have been reviewed by professional editors (see full disclaimer)

Search unanswered questions...

Enter a question here...
Search: All sources Community Q&A Reference topics

 
 

 

Copyrights:

Wikipedia. This article is licensed under the Creative Commons Attribution/Share-Alike License. It uses material from the Wikipedia article "Fatty acid synthase".  Read more