Structure and function of animal fatty acid synthase.
Fatty acid synthase (FAS; EC 2.3.1.85) of animal tissues is a complex multifunctional enzyme consisting of two identical monomers. The FAS monomer (approximately 270 kDa) contains six catalytic activities and from the N-terminus the order is beta-ketoacyl synthase (KS), acetyl/malonyl transacylase (AT/MT), beta-hydroxyacyl dehydratase (DH), enoyl reductase (ER), beta-ketoacyl reductase (KR), acyl carrier protein (ACP), and thioesterase (TE). Although the FAS monomer contains all the activities needed for palmitate synthesis, only the dimer form of the synthase is functional. Both the biochemical analyses and the small-angle neutron-scattering analysis determined that in the dimer form of the enzyme the monomers are arranged in a head-to-tail manner generating two centers for palmitate synthesis. Further, these analyses also suggested that the component activities of the monomer are organized in three domains. Domain I contains KS, AT/MT, and DH, domain II contains ER, KR, and ACP, and domain III contains TE. Approximately one fourth of the monomer protein located between domains I and II contains no catalytic activities and is called the interdomain/core region. This region plays an important role in the dimer formation. Electron cryomicrographic analyses of FAS revealed a quaternary structure at approximately 19 A resolution, containing two monomers (180 x 130 x 75 A) that are separated by about 19 A, and arranged in an antiparallel fashion, which is consistent with biochemical and neutron-scattering data. The monomers are connected at the middle by a hinge generating two clefts that may be the two active centers of fatty acid synthesis. Normal mode analysis predicted that the intersubunit hinge region and the intrasubunit hinge located between domains II and III are highly flexible. Analysis of FAS particle images by using a simultaneous multiple model single particle refinement method confirmed that FAS structure exists in various conformational states. Attempts to get higher resolution of the structure are under way.
Chirala
Subrahmanyam S
SS
Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Wakil
Salih J
SJ
D000818:Animals; D002384:Catalysis; D064429:Fatty Acid Synthases / Q000737:chemistry* / Q000378:metabolism*; D005227:Fatty Acids / Q000096:biosynthesis / Q000737:chemistry; D006801:Humans; D020836:Protein Structure, Quaternary; D013329:Structure-Activity Relationship
D005227:Fatty Acids; D064429:Fatty Acid Synthases
J Struct Biol. 1999 Dec 1;128(1):82-97
10600563
Proc Natl Acad Sci U S A. 1975 May;72(5):1940-4
1098047
J Biol Chem. 1987 Jul 25;262(21):10246-51
3611059
Proc Natl Acad Sci U S A. 1995 Sep 12;92(19):8695-9
7567999
Arch Biochem Biophys. 1994 Oct;314(1):45-9
7944406
Structure. 2004 Feb;12(2):185-91
14962379
J Biol Chem. 1993 Oct 25;268(30):22508-13
8226759
J Biol Chem. 1996 Dec 6;271(49):31749-55
8940200
Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10715-20
15235125
Biochemistry. 2002 Sep 3;41(35):10877-87
12196027
Biochemistry. 2001 Sep 11;40(36):10792-9
11535054
Proc Natl Acad Sci U S A. 1964 Jul;52:106-14
14192647
Biochemistry. 1998 Feb 24;37(8):2515-23
9485400
Proc Natl Acad Sci U S A. 1997 May 27;94(11):5588-93
9159116
Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):7895-9
12060737
J Biol Chem. 1988 Nov 5;263(31):16225-9
3182791
J Biol Chem. 1981 May 25;256(10):5128-33
6112225
Proc Natl Acad Sci U S A. 1989 Jun;86(12):4387-91
2734291
Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8620-5
12084922
Proc Natl Acad Sci U S A. 1997 Nov 11;94(23):12326-30
9356448
J Biol Chem. 1989 Oct 25;264(30):18195-201
2681189
Biochemistry. 1999 Sep 7;38(36):11643-50
10512619
Annu Rev Biochem. 1983;52:537-79
6137188
Proc Natl Acad Sci U S A. 2004 Nov 2;101(44):15567-72
15507492
Proc Natl Acad Sci U S A. 1989 May;86(9):3114-8
2717611
Cancer Res. 2000 Jan 15;60(2):213-8
10667561
J Biol Chem. 2002 Jul 19;277(29):25847-50
12011103
J Biol Chem. 1991 Nov 5;266(31):20946-52
1939144
J Biol Chem. 1999 Apr 23;274(17):11557-63
10206962
J Biol Chem. 1997 May 2;272(18):11975-8
9115261
Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6379-83
8022791
Proc Natl Acad Sci U S A. 2002 Jan 8;99(1):138-43
11756679
Biochemistry. 1989 May 30;28(11):4523-30
2669958
Biochemistry. 1997 Feb 25;36(8):2316-22
9047334
Chem Biol. 2003 Feb;10(2):169-73
12618189
FASEB J. 1994 Dec;8(15):1248-59
8001737
Biochem Biophys Res Commun. 1989 Feb 15;158(3):690-5
2920037
Prog Lipid Res. 2003 Jul;42(4):289-317
12689621
Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1852-6
8446599
DNA Seq. 1992;2(6):359-86
1339331
Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3104-8
11248039
J Biol Chem. 1984 Mar 25;259(6):3605-11
6706971
Proc Natl Acad Sci U S A. 2003 May 27;100(11):6358-63
12738878
Science. 2000 Jun 30;288(5475):2379-81
10875926
J Biol Chem. 1989 Mar 5;264(7):3750-7
2917973