Pathway maps

Saturated fatty acid biosynthesis
Saturated fatty acid biosynthesis

Object List (links open in MetaCore):

Crotonyl-ACP, 1.3.1.10, D-beta-Hydroxy- butyryl-ACP, Butyryl-ACP, 1.3.1.10, 3-Oxododecanoyl-ACP, 1.1.1.100, 3-Oxo-hexadeca- noyl-ACP, (E)-Dec-2-enoyl-ACP, Decanoyl-ACP, (R)-3-Hydroxy- hexa-decanoyl-ACP, 4.2.1.61, 4.2.1.58/4.2.1.61, (E)-Hexadec-2- enoyl-ACP, 2.3.1.41, 1.1.1.100, Acetoacyl-ACP, 2.3.1.39, 2.3.1.41, (R)-3-Hydroxy- hexanoyl-ACP, (E)-Hex-2-enoyl-ACP, 2.3.1.41, 1.3.1.10, 2.3.1.41, 1.3.1.10, 3-Oxo-tetradecanoyl-ACP, (R)-3-Hydroxy- tetradecanoyl-ACP, 2.3.1.41, (E)-Tetradec-2-enoyl-ACP, 4.2.1.58/4.2.1.61, Tetradeca- noyl-ACP, 1.3.1.10, 3-Oxohexanoyl-ACP, 1.1.1.100, 2.3.1.38, 3.1.2.14, 4.2.1.58, (R)-3-Hydroxy -octanoyl-ACP, 3-Oxooctonoyl-ACP, Hexanoyl-Acp, 2.3.1.41, 6.4.1.2, ACACB, Dodecanoyl-ACP, ACACA, (E)-Dodec-2- enoyl-ACP, (R)-3-Hydroxy- dodecanoyl-ACP, 1.1.1.100, 1.1.1.100, Malonyl-ACP, 1.3.1.10, Malonyl CoA, 2.3.1.41, 4.2.1.58, 3-Oxocaproyl-ACP, (R)-3-Hydroxy- decanoyl-ACP, 1.1.1.100, 1.3.1.10, Octanoyl-Acp, Palmitic acid, FASN, 4.2.1.58/4.2.1.61, 1.1.1.100, Hexadeca- noyl-ACP, 4.2.1.61, (E)-Oct-2-enoyl-ACP, 4.2.1.58, Acetyl-CoA, Acetyl-ACP

Description

Saturated fatty acid biosynthesis.

Saturated fatty acids play an important role in the organism. They are essential for growth and development of the body and for normal functioning of many systems, in prevention of atherosclerosis, regulation of the blood pressure, muscles activity and enzymes. The lack of any of saturated fatty acid causes multiple diseases.

The first reaction in the biosynthesis of saturated fatty acids is carboxylation of Acetyl-CoA to form Malonyl-CoA. This reaction takes place in the presence of two enzymes, Acetyl-Coenzyme A carboxylase alpha 1 ( ACACA ) [1], [2], [3], [4], [5], [6], [7] and Acetyl-Coenzyme A carboxylase beta ( ACACB ), [1], [2], [8], [9], [4], [10], [6].

Malonyl-CoA forms complex with acyl-carrier protein Malonyl-ACP as the result of reaction catalyzed by fatty acid synthase ( FASN ) [11], [12], [13], [14], [15]. FASN is a multifunctional protein that has 7 catalytic activities. FASN complex consists of the enzymes cound to the acyl carrier protein. Acetyl-ACP is formed by condensation of Acyl-carrier protein and Acetyl-CoA catalyzed by FASN [11], [12], [13], [14], [16], [15], [17]. Acetoacetyl -ACP is then synthesized from Acetyl-ACP and Malonyl-ACP in the reaction also catalyzed by FASN complex [14], [12], [13], [14], [16], [15], [18], [17]. The three recurring reactions then take place. The first reaction is the reduction of keto group of Acetoacetyl-ACP to alcohol group of D-beta-Hydroxybutyryl-ACP. The second reaction is the dehydratation of D-beta-Hydroxybutyryl-ACP resulting in formation of Crotonyl-ACP. The third reaction is a reduction of double bond in Crotonyl-ACP resulting in formation of Butyryl-ACP [11], [12], [13], [14], [15], [17].

The above 3 reactions continue in a cycle. With each new turn of the cycle FASN catalyzes attachment of a compound formed in the previous cycle to the Malonyl-ACP complex. This results in elongation of the saturated fatty acid chain by two carbon atoms. For example, Butyryl-ACP from the first cycle will react with Malonyl-ACP to form Hexanoyl-ACP.

Hexadecanoyl-ACP is formed as a result of six consecutive cycles [11], [12], [13], [14], [15], [17], at which point the process of biosynthesis of saturated fatty acids ends by hydrolysis of Hexadecanoyl - ACP and release of Palmitic acid as a final product catalyzed by FASN [11], [12], [19], [13], [14], [20], [15], [17].

References:

  1. Wakil SJ, Stoops JK, Joshi VC
    Fatty acid synthesis and its regulation. Annual review of biochemistry 1983;52:537-79
  2. Mohamed AH, Huang WY, Huang W, Venkatachalam KV, Wakil SJ
    Isolation and characterization of a novel acetyl-CoA carboxylase kinase from rat liver. The Journal of biological chemistry 1994 Mar 4;269(9):6859-65
  3. Abu-Elheiga L, Jayakumar A, Baldini A, Chirala SS, Wakil SJ
    Human acetyl-CoA carboxylase: characterization, molecular cloning, and evidence for two isoforms. Proceedings of the National Academy of Sciences of the United States of America 1995 Apr 25;92(9):4011-5
  4. Kim KH
    Regulation of mammalian acetyl-coenzyme A carboxylase. Annual review of nutrition 1997;17:77-99
  5. Sinilnikova OM, Ginolhac SM, Magnard C, Leone M, Anczukow O, Hughes D, Moreau K, Thompson D, Coutanson C, Hall J, Romestaing P, Gerard JP, Bonadona V, Lasset C, Goldgar DE, Joulin V, Venezia ND, Lenoir GM
    Acetyl-CoA carboxylase alpha gene and breast cancer susceptibility. Carcinogenesis 2004 Dec;25(12):2417-24
  6. Tong L, Harwood HJ Jr
    Acetyl-coenzyme A carboxylases: versatile targets for drug discovery. Journal of cellular biochemistry 2006 Dec 15;99(6):1476-88
  7. Guarente L
    Sirtuins as potential targets for metabolic syndrome. Nature 2006 Dec 14;444(7121):868-74
  8. Allred JB, Reilly KE
    Short-term regulation of acetyl CoA carboxylase in tissues of higher animals. Progress in lipid research 1996 Dec;35(4):371-85
  9. Abu-Elheiga L, Almarza-Ortega DB, Baldini A, Wakil SJ
    Human acetyl-CoA carboxylase 2. Molecular cloning, characterization, chromosomal mapping, and evidence for two isoforms. The Journal of biological chemistry 1997 Apr 18;272(16):10669-77
  10. Abu-Elheiga L, Brinkley WR, Zhong L, Chirala SS, Woldegiorgis G, Wakil SJ
    The subcellular localization of acetyl-CoA carboxylase 2. Proceedings of the National Academy of Sciences of the United States of America 2000 Feb 15;97(4):1444-9
  11. Jayakumar A, Tai MH, Huang WY, al-Feel W, Hsu M, Abu-Elheiga L, Chirala SS, Wakil SJ
    Human fatty acid synthase: properties and molecular cloning. Proceedings of the National Academy of Sciences of the United States of America 1995 Sep 12;92(19):8695-9
  12. Jayakumar A, Chirala SS, Wakil SJ
    Human fatty acid synthase: assembling recombinant halves of the fatty acid synthase subunit protein reconstitutes enzyme activity. Proceedings of the National Academy of Sciences of the United States of America 1997 Nov 11;94(23):12326-30
  13. Brink J, Ludtke SJ, Yang CY, Gu ZW, Wakil SJ, Chiu W
    Quaternary structure of human fatty acid synthase by electron cryomicroscopy. Proceedings of the National Academy of Sciences of the United States of America 2002 Jan 8;99(1):138-43
  14. Smith S, Witkowski A, Joshi AK
    Structural and functional organization of the animal fatty acid synthase. Progress in lipid research 2003 Jul;42(4):289-317
  15. Carlisle-Moore L, Gordon CR, Machutta CA, Miller WT, Tonge PJ
    Substrate recognition by the human fatty-acid synthase. The Journal of biological chemistry 2005 Dec 30;280(52):42612-8
  16. Chirala SS, Wakil SJ
    Structure and function of animal fatty acid synthase. Lipids 2004 Nov;39(11):1045-53
  17. Maier T, Jenni S, Ban N
    Architecture of mammalian fatty acid synthase at 4.5 A resolution. Science 2006 Mar 3;311(5765):1258-62
  18. von Wettstein-Knowles P, Olsen JG, McGuire KA, Henriksen A
    Fatty acid synthesis. Role of active site histidines and lysine in Cys-His-His-type beta-ketoacyl-acyl carrier protein synthases. The FEBS journal 2006 Feb;273(4):695-710
  19. Bellizzi JJ 3rd, Widom J, Kemp C, Lu JY, Das AK, Hofmann SL, Clardy J
    The crystal structure of palmitoyl protein thioesterase 1 and the molecular basis of infantile neuronal ceroid lipofuscinosis. Proceedings of the National Academy of Sciences of the United States of America 2000 Apr 25;97(9):4573-8
  20. Chakravarty B, Gu Z, Chirala SS, Wakil SJ, Quiocho FA
    Human fatty acid synthase: structure and substrate selectivity of the thioesterase domain. Proceedings of the National Academy of Sciences of the United States of America 2004 Nov 2;101(44):15567-72