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MetaCyc Pathway: palmitate biosynthesis I (animals and fungi)
Inferred from experiment

Pathway diagram: palmitate biosynthesis I (animals and fungi)

If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.

Synonyms: palmitic acid biosynthesis, de novo lipogenesis

Superclasses: BiosynthesisFatty Acid and Lipid BiosynthesisFatty Acid BiosynthesisPalmitate Biosynthesis

Some taxa known to possess this pathway include : Homo sapiens, Saccharomyces cerevisiae

Expected Taxonomic Range: Opisthokonta

General Background

Fatty acids are key building blocks for the phospholipid components of cell membranes and are determinants of intracellular communication, in the form of lipid second messengers [Prieschl00], and fatty acyl moieties of proteins that modify their location and function [Resh99].

There are two basic types of fatty acid (FAS) biosynthesis mechanisms, named type I and type II. The type I system is found in mammals and lower eukaryotes. The mammalian system consists of a single gene product that contains all of the reaction centers required to produce a fatty acid (see fatty acid synthase from Homo sapiens), while the system of lower eukaryotes (such as yeast) consists of two genes, whose polypeptide products combine to form a multifunctional complex (see fatty acid synthase from Saccharomyces cerevisiae).

Type II systems are found in bacteria, plants [White05], parasites of the Apicomplexa phylum [Ferguson07] and mitochondria [Zhang03, Miinalainen03]. The reactions in these systems are catalyzed by a series of individual soluble proteins that are each encoded by a discrete gene, and the pathway intermediates are transferred between the enzymes as thioesters of a holo-[acyl-carrier protein].

A major difference between the two pathways is that the type I systems accept malonyl-CoA as the source of two-carbon units, while the type II systems accept a malonyl-[acp]. The pathway catalyzed by the type II systems is available at palmitate biosynthesis II (bacteria and plants).

About This Pathway

Mammalian fatty acid synthase enzymes are homodimers whose gigantic subunits (about 240 kDa) are encoded by a single gene [Guy78]. Each subunit is multifunctional protein, whose main function is to catalyze the synthesis of palmitate from acetyl-CoA and malonyl-CoA in the presence of NADPH. The two subunits are arranged in a head to tail fashion, and each subunit contains, in addition to an acyl-carrier-protein (acp) domain, additional domains that catalyze 7 different catalytic activities.

The complex catalyzes seven successive cycles, and the final product is palmitoyl-CoA. Although small amounts of stearate are sometimes formed through the actions of FAS, the process generally stops at 16 carbons, and palmitate is released from the ACP moiety [Sampath05].

A general description of the reactions catalyzed by the mammalian fatty acid synthase complex is provided by EC reaction

acetyl-CoA + n malonyl-CoA + 2n NADPH + 2n H+ = a long-chain fatty acid + n CO2 + (n+1) coenzyme A + 2n NADP+

The sum of reactions catalyzed by the yeast enzyme is described by EC reaction

acetyl-CoA + n malonyl-CoA + 2n NADPH + 4n H+ = a long-chain acyl-CoA + n CO2 + n coenzyme A + 2n NADP+

Palmitate is one of the most common saturated fatty acids found in animals and plants. It was discovered by Edmond Fremy in 1840 in saponified palm oil, of which it is a major component, hence its name.

Insulin, 3,5,3'-triiodo-L-thyronine, glucocorticoids, and D-glucose induce de novo lipogenesis, while C20 PUFAs (polyunsaturated fatty acids), glucagon, and (R)-adrenaline suppress it [Hillgartner95].

Variants: palmitate biosynthesis II (bacteria and plants)

Created 01-Aug-2008 by Caspi R, SRI International


Ferguson07: Ferguson DJ, Campbell SA, Henriquez FL, Phan L, Mui E, Richards TA, Muench SP, Allary M, Lu JZ, Prigge ST, Tomley F, Shirley MW, Rice DW, McLeod R, Roberts CW (2007). "Enzymes of type II fatty acid synthesis and apicoplast differentiation and division in Eimeria tenella." Int J Parasitol 37(1);33-51. PMID: 17112527

Guy78: Guy P, Law S, Hardie G (1978). "Mammalian fatty acid synthetase: evidence for subunit identity and specific removal of the thioesterase component using elastase digestion." FEBS Lett 94(1);33-7. PMID: 700134

Hillgartner95: Hillgartner FB, Salati LM, Goodridge AG (1995). "Physiological and molecular mechanisms involved in nutritional regulation of fatty acid synthesis." Physiol Rev 75(1);47-76. PMID: 7831398

Miinalainen03: Miinalainen IJ, Chen ZJ, Torkko JM, Pirila PL, Sormunen RT, Bergmann U, Qin YM, Hiltunen JK (2003). "Characterization of 2-enoyl thioester reductase from mammals. An ortholog of YBR026p/MRF1'p of the yeast mitochondrial fatty acid synthesis type II." J Biol Chem 278(22);20154-61. PMID: 12654921

Prieschl00: Prieschl EE, Baumruker T (2000). "Sphingolipids: second messengers, mediators and raft constituents in signaling." Immunol Today 21(11);555-60. PMID: 11094259

Resh99: Resh MD (1999). "Fatty acylation of proteins: new insights into membrane targeting of myristoylated and palmitoylated proteins." Biochim Biophys Acta 1451(1);1-16. PMID: 10446384

Sampath05: Sampath H, Ntambi JM (2005). "The fate and intermediary metabolism of stearic acid." Lipids 40(12);1187-91. PMID: 16477801

Wakil89: Wakil SJ (1989). "Fatty acid synthase, a proficient multifunctional enzyme." Biochemistry 28(11);4523-30. PMID: 2669958

White05: White SW, Zheng J, Zhang YM, Rock (2005). "The structural biology of type II fatty acid biosynthesis." Annu Rev Biochem 74;791-831. PMID: 15952903

Zhang03: Zhang L, Joshi AK, Smith S (2003). "Cloning, expression, characterization, and interaction of two components of a human mitochondrial fatty acid synthase. Malonyltransferase and acyl carrier protein." J Biol Chem 278(41);40067-74. PMID: 12882974

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

Airenne03: Airenne TT, Torkko JM, Van den plas S, Sormunen RT, Kastaniotis AJ, Wierenga RK, Hiltunen JK (2003). "Structure-function analysis of enoyl thioester reductase involved in mitochondrial maintenance." J Mol Biol 327(1);47-59. PMID: 12614607

Bi13: Bi H, Wang H, Cronan JE (2013). "FabQ, a dual-function dehydratase/isomerase, circumvents the last step of the classical fatty acid synthesis cycle." Chem Biol 20(9);1157-67. PMID: 23972938

Brink02: Brink J, Ludtke SJ, Yang CY, Gu ZW, Wakil SJ, Chiu W (2002). "Quaternary structure of human fatty acid synthase by electron cryomicroscopy." Proc Natl Acad Sci U S A 99(1);138-43. PMID: 11756679

Byers07: Byers DM, Gong H (2007). "Acyl carrier protein: structure-function relationships in a conserved multifunctional protein family." Biochem Cell Biol 85(6);649-62. PMID: 18059524

Chi09: Chi A, Rhee S (2009). "The functional annotation of Arabidopsis protein sequences was performed by BLAST queries against a reference set of experimentally verified enzymes. For each Arabidopsis sequence, the enzymatic activity of the top BLAST hit (or hits if they had equivalent E-values) was assigned to the protein if its E-value fell below a specific E-value threshold established for the corresponding enzymatic activity. Note: The annotation thresholds were established by doing a self BLAST of the reference enzyme dataset. For each enzymatic activity represented by multiple proteins, the mean E-value of all the correct hits generated by the self BLAST was selected as the cut-off. All of these means were averaged and used as the cut-off for assigning annotations for any enzymatic activities that were represented by a single protein in the reference dataset."

Field02: Field FJ, Born E, Murthy S, Mathur SN (2002). "Polyunsaturated fatty acids decrease the expression of sterol regulatory element-binding protein-1 in CaCo-2 cells: effect on fatty acid synthesis and triacylglycerol transport." Biochem J 368(Pt 3);855-64. PMID: 12213084

Heath95: Heath RJ, Rock CO (1995). "Enoyl-acyl carrier protein reductase (fabI) plays a determinant role in completing cycles of fatty acid elongation in Escherichia coli." J Biol Chem 270(44);26538-42. PMID: 7592873

Heath96b: Heath RJ, Rock CO (1996). "Roles of the FabA and FabZ beta-hydroxyacyl-acyl carrier protein dehydratases in Escherichia coli fatty acid biosynthesis." J Biol Chem 1996;271(44);27795-801. PMID: 8910376

Hsu96: Hsu MH, Chirala SS, Wakil SJ (1996). "Human fatty-acid synthase gene. Evidence for the presence of two promoters and their functional interaction." J Biol Chem 271(23);13584-92. PMID: 8662758

Huh03: Huh WK, Falvo JV, Gerke LC, Carroll AS, Howson RW, Weissman JS, O'Shea EK (2003). "Global analysis of protein localization in budding yeast." Nature 425(6959);686-91. PMID: 14562095

Hunt06: Hunt MC, Rautanen A, Westin MA, Svensson LT, Alexson SE (2006). "Analysis of the mouse and human acyl-CoA thioesterase (ACOT) gene clusters shows that convergent, functional evolution results in a reduced number of human peroxisomal ACOTs." FASEB J 20(11);1855-64. PMID: 16940157

Imaishi07: Imaishi H, Petkova-Andonova M (2007). "Molecular cloning of CYP76B9, a cytochrome P450 from Petunia hybrida, catalyzing the omega-hydroxylation of capric acid and lauric acid." Biosci Biotechnol Biochem 71(1);104-13. PMID: 17213671

Isbell06: Isbell, T.A, Lowery, B.A, DeKeyser, S.S, Winchell, A.L, Cermak, S.C (2006). "Physical properties of triglyceride estolides from lesquerella and castor oils." Industrial Crops and Products, 23, 256-263.

Jayakumar94: Jayakumar A, Chirala SS, Chinault AC, Baldini A, Abu-Elheiga L, Wakil SJ (1994). "Isolation and chromosomal mapping of genomic clones encoding the human fatty acid synthase gene." Genomics 23(2);420-4. PMID: 7835891

Jayakumar95: Jayakumar A, Tai MH, Huang WY, al-Feel W, Hsu M, Abu-Elheiga L, Chirala SS, Wakil SJ (1995). "Human fatty acid synthase: properties and molecular cloning." Proc Natl Acad Sci U S A 92(19);8695-9. PMID: 7567999

Jones00: Jones JM, Gould SJ (2000). "Identification of PTE2, a human peroxisomal long-chain acyl-CoA thioesterase." Biochem Biophys Res Commun 275(1);233-40. PMID: 10944470

Joseph02: Joseph SB, Laffitte BA, Patel PH, Watson MA, Matsukuma KE, Walczak R, Collins JL, Osborne TF, Tontonoz P (2002). "Direct and indirect mechanisms for regulation of fatty acid synthase gene expression by liver X receptors." J Biol Chem 277(13);11019-25. PMID: 11790787

Kastaniotis04: Kastaniotis AJ, Autio KJ, Sormunen RT, Hiltunen JK (2004). "Htd2p/Yhr067p is a yeast 3-hydroxyacyl-ACP dehydratase essential for mitochondrial function and morphology." Mol Microbiol 53(5);1407-21. PMID: 15387819

Kristan09: Kristan K, Bratkovic T, Sova M, Gobec S, Prezelj A, Urleb U (2009). "Novel inhibitors of beta-ketoacyl-ACP reductase from Escherichia coli." Chem Biol Interact 178(1-3);310-6. PMID: 18977209

Kuhajda94: Kuhajda FP, Jenner K, Wood FD, Hennigar RA, Jacobs LB, Dick JD, Pasternack GR (1994). "Fatty acid synthesis: a potential selective target for antineoplastic therapy." Proc Natl Acad Sci U S A 91(14);6379-83. PMID: 8022791

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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
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